补肾活血法对卵巢储备功能低下干预的效应机理研究与临床证治探讨
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摘要
目的意义：卵巢储备功能是指卵巢内存留卵泡的数量和质量,反映女性的生育潜能和生殖内分泌功能。卵巢储备功能低下(DOR)导致女性生育能力减弱及性激素缺乏,表现为月经稀发、闭经、不孕等,进一步可发展为卵巢早衰(POF)。近年来,随着社会的发展,文化观念、生活环境、工作压力等的改变,使DOR发病率有逐年上升趋势,严重影响着女性的生殖健康和生活质量。而现有国内高等院校中、西医统编教材中并无卵巢储备功能低下病症的专门论述,所涉及内容偶见于闭经、不孕症、围绝经期综合征中,相关的文献报道也甚少,更缺乏系统、全面的理论阐述和规范、具有指导意义的临床证治路径。因此,本研究以中医基础理论、相关实验研究结果、临床疗效观察等为依据,用现代科学的理念和方法阐释补肾活血法对卵巢储备功能低下干预的效应机理,探讨补肾活血法有效干预卵巢储备功能低下的临床证治规律,为中医药有效治疗卵巢储备功能低下提供科学依据。
研究方法：本研究在前期(2003-2006年)补肾活血中药有效改善DOR患者卵巢储备功能的初步临床观察基础之上,再次进行了实验及临床研究。实验研究：分三部分进行。第一部分“拆方比较补肾活血法干预雷公藤多甙致DOR大鼠卵巢功能和形态结构的研究”,分别观察了补肾、活血法对雷公藤多甙致DOR大鼠一般情况(体重、饮食、活动、动情周期变化、卵巢指数)、生殖激素(E2、FSH、P、T)、卵巢组织形态(光镜)、细胞凋亡(Bax、Bcl-2、Caspase-3蛋白)、血管生成(VEGF及VEGF受体)的影响。第二部分“补肾活血法促进雷公藤多甙致DOR大鼠离体颗粒细胞分泌功能及生长的研究”,观察补肾活血法促进雷公藤多甙致DOR大鼠离体卵巢颗粒细胞分泌E2功能及生长情况。第三部分“补肾活血方急性毒性试验”,观察补肾活血方一次性给予小鼠后所产生的急性毒性反应和死亡情况,计算LD50值和95%可信区间,或测定其最大耐受量,观察药物的急性毒性反应；临床研究：进一步证实补肾活血法干预卵巢储备功能低下的有效性,观察DOR及POF患者运用补肾活血法治疗后症状和体征积分,基础血E2, FSH、LH、INHB水平,平均卵巢直径(ADO),窦卵泡计数(AFC),卵巢基质血流阻力指数(RI)等的改变。
研究结果：实验研究：补肾、活血方药均能升高DOR大鼠血清E2水平,降低FSH、T水平,而补肾方药能升高P水平,活血方药降低P水平；补肾、活血方药均能上调DOR大鼠颗粒细胞凋亡抑制因子Bcl-2,下调凋亡促进因子Bax、Caspase-3蛋白的表达；补肾方药能降低DOR大鼠卵巢颗粒细胞VEGF及VEGF受体的表达,而活血方药能增加卵巢颗粒细胞VEGF及VEGF受体的表达。补肾与活血方药的协同作用能升高DOR大鼠血清E2、P水平,降低FSH、T水平,上调颗粒细胞凋亡抑制因子Bcl-2,下调凋亡促进因子Bax、Caspase-3蛋白的表达,增加卵巢颗粒细胞VEGF及VEGF受体。补肾活血法中高剂量组大鼠含药血清均能升高雷公藤多甙干预后离体GC培养液中E2水平,促进GC生长。补肾活血方的LD50无法做出,其最大耐受量为240g生药／Kg／日,相当于临床剂量的128倍。临床研究：补肾活血法能有效提高DOR及POF患者INHB、AFC水平,降低FSH.LH.RI、症状积分水平,且总有效率DOR组89.30%,POF组64.44%,两组相比有显著性差异。
研究结论：补肾活血法对卵巢储备功能低下干预的效应机理为调节生殖激素、抑制卵巢颗粒细胞凋亡、促进卵巢血管生成；肾虚血瘀卵巢储备功能低下的主要临床证候为月经后期而至、经来涩少、闭绝不行或年未老经水断,伴有婚久不孕、腰膝酸软、头晕目眩、带下稀少、性欲淡漠、口渴不欲饮,舌淡或紫暗边有瘀斑、脉沉细或沉涩等；补肾活血法对卵巢储备功能低下干预的效应明显优于单纯补肾法或活血法,及时运用补肾活血法干预DOR,疗效显著,对预防、延缓POF的发生具有非常积极的意义；基础血FSH、INHB及B超AFC、RI可作为临床诊断、评估卵巢储备功能低下的可靠实验室指标。
Purpose :Ovarian reserve function refers to the remaining number and quality of ovarian follicles, reflecting women's reproductive potential and reproductive endocrine function. Decline in ovarian reserve (DOR) led to reduced fertility and sex hormones in women, performance as oligomenorrhea, amenorrhea, infertility, etc., and further can develop premature ovarian failure (POF). In recent years, with the development of society, cultural, living environment, work pressure and so changes lead to the increasing of DOR incidence rate every year, seriously affecting women's reproductive health and quality of life. There is no detail disscussion in Western medicine and TCM textbooks used by all universities and colleges througabout the country, It occasionally appears in amenorrhea, infertility climacteric syndrome and other diseases, the relevant literature is also very little, it also lacks systematic and comprehensive theoretical explanation and criterion the clinical treatment path with guiding significance. Therefore, this study based on the basic theory of TCM, relevant experimental results, the observation of clinical effect, and discussed the working mechanism and therapy rule that the method of replenishing the kidney and activating blood have intervention in DOR, and provide a scientific basis for it.
Research methods:Prophase(2003-2006), On the base of preliminary clinical observation that Chinese medicine herbal of replenishing the kidney and activating blood improves DOR patients'ovarian reserve function, and now do experimental and clinical research again. experimental research: for three parts. First, compare effect in ovarian function and morphology of DOR rats that induced by TWP by useing the decoction that is broken partly. Observe the rats'general conditions (weight, diet, activity, estrous cycle, ovarian index), reproductive hormones (E2, FSH, P, T), ovarian morphology (light microscopy), apoptosis (Bax, Bcl-2, Caspase-3 protein), vascular generation (VEGF and VEGF receptor) separately by replenishing the kidney and activating blood. Second, Study promotion of granulosa cells secreting E2 and growth of TWP induced DOR rats by replenishing the kidney and activating blood, and observe it. Third, acute toxicity test, Observe the acute toxicity and death when the decocotion is given one-time.,and calculate LD50 values and 95% confidence interval, or maximum tolerated dose, or observe the acute toxicity. Clinical research: it further comfirmed available. And after patients with DOR or POF are therapied by replenishing the kidney and activating blood, then observe the symptoms and signs degree, the level of basic blood E2, FSH, LH, INHB,the changes of the average ovarian diameter (ADO), antral follicle count (AFC), ovarian stromal blood flow resistance index (RI) after replenishing the kidney and activating blood; experimental study.
Results:The herbal of replenishing the kidney and activating blood can increase the level of E2, decreased the level of FSH and T, while the former can reduce the level of P, the latter can increase it; ALL can raise apoptosis inhibitor Bcl-2, while reduce apoptosis promoting factor Bax, Caspase-3 protein; and also can increase the expression of the ovarian granulosa cells VEGF and VEGF receptor.In high dose group,the serum contain decoction can increase the E2 levels in culture supernatants that in vitro GC after intervention by TWP,and promote GC growth; LD50 can not make out,the maximum tolerance dose is 240g crude drug/Kg/day, clinical dose is 112g crude drug/person/day, equivalent to 128 times of the clinical dose. Clinical research: the method can improve the DOR and POF patients'INHB, AFC level, lower FSH, LH, RI level, and in DOR group,the total effective rate is 89.30%, POF group total effective rate is 64.44%, there was significant difference between two groups.
Conclusion:The effect mechanism is to improve the ovarian reserve function, the mechanisms is to regulate reproductive hormones, inhibit the apoptosis of ovarian granulosa cell, promot ovarian angiogenesis; the main clinical syndromes of DOR which is deficiency of the kidney and blood stasis:delayed of menstruation, scanty menstruation, amenorrhea,or no pregnancy long after marriage, accompanied the aching and flaccid sensation in the loins and knees, dizziness, scanty leukorrhea, sexual frigidity, thirst without desire for drinking,light-colored or dark purplish tongue with petechia arround it, deep-thin pulse or deep-unsmooth pulse, etc. The method is better than the one only replenishing the kidney The basic blood FSH, INHB and ultrasound B-AFC, RI are used as reliable laboratory index in diagnosis of DOR.
研究方法：本研究在前期(2003-2006年)补肾活血中药有效改善DOR患者卵巢储备功能的初步临床观察基础之上,再次进行了实验及临床研究。实验研究：分三部分进行。第一部分“拆方比较补肾活血法干预雷公藤多甙致DOR大鼠卵巢功能和形态结构的研究”,分别观察了补肾、活血法对雷公藤多甙致DOR大鼠一般情况(体重、饮食、活动、动情周期变化、卵巢指数)、生殖激素(E2、FSH、P、T)、卵巢组织形态(光镜)、细胞凋亡(Bax、Bcl-2、Caspase-3蛋白)、血管生成(VEGF及VEGF受体)的影响。第二部分“补肾活血法促进雷公藤多甙致DOR大鼠离体颗粒细胞分泌功能及生长的研究”,观察补肾活血法促进雷公藤多甙致DOR大鼠离体卵巢颗粒细胞分泌E2功能及生长情况。第三部分“补肾活血方急性毒性试验”,观察补肾活血方一次性给予小鼠后所产生的急性毒性反应和死亡情况,计算LD50值和95%可信区间,或测定其最大耐受量,观察药物的急性毒性反应；临床研究：进一步证实补肾活血法干预卵巢储备功能低下的有效性,观察DOR及POF患者运用补肾活血法治疗后症状和体征积分,基础血E2, FSH、LH、INHB水平,平均卵巢直径(ADO),窦卵泡计数(AFC),卵巢基质血流阻力指数(RI)等的改变。
研究结果：实验研究：补肾、活血方药均能升高DOR大鼠血清E2水平,降低FSH、T水平,而补肾方药能升高P水平,活血方药降低P水平；补肾、活血方药均能上调DOR大鼠颗粒细胞凋亡抑制因子Bcl-2,下调凋亡促进因子Bax、Caspase-3蛋白的表达；补肾方药能降低DOR大鼠卵巢颗粒细胞VEGF及VEGF受体的表达,而活血方药能增加卵巢颗粒细胞VEGF及VEGF受体的表达。补肾与活血方药的协同作用能升高DOR大鼠血清E2、P水平,降低FSH、T水平,上调颗粒细胞凋亡抑制因子Bcl-2,下调凋亡促进因子Bax、Caspase-3蛋白的表达,增加卵巢颗粒细胞VEGF及VEGF受体。补肾活血法中高剂量组大鼠含药血清均能升高雷公藤多甙干预后离体GC培养液中E2水平,促进GC生长。补肾活血方的LD50无法做出,其最大耐受量为240g生药／Kg／日,相当于临床剂量的128倍。临床研究：补肾活血法能有效提高DOR及POF患者INHB、AFC水平,降低FSH.LH.RI、症状积分水平,且总有效率DOR组89.30%,POF组64.44%,两组相比有显著性差异。
研究结论：补肾活血法对卵巢储备功能低下干预的效应机理为调节生殖激素、抑制卵巢颗粒细胞凋亡、促进卵巢血管生成；肾虚血瘀卵巢储备功能低下的主要临床证候为月经后期而至、经来涩少、闭绝不行或年未老经水断,伴有婚久不孕、腰膝酸软、头晕目眩、带下稀少、性欲淡漠、口渴不欲饮,舌淡或紫暗边有瘀斑、脉沉细或沉涩等；补肾活血法对卵巢储备功能低下干预的效应明显优于单纯补肾法或活血法,及时运用补肾活血法干预DOR,疗效显著,对预防、延缓POF的发生具有非常积极的意义；基础血FSH、INHB及B超AFC、RI可作为临床诊断、评估卵巢储备功能低下的可靠实验室指标。
Purpose :Ovarian reserve function refers to the remaining number and quality of ovarian follicles, reflecting women's reproductive potential and reproductive endocrine function. Decline in ovarian reserve (DOR) led to reduced fertility and sex hormones in women, performance as oligomenorrhea, amenorrhea, infertility, etc., and further can develop premature ovarian failure (POF). In recent years, with the development of society, cultural, living environment, work pressure and so changes lead to the increasing of DOR incidence rate every year, seriously affecting women's reproductive health and quality of life. There is no detail disscussion in Western medicine and TCM textbooks used by all universities and colleges througabout the country, It occasionally appears in amenorrhea, infertility climacteric syndrome and other diseases, the relevant literature is also very little, it also lacks systematic and comprehensive theoretical explanation and criterion the clinical treatment path with guiding significance. Therefore, this study based on the basic theory of TCM, relevant experimental results, the observation of clinical effect, and discussed the working mechanism and therapy rule that the method of replenishing the kidney and activating blood have intervention in DOR, and provide a scientific basis for it.
Research methods:Prophase(2003-2006), On the base of preliminary clinical observation that Chinese medicine herbal of replenishing the kidney and activating blood improves DOR patients'ovarian reserve function, and now do experimental and clinical research again. experimental research: for three parts. First, compare effect in ovarian function and morphology of DOR rats that induced by TWP by useing the decoction that is broken partly. Observe the rats'general conditions (weight, diet, activity, estrous cycle, ovarian index), reproductive hormones (E2, FSH, P, T), ovarian morphology (light microscopy), apoptosis (Bax, Bcl-2, Caspase-3 protein), vascular generation (VEGF and VEGF receptor) separately by replenishing the kidney and activating blood. Second, Study promotion of granulosa cells secreting E2 and growth of TWP induced DOR rats by replenishing the kidney and activating blood, and observe it. Third, acute toxicity test, Observe the acute toxicity and death when the decocotion is given one-time.,and calculate LD50 values and 95% confidence interval, or maximum tolerated dose, or observe the acute toxicity. Clinical research: it further comfirmed available. And after patients with DOR or POF are therapied by replenishing the kidney and activating blood, then observe the symptoms and signs degree, the level of basic blood E2, FSH, LH, INHB,the changes of the average ovarian diameter (ADO), antral follicle count (AFC), ovarian stromal blood flow resistance index (RI) after replenishing the kidney and activating blood; experimental study.
Results:The herbal of replenishing the kidney and activating blood can increase the level of E2, decreased the level of FSH and T, while the former can reduce the level of P, the latter can increase it; ALL can raise apoptosis inhibitor Bcl-2, while reduce apoptosis promoting factor Bax, Caspase-3 protein; and also can increase the expression of the ovarian granulosa cells VEGF and VEGF receptor.In high dose group,the serum contain decoction can increase the E2 levels in culture supernatants that in vitro GC after intervention by TWP,and promote GC growth; LD50 can not make out,the maximum tolerance dose is 240g crude drug/Kg/day, clinical dose is 112g crude drug/person/day, equivalent to 128 times of the clinical dose. Clinical research: the method can improve the DOR and POF patients'INHB, AFC level, lower FSH, LH, RI level, and in DOR group,the total effective rate is 89.30%, POF group total effective rate is 64.44%, there was significant difference between two groups.
Conclusion:The effect mechanism is to improve the ovarian reserve function, the mechanisms is to regulate reproductive hormones, inhibit the apoptosis of ovarian granulosa cell, promot ovarian angiogenesis; the main clinical syndromes of DOR which is deficiency of the kidney and blood stasis:delayed of menstruation, scanty menstruation, amenorrhea,or no pregnancy long after marriage, accompanied the aching and flaccid sensation in the loins and knees, dizziness, scanty leukorrhea, sexual frigidity, thirst without desire for drinking,light-colored or dark purplish tongue with petechia arround it, deep-thin pulse or deep-unsmooth pulse, etc. The method is better than the one only replenishing the kidney The basic blood FSH, INHB and ultrasound B-AFC, RI are used as reliable laboratory index in diagnosis of DOR.
引文
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