中药复方对卵泡调控及卵巢VEGF、IGF-I影响的研究
摘要
目的 了解中药复方癸息汤及资冲颗粒对实验动物卵泡发育及卵巢VEGF、IGF-Ⅰ的影响。
方法 将早幼大鼠(90±10g)随机分为予癸息汤1号(尔勿忧)组、癸息汤2号组、癸息汤3号组，采用灌肠和灌胃两种方法给药，与空白对照组、皮下埋植LNG组(LNG组)对照。观察早幼大鼠卵巢指数、各级卵泡及黄体、卵巢血管、血清E_2、P水平、子宫指数、子宫组织形态学等指标的变化。
将成熟大鼠(210±10g)随机分为癸息汤1号(尔勿忧)组、癸息汤3号组，分别采用灌胃和灌肠给药，并与空白对照组、LNG组对照。对皮下埋植LNG的成熟大鼠分别灌胃和灌肠给予资冲颗粒，与未皮埋LNG空白对照组、LNG组及LNG加PMSG组对照。观察成熟大鼠卵巢VEGF、IGF-1，动情周期，其余观察指标同上。
结果 早幼大鼠癸息汤各组卵巢血管数减少，LNG组、癸息汤2号灌肠和灌胃组、癸息汤1号(尔勿忧)灌胃组横径＞20 um的卵巢血管数减少，均较空白对照组有显著差异，P＜0.05。癸息汤1号(尔勿忧)、癸息汤2号、癸息汤3号灌肠组、癸息汤1号、癸息汤2号灌胃组均可使早幼大鼠黄体数减少，与LNG组作用相似，P＞0.05，与空白对照组比较P＜0.05。癸息汤1号(尔勿忧)灌胃组卵巢指数，癸息汤2号灌肠组子宫指数减少，与空白对照组比较，P＜0.05，其中癸息汤2号灌肠组子宫指数与LNG组比较，P＜0.05。LNG组和癸息汤1号(尔勿忧)灌胃组血清孕激素值降低，与空白对照组有显著差异(P＜0.05)。癸息汤各组子宫腺体直径、腺腔内径和腺上皮高度均有减少，与空白对照组有显著差异(P＜0.05)；灌胃各组腺体个数与空白对照组比较有显著差异(P＜0.05)。癸息汤1号(尔勿忧)灌胃组卵巢指数、血清孕激素，癸息汤各组子宫腺体直径、腺腔内径和腺上皮高度，癸息汤灌胃各组腺体个数与LNG组比均P＞0.05。
成熟大鼠癸息汤1号(尔勿忧)灌胃组卵巢VEGF的积分光密度、平均光密度、目标面积与空白对照组比P＜0.05；IGF1-1积分光密度与空白对照组比
P<0.05;卵巢血管尤其较大血管减少，较空白对照组P<0 .05。癸息汤1号(尔
勿忧)灌胃组黄体数目减少，与空白对照组相比P<0 .05。癸息汤各组卵巢指数
减少，部分出现性周期消失，子宫内膜腺体直径、腺腔内径和腺上皮高度均有
减少，与空白对照组相比均P<0.05。
LNG组、LNG+资冲颗粒灌胃、灌肠组窦状卵泡数目与空白对照组比较有显
著性差异(P<0 .05)，但LNG+资冲颗粒灌胃、灌肠组与LNG组之间卵泡无显著差
异(P>0.05)。LNG+资冲颗粒灌肠组窦前卵泡较LNG组有增加趋势。LNG十资冲颗
粒灌肠组卵巢VEGF的积分光密度增加，与LNG组比较，P<0 .05;LNG+资冲颗粒
灌肠组IGF一I积分光密度、平均光密度较LNG组明显增加，P<0.既。资冲颗粒
灌肠组卵巢血管数目特别是较大血管增加，较LNG组比较，P<0 .05。LNG+资冲
颗粒灌胃及灌肠组被覆上皮及腺体数目均较LNG组增加，P(0 .05。LNG十PMSG组
血清孕激素、卵巢指数、卵巢成熟卵泡、黄体、血管尤其是小血管，腺体直径、
腺上皮高度、腺体个数以及被覆上皮高度均较LNG组有显著差异，P<0 .05。
结论
1.癸息汤1号(尔勿忧)具有显著抑制早幼大鼠、成熟大鼠黄体数量，减
少卵巢血管，尤其是大血管数量，减少卵巢VEGF积分光密度、平均光密度、目
标面积、IGF一I积分光密度的作用，与皮下埋植孕激素LNG的作用相似。
2.资冲颗粒具有明显增加皮下埋植LNG大鼠卵巢血管，尤其是大血管数量，
增加卵巢VEGF积分光密度、IGF一I积分光密度、平均光密度及增加子宫腺体数
量和被覆上皮高度的作用。
3.影响细胞因子VEGF、IGF一I在卵巢的表达是癸息汤、资冲颗粒对大鼠卵
巢调控的机制之一。
ObjectiverTo study the effect of the GuiXiTang and ZichongKeLi medicatied by different ways upon the follicle development and the expression of VEGF and IGF-1 in the ovary of the rats.
Method:early immature rats were divided into groups with treatments of GuiXiTang(No.l,No.2,No3) separately by the medication of clyster and oral perfus. Subcutaneous inbeded LNG was taken as control group.Ovarian index,ovarian follical ,corpus iuteurruovarian vessels,E2 and P in the blood ,uterus index and histomorphology of uterus were detected separately.
Immature rats wre divided into groups with the application of GuiXiTang(No.l and No.3) and ZiChongKeLi separately by the medication of clyster and oral perfus. Subcutaneous inbeded LNG was taken as control group,while PMSG was also taken as the control group to ZiChongKeLi.AU the groups in the experiment of ZiChongKeLi were Subcutaneous inbeded with LNG except blank contol group.Ovarian VEGF and IGF- I were checked by immunohistochemical method.The others index were same with early immature rats besides cornification index.
Results:The effect of GuiXiTang was similar with Subcutaneous inbeded LNG to early immature rats and Immature rats .They both can decrease corpus luteum, the ovarian vessels especially the big vessels, ovarian index, ,P in the blood, uterus index and glands fn uterus of early immature rats and Immature rats (P<0.05). GuiXiTang also can weaken the IOD,Mean IOD and Area of VEGF and IOD of IGF- I in their ovaries (P<0.05). The group LNG+ZiChongkeLi can incease the antal follicles,but it is not obvious defferent from LNG(P>0.05).Both groups of ZiChongKeLi can increase the glands and lining epithelium of uterus.To be mentioned,the group ZiChongKeli which was medicated by clyster can increase ovarian vessels, IOD of VEGF, IOD and Mean IOD of IGF-1 (P<0.05).It has a trend of ZiChongKeli to increase the preantral follicles.The group which was used LNG+PMSG manifested the increase of mature follicles, corpus luteum.ovarian index,P in blood,ovarian vessels especially small vesells,glands of uterus of mature rats(P<0.0
5).
Conclusion:
1.GuixiTang l(ErWuYou) has the similar action to decrease corpus luteum, the 10D,Mean IOD and Area of VEGF and IOD of IGF-1 with LNG.
2.ZiChongkeLi has the effect to increase ovarian vessels especially the big vessels, IOD of VEGF, IOD and Mean IOD of IGF-1 ,glands of uterus and lining epithelium of uterus of the rats with inbeded LNG.
3.One of the mechanism by which GuiXiTang and Zichongkeli influence the ovary is to regulate the ovarian microcirculation and the expression of VEGF and IGF- I in the ovary.
方法 将早幼大鼠(90±10g)随机分为予癸息汤1号(尔勿忧)组、癸息汤2号组、癸息汤3号组，采用灌肠和灌胃两种方法给药，与空白对照组、皮下埋植LNG组(LNG组)对照。观察早幼大鼠卵巢指数、各级卵泡及黄体、卵巢血管、血清E_2、P水平、子宫指数、子宫组织形态学等指标的变化。
将成熟大鼠(210±10g)随机分为癸息汤1号(尔勿忧)组、癸息汤3号组，分别采用灌胃和灌肠给药，并与空白对照组、LNG组对照。对皮下埋植LNG的成熟大鼠分别灌胃和灌肠给予资冲颗粒，与未皮埋LNG空白对照组、LNG组及LNG加PMSG组对照。观察成熟大鼠卵巢VEGF、IGF-1，动情周期，其余观察指标同上。
结果 早幼大鼠癸息汤各组卵巢血管数减少，LNG组、癸息汤2号灌肠和灌胃组、癸息汤1号(尔勿忧)灌胃组横径＞20 um的卵巢血管数减少，均较空白对照组有显著差异，P＜0.05。癸息汤1号(尔勿忧)、癸息汤2号、癸息汤3号灌肠组、癸息汤1号、癸息汤2号灌胃组均可使早幼大鼠黄体数减少，与LNG组作用相似，P＞0.05，与空白对照组比较P＜0.05。癸息汤1号(尔勿忧)灌胃组卵巢指数，癸息汤2号灌肠组子宫指数减少，与空白对照组比较，P＜0.05，其中癸息汤2号灌肠组子宫指数与LNG组比较，P＜0.05。LNG组和癸息汤1号(尔勿忧)灌胃组血清孕激素值降低，与空白对照组有显著差异(P＜0.05)。癸息汤各组子宫腺体直径、腺腔内径和腺上皮高度均有减少，与空白对照组有显著差异(P＜0.05)；灌胃各组腺体个数与空白对照组比较有显著差异(P＜0.05)。癸息汤1号(尔勿忧)灌胃组卵巢指数、血清孕激素，癸息汤各组子宫腺体直径、腺腔内径和腺上皮高度，癸息汤灌胃各组腺体个数与LNG组比均P＞0.05。
成熟大鼠癸息汤1号(尔勿忧)灌胃组卵巢VEGF的积分光密度、平均光密度、目标面积与空白对照组比P＜0.05；IGF1-1积分光密度与空白对照组比
P<0.05;卵巢血管尤其较大血管减少，较空白对照组P<0 .05。癸息汤1号(尔
勿忧)灌胃组黄体数目减少，与空白对照组相比P<0 .05。癸息汤各组卵巢指数
减少，部分出现性周期消失，子宫内膜腺体直径、腺腔内径和腺上皮高度均有
减少，与空白对照组相比均P<0.05。
LNG组、LNG+资冲颗粒灌胃、灌肠组窦状卵泡数目与空白对照组比较有显
著性差异(P<0 .05)，但LNG+资冲颗粒灌胃、灌肠组与LNG组之间卵泡无显著差
异(P>0.05)。LNG+资冲颗粒灌肠组窦前卵泡较LNG组有增加趋势。LNG十资冲颗
粒灌肠组卵巢VEGF的积分光密度增加，与LNG组比较，P<0 .05;LNG+资冲颗粒
灌肠组IGF一I积分光密度、平均光密度较LNG组明显增加，P<0.既。资冲颗粒
灌肠组卵巢血管数目特别是较大血管增加，较LNG组比较，P<0 .05。LNG+资冲
颗粒灌胃及灌肠组被覆上皮及腺体数目均较LNG组增加，P(0 .05。LNG十PMSG组
血清孕激素、卵巢指数、卵巢成熟卵泡、黄体、血管尤其是小血管，腺体直径、
腺上皮高度、腺体个数以及被覆上皮高度均较LNG组有显著差异，P<0 .05。
结论
1.癸息汤1号(尔勿忧)具有显著抑制早幼大鼠、成熟大鼠黄体数量，减
少卵巢血管，尤其是大血管数量，减少卵巢VEGF积分光密度、平均光密度、目
标面积、IGF一I积分光密度的作用，与皮下埋植孕激素LNG的作用相似。
2.资冲颗粒具有明显增加皮下埋植LNG大鼠卵巢血管，尤其是大血管数量，
增加卵巢VEGF积分光密度、IGF一I积分光密度、平均光密度及增加子宫腺体数
量和被覆上皮高度的作用。
3.影响细胞因子VEGF、IGF一I在卵巢的表达是癸息汤、资冲颗粒对大鼠卵
巢调控的机制之一。
ObjectiverTo study the effect of the GuiXiTang and ZichongKeLi medicatied by different ways upon the follicle development and the expression of VEGF and IGF-1 in the ovary of the rats.
Method:early immature rats were divided into groups with treatments of GuiXiTang(No.l,No.2,No3) separately by the medication of clyster and oral perfus. Subcutaneous inbeded LNG was taken as control group.Ovarian index,ovarian follical ,corpus iuteurruovarian vessels,E2 and P in the blood ,uterus index and histomorphology of uterus were detected separately.
Immature rats wre divided into groups with the application of GuiXiTang(No.l and No.3) and ZiChongKeLi separately by the medication of clyster and oral perfus. Subcutaneous inbeded LNG was taken as control group,while PMSG was also taken as the control group to ZiChongKeLi.AU the groups in the experiment of ZiChongKeLi were Subcutaneous inbeded with LNG except blank contol group.Ovarian VEGF and IGF- I were checked by immunohistochemical method.The others index were same with early immature rats besides cornification index.
Results:The effect of GuiXiTang was similar with Subcutaneous inbeded LNG to early immature rats and Immature rats .They both can decrease corpus luteum, the ovarian vessels especially the big vessels, ovarian index, ,P in the blood, uterus index and glands fn uterus of early immature rats and Immature rats (P<0.05). GuiXiTang also can weaken the IOD,Mean IOD and Area of VEGF and IOD of IGF- I in their ovaries (P<0.05). The group LNG+ZiChongkeLi can incease the antal follicles,but it is not obvious defferent from LNG(P>0.05).Both groups of ZiChongKeLi can increase the glands and lining epithelium of uterus.To be mentioned,the group ZiChongKeli which was medicated by clyster can increase ovarian vessels, IOD of VEGF, IOD and Mean IOD of IGF-1 (P<0.05).It has a trend of ZiChongKeli to increase the preantral follicles.The group which was used LNG+PMSG manifested the increase of mature follicles, corpus luteum.ovarian index,P in blood,ovarian vessels especially small vesells,glands of uterus of mature rats(P<0.0
5).
Conclusion:
1.GuixiTang l(ErWuYou) has the similar action to decrease corpus luteum, the 10D,Mean IOD and Area of VEGF and IOD of IGF-1 with LNG.
2.ZiChongkeLi has the effect to increase ovarian vessels especially the big vessels, IOD of VEGF, IOD and Mean IOD of IGF-1 ,glands of uterus and lining epithelium of uterus of the rats with inbeded LNG.
3.One of the mechanism by which GuiXiTang and Zichongkeli influence the ovary is to regulate the ovarian microcirculation and the expression of VEGF and IGF- I in the ovary.
引文
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35 罗文祥，祝诚．胰岛素样生长因子-Ⅰ受体和LH受体mRNA在黄体中的表达及调节．中国科学·C辑．2000．04．15；30(2)：131-136
36 魏志新，张丽珠，李美芝．促超排卵周期胰岛素样生长因子-1对人卵泡发育的调控．中华妇产科杂志．1997．08．18；32(8)：486-488
37 李桂玲，归绥琪．补肾中药对雄激素致不孕大鼠胰岛素样生长因子1及胰岛素样生长因子1受体的影响．中国中西医结合杂志．2000，20(9)：677—678
38 张新艳，戴淑真，曹积功．子宫内膜异位症患者腹腔液中血管内皮生长因子及白细胞介素8的测定．中华妇产科杂志．2001，(8)：497—498
39 周灿权，于丛一，庄广伦．血管内皮生长因子在卵巢过度刺激综合征发病理中作用的初步研究．中华妇产科杂志．2001，36(11)：654—656
41 梁晓燕，庄广伦，方群．胰岛素与类胰岛素生长因子1对多囊卵巢综合征患者雄激素产生的作用．中华医学杂志．1997，77(4)：266-269
42 Kanety H, Golsvweg I, Kopolovix J, et al. Increase IGFBp-2 gene expression and protein production lead to high IGF-Bp-2 content in malignant ovarian cyst fluid. Br J Cancer, 1996; 73(9): 1069
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34 陈丹青，石一复，陈怀增．超排卵时卵泡发育数与颗粒细胞胰岛素样生长因子Ⅰ受体的
表达．中华妇产科杂志 2001．02．18；36(2)：98-100
35 罗文祥，祝诚．胰岛素样生长因子-Ⅰ受体和LH受体mRNA在黄体中的表达及调节．中国科学·C辑．2000．04．15；30(2)：131-136
36 魏志新，张丽珠，李美芝．促超排卵周期胰岛素样生长因子-1对人卵泡发育的调控．中华妇产科杂志．1997．08．18；32(8)：486-488
37 李桂玲，归绥琪．补肾中药对雄激素致不孕大鼠胰岛素样生长因子1及胰岛素样生长因子1受体的影响．中国中西医结合杂志．2000，20(9)：677—678
38 张新艳，戴淑真，曹积功．子宫内膜异位症患者腹腔液中血管内皮生长因子及白细胞介素8的测定．中华妇产科杂志．2001，(8)：497—498
39 周灿权，于丛一，庄广伦．血管内皮生长因子在卵巢过度刺激综合征发病理中作用的初步研究．中华妇产科杂志．2001，36(11)：654—656
41 梁晓燕，庄广伦，方群．胰岛素与类胰岛素生长因子1对多囊卵巢综合征患者雄激素产生的作用．中华医学杂志．1997，77(4)：266-269
42 Kanety H, Golsvweg I, Kopolovix J, et al. Increase IGFBp-2 gene expression and protein production lead to high IGF-Bp-2 content in malignant ovarian cyst fluid. Br J Cancer, 1996; 73(9): 1069