雌孕激素对雷公藤多苷致雌鼠生殖系统损害的保护作用
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摘要
背景与目的雷公藤多苷(tripterygium wilfordii polyglycosidium,TWP)是从雷公藤的去皮根中提取并反复精制而成的药物,在临床应用较广,主要用于治疗类风湿关节炎、肾脏疾病、系统性红斑狼疮等,但其不良反应特别是对生殖系统的损害限制了其应用。雌孕激素替代治疗(hormone replacement therapy,HRT)是临床上对进入围绝经期或因手术、放化疗损伤卵巢功能患者替代治疗的常用方法。有研究发现Fas-FasL系统表达于包括人、大鼠在内大多数生物的卵巢颗粒细胞上,参与颗粒细胞的凋亡。本研究旨在探讨HRT对TWP致雌鼠生殖系统损害的保护作用,并从颗粒细胞上凋亡基因的表达情况探讨其可能机制。
方法选出有正常动情周期的雌性大鼠60只,随机分为3组:对照组、雷公藤多苷组(TWP组)、联合用药组(TWP伍用雌、孕激素序贯性替代治疗,TWP+HRT组),分别灌胃12w,TWP组予TWP 12mg'kg~(-1)'d~(-1),对照组予同等剂量的溶媒,TWP+HRT组除每天灌胃TWP 12mg'kg~(-1)'d~(-1)外,另予HRT(即戊酸雌二醇片0.12mgmg'kg~(-1)'d~(-1)灌胃3天后,加醋酸甲轻孕酮片0.96mg'kg~(-1)'d~(-1)联用1天,共同停药1天,后继续此循环至12周)。大鼠子宫卵巢的重量由电子天平测定,动情周期由巴氏染色观察大鼠阴道脱落细胞学变化,血清雌激素(estrogen,E_2)、卵泡刺激素(follicle-stimulatinghormone,FSH)、黄体生成素(luteinizing hormone,LH)水平由放射免疫法测定,苏木素伊红(hematoxylin and eosin,HE)染色对卵巢子宫的病理变化作形态学观察,卵巢颗粒细胞上凋亡基因Fas及FasLmRNA的表达由逆转录聚合酶链式反应(reversetranscriptase polymerase chain reaction,RT-PCR)测定。
结果(1)各组大鼠的一般指标的变化与对照组相比,TWP组大鼠大多动情周期延长或紊乱(P＜0.05,提示差异有统计学意义),血清E_2降低(P＜0.05),血清FSH及LH上升(P＜0.05),卵巢及子宫相对重量明显下降(P＜0.05);而TWP+HRT组无明显改变(P＞0.05,提示差异无统计学意义)。(2)光镜下形态学观察与对照组相比,TWP组光镜形态学观察可见卵巢萎缩,各级卵泡减少,黄体退化萎缩,子宫内膜变薄,腺体减少,胶原纤维的增多;而TWP+HRT组与对照组相似。(3)各组大鼠颗粒细胞上凋亡基因Fas及FasL的表达本实验研究发现Fas及FasL基因均表达于卵巢颗粒细胞上。与对照组相比,TWP组及TWP+HRT组大鼠颗粒细胞上凋亡基因FasL的表达无明显差异(P＞0.05,提示差异无统计学意义)。
结论在TWP治疗的同时伍用HRT可减少TWP对雌鼠生殖系统的损伤,保护卵巢功能。
Background and objective TWP (tripterygium wilfordii polyglycosidium) not only retains the action of immune suppression but also removes many toxicity compositions as the extract of tripterygium wilfordii Hook f. It is applied in clinic generally including renal glomerular disease、systemic lupus erythematosus、rheumatoid arthritis and so on but it's adverse effects confine clinicial application especially its disadvantage of genital system. Estrogen- Progestogen sequential replacement therapy is often applied in the patient whose ovary was injuried because of in critique age or operation or radiotherapy and chems in clinic. It is reported that Fas-FasL system found on granulosa cell of the majority of living being ovary including the human being and rat participates apoptosis of granulosa cell. The objective of this study is to observe the effect of Estrogen- Progestogen sequential therapy on the changes of female rat genital system induced by tripterygiumw ilfordiipo lyglycosidium and to approach the possible mechanism on the basis of the expression of Fas and FasL.
Methods Sixty female rats with normal oestrus cycle were randomly divided into three groups: control group, TWP group, TWP and estrogen combined with progestogen replacement therapy periodical group(TWP+HRT). these three-group rats were feeded in normal sodium, TWP and TWP+HRT differently. The dose of TWP was tevlve mg per mg per day and the dircetion of HRT was that Estradiol Valerate Tabletes after three-day dosis was used one day combining with Medroxyprogesterone Acetate Tablets then these were stop using one day . HRT was always repeated to use by time of tevlve weeks. These rats were put to death after tevlve weeks. The weight of the ovary and uterus were measured by electronic balance. Oestrus cycle was observed by Pap staining. The serum level of E_2 (estrogen)、FSH (follicle-stimulating hormone) and LH(luteinizing hormone) were detected by RIA. Pathological changes of the ovary and uterus were observed by light microscope according to hematoxylin and eosin stain. The expression of Fas and FasLmRNA were detected by RT-PCR on granulosa cell.
Results 1. Clinical and general parameters compared with control group, oestrus cycle was disorder or extension, estrogen level and the weight of the ovary and uterus lowered (PO.05) ,the level of FSH and LH increased (P<0.05) in TWP group. No obvious change was found in TWP+HRT group(P>0.05).2. pathologic morphology Worse-growing follicle, degenerating corpus luteum and thinner endometrium with diminishing uterine gland were found in TWP group compared with control group. But the ovary and uterus of TWP+HRT group rat were similar to the rat of control group.3. the expression of Fas and FasLmRNA on granulosa cell This study indicated Fas and FasLmRNA can also express on granulosa cell of the ovary. But No difference of the expression of FasLmRNA was found in these three groups(P>0.05). FasmRNA cann't be detected because of its quick apoptosis.
Conclusion TWP combined with HRT can decrease the toxic and side effects of TWP on the genital system of female rat and protect the ovary.
方法选出有正常动情周期的雌性大鼠60只,随机分为3组:对照组、雷公藤多苷组(TWP组)、联合用药组(TWP伍用雌、孕激素序贯性替代治疗,TWP+HRT组),分别灌胃12w,TWP组予TWP 12mg'kg~(-1)'d~(-1),对照组予同等剂量的溶媒,TWP+HRT组除每天灌胃TWP 12mg'kg~(-1)'d~(-1)外,另予HRT(即戊酸雌二醇片0.12mgmg'kg~(-1)'d~(-1)灌胃3天后,加醋酸甲轻孕酮片0.96mg'kg~(-1)'d~(-1)联用1天,共同停药1天,后继续此循环至12周)。大鼠子宫卵巢的重量由电子天平测定,动情周期由巴氏染色观察大鼠阴道脱落细胞学变化,血清雌激素(estrogen,E_2)、卵泡刺激素(follicle-stimulatinghormone,FSH)、黄体生成素(luteinizing hormone,LH)水平由放射免疫法测定,苏木素伊红(hematoxylin and eosin,HE)染色对卵巢子宫的病理变化作形态学观察,卵巢颗粒细胞上凋亡基因Fas及FasLmRNA的表达由逆转录聚合酶链式反应(reversetranscriptase polymerase chain reaction,RT-PCR)测定。
结果(1)各组大鼠的一般指标的变化与对照组相比,TWP组大鼠大多动情周期延长或紊乱(P＜0.05,提示差异有统计学意义),血清E_2降低(P＜0.05),血清FSH及LH上升(P＜0.05),卵巢及子宫相对重量明显下降(P＜0.05);而TWP+HRT组无明显改变(P＞0.05,提示差异无统计学意义)。(2)光镜下形态学观察与对照组相比,TWP组光镜形态学观察可见卵巢萎缩,各级卵泡减少,黄体退化萎缩,子宫内膜变薄,腺体减少,胶原纤维的增多;而TWP+HRT组与对照组相似。(3)各组大鼠颗粒细胞上凋亡基因Fas及FasL的表达本实验研究发现Fas及FasL基因均表达于卵巢颗粒细胞上。与对照组相比,TWP组及TWP+HRT组大鼠颗粒细胞上凋亡基因FasL的表达无明显差异(P＞0.05,提示差异无统计学意义)。
结论在TWP治疗的同时伍用HRT可减少TWP对雌鼠生殖系统的损伤,保护卵巢功能。
Background and objective TWP (tripterygium wilfordii polyglycosidium) not only retains the action of immune suppression but also removes many toxicity compositions as the extract of tripterygium wilfordii Hook f. It is applied in clinic generally including renal glomerular disease、systemic lupus erythematosus、rheumatoid arthritis and so on but it's adverse effects confine clinicial application especially its disadvantage of genital system. Estrogen- Progestogen sequential replacement therapy is often applied in the patient whose ovary was injuried because of in critique age or operation or radiotherapy and chems in clinic. It is reported that Fas-FasL system found on granulosa cell of the majority of living being ovary including the human being and rat participates apoptosis of granulosa cell. The objective of this study is to observe the effect of Estrogen- Progestogen sequential therapy on the changes of female rat genital system induced by tripterygiumw ilfordiipo lyglycosidium and to approach the possible mechanism on the basis of the expression of Fas and FasL.
Methods Sixty female rats with normal oestrus cycle were randomly divided into three groups: control group, TWP group, TWP and estrogen combined with progestogen replacement therapy periodical group(TWP+HRT). these three-group rats were feeded in normal sodium, TWP and TWP+HRT differently. The dose of TWP was tevlve mg per mg per day and the dircetion of HRT was that Estradiol Valerate Tabletes after three-day dosis was used one day combining with Medroxyprogesterone Acetate Tablets then these were stop using one day . HRT was always repeated to use by time of tevlve weeks. These rats were put to death after tevlve weeks. The weight of the ovary and uterus were measured by electronic balance. Oestrus cycle was observed by Pap staining. The serum level of E_2 (estrogen)、FSH (follicle-stimulating hormone) and LH(luteinizing hormone) were detected by RIA. Pathological changes of the ovary and uterus were observed by light microscope according to hematoxylin and eosin stain. The expression of Fas and FasLmRNA were detected by RT-PCR on granulosa cell.
Results 1. Clinical and general parameters compared with control group, oestrus cycle was disorder or extension, estrogen level and the weight of the ovary and uterus lowered (PO.05) ,the level of FSH and LH increased (P<0.05) in TWP group. No obvious change was found in TWP+HRT group(P>0.05).2. pathologic morphology Worse-growing follicle, degenerating corpus luteum and thinner endometrium with diminishing uterine gland were found in TWP group compared with control group. But the ovary and uterus of TWP+HRT group rat were similar to the rat of control group.3. the expression of Fas and FasLmRNA on granulosa cell This study indicated Fas and FasLmRNA can also express on granulosa cell of the ovary. But No difference of the expression of FasLmRNA was found in these three groups(P>0.05). FasmRNA cann't be detected because of its quick apoptosis.
Conclusion TWP combined with HRT can decrease the toxic and side effects of TWP on the genital system of female rat and protect the ovary.
引文
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11.Hakuno N,Koji T,Yano T,et al.Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia.Endocrinology,1996,137(5):1938-1948.
12.Kim JM,Boone DL,Auyeung A,et al.Granulosa cell apoptosis induced at the penultimate stage of follicular development is associated with increased levels of Fas and Fas ligand in the rat ovary.Bio Reprod.1998,58(5):1170-1176.
13.Kim JM,Yoon YD,Tsang BK.Involvement of the Fas/Fas ligand system in p53-mediated granulosa cell apoptosis during follicular development and atresia.Endocrinology,1999,140(5):2307-2317.
14.Cataldo NA,Dumesic DA,Goldsmith PC,et al.Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome:relationship to apoptosis.Hum Reprod,2000,15(9):1889-1897.
15.Porter DA,Harman RM,Cowan RG,et al.Relationship of Fas ligand expression and atresia during bovine follicle development.Reproduction,2001,121(4):561-566.
16.Sakamaki K,Yoshida H,Nishimura Y,et al.Involvement of Fas antigen in ovarian follicular atresia and luteolysis.Mol Reprod Dev,1997,47(1):11-18.
17.Chen Q,Yano T,Matsumi H,et al.Cross-Talk between Fas/Fas Ligand System and Nitric Oxide in the Pathway Subserving Granulosa Cell Apoptosis:A Possible Regulatory Mechanism for Ovarian Follicle Atresia.Endocrinology,2005,146(2):808-815.
18.Boghaert ER,Sells SF,Walid A J,et al.Immunohistochemical analysis of the proapoptotic protein Par-4 in normal rat tissues.Cell Growth Differ,1997,8(8):881-890.
19.曲喜英,梅寒芳,祝其锋.H_2O_2对PC12细胞par-4和NF-KBP65基因表达的影响. 中风与神经疾病杂志, 2004,4(21): 335-337.
20. Guo Q, FuW, Xie J, et al. Par-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease. Nat Med, 1998,4(8): 957-962.
21. Duan W, Zhang Z, Gash DM, et al. Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease. Ann Neurol. 1999, 46(4): 587-597.
22. Pedersen WA, Luo H, Kruman I, et al. The prostate apoptosis response-4 protein participates in motor degeneration in amyotrophic lateral sclerosis. FASEB J, 2000,14(7): 913-924.
23. Kruman II, Nath A, Maragos WF, et al. Evidence that Par-4 participates in the pathogenesis of HIV encephalitis. Am J Pathol, 1999,155(1): 39-46.
24. Gonzalez IH, Santana P, et al. Regulation of the expression of prostate apoptosis response protein 4 (Par-4) in rat granulosa cells. Apoptosis, 2007, 12(4): 769-779.
25. Kim H, Yamanouchi K, Nishihara M, et al. Expression of Ski in the granulosa cell of atretic follicles in the rat ovary. Journal of Reproduction and Development, 2006,52(6): 715-721.
26. Tilly KI, Banerjee S, Banerjee PP, et al. Expression of the p53 and Wilms' tumor suppressor genes in the rat ovary:gonadotropin repression in vivo and immunohistochemical localization of nuclear p53 protein to apoptotic granulosa cells of atretic follicles. Endocrinology, 136(4): 1394-1402.
27. Changes in expression and localization of connexin 43 mRNA and protein in Porcine ovary granulose cells during follicular atresia, Cheng Y, Inoue N,Matsuda-Minehata F,et al. Journal Of Reproduction and Development, 2005, 51(5):627-637.
28. Salmassi A, Lu s, Hedderich J, et al. Interaction of interleukin-6 on human granulose cell steroid secretion. J Endocrinol, 2001,170(2): 471-478.
29. Maeda A, Inoue N, Matsuda-Minehata F, et al. The role of Interleukin-6 in the regulation of granulose cell apoptosis during follicular atresia in pig ovaries. Journal of Reproduction and Development, 2007, 53(3): 481 -490.
30. Aaltonen J, Laitinen MP, Vuojolainen K, et al. Human growth differentiation factor 9 (GDF-9) and its novel homolog GDF-9B are expressed in oocytes during early folliculogenesis. J Clin Endocrinol Metab, 1999, 84(8): 2744-2750.
31. Vitt UA, Hayashi M, Klein C, et al. Growth differentiation factor-9 stimulates proliferation but suppresses the follicle-stimulating hormone-induced differentiation of cultured granulosa cells from small antral and preovulatory rat follicles. Biol Reprod, 2000, 62(2): 370-377.
32. Elvin JA, Clark AT, Wang P et al. Paracrine actions of growth differentiation factor-9 in the mammalian ovary. Mol Endocrinol, 1999,13(6): 1035-1048.
33. Makoto Orisaka, Sanae Orisaka, Jin-Yi Jiang, et al. Growth Differentiation Factor 9 Is Antiapoptotic during Follicular Development from Preantral to Early Antral Stage. Molecular Endocrinology, 2006,20(10): 2456-2468.
34. Hu CL,Cowan RG,Harman RM, et al. Cell cycle progression and activation of Akt kinasa are required for insulin-like growth factor I -mediated suppression of apoptosis in granulose cells. Mol Endocrinol, 2004,18(2): 326-328.
35. Sun GW, Kobayashi H, Suzuki M, et al. Follicle-stimulating hormone and insulin-like growth factor I synergistically induce upregulation of cartilage link protein via activation of phosphatidylinositol-dependent kinase/Akt in rat granulose cells. Endocrinology, 2003, 144(3): 793-801.
36. Grieshaber NA, Boitano S, Ji I, et al. Differentiation of granulosa cell line:follicle-stimulating hormone induces formation of lamellipodia and filopodia via the adenylyl cyclase/cyclic adeno sine monophosphate signal. Endcrinology, 2000,141(9): 3 461-3 470.
37. Makrigiannakis A, Coukos G, Christofidou-Solomidou M ,et al. N-cadherin-mediated human granulosa cell adhesion prevents apoptosis : a role in follicular atresia and luteolysis ?Am J Pathol. 1999,154(5): 1391-1406.
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