亮丙瑞林、维生素E对顺铂所致大鼠生殖毒性保护及血清抑制素B变化的研究

目的:探讨亮丙瑞林、维生素E对顺铂所致大鼠子宫、卵巢毒性保护,及测定抑制素B对卵巢储备功能预测的价值。方法:选用清洁级、12周龄雌性SD大鼠64只,体重(270±20)g,随机分为A、B、C、D4组(每组16只),A组为正常对照组,B组为顺铂组,C组为抑那通(GnRHa类药物)+顺铂组,D组为维生素E(自由基清除剂)+顺铂组。A组给予生理盐水2mg/d腹腔注射,连续10天;B组给予顺铂2mg/(kg.d)腹腔注射,连续10天;C组给予亮丙瑞林0.25mg/只1皮下注射,期间持续观察性周期10天,待全部处于间情期,即第11天给予顺铂2mg/(kg.d),连续10天,D组给予维生素E50mg/(kg.d),胃灌注同时腹腔注射顺铂2mg/(kg.d),连续10天。用药结束后当天及用药结束后30天雌鼠分别各组处死8只,经心脏采血,测血清抑制素B水平、卵泡刺激素(FSH)水平,摘除双侧卵巢在光镜下进行形态学病理学观察,进行各级卵泡计数。结果:用药结束后当天:B组与其他各组比较,各级卵泡数目,抑制素B水平均明显降低,FSH水平升高,且卵巢伴有间质纤维化、坏死;C组原始卵泡数量明显多于B组;D组各级卵泡数量均减少,但多于B组(P0.05),出血、坏死现象较B组减轻,两组抑制素B水平与A组相比降低但高于B组,C组FSH水平降低。用药结束后30天:B组、D组各级卵泡数量均减少,但多于用药结束后当天(P0.05),有成熟卵泡发育;各组抑制素B水平比用药结束后当天均升高,但同组相比B组最低(P0.05),FSH水平未见明显差异。结论:①顺铂分别与亮丙瑞林、维生素E的联合应用对预防化疗所致的大鼠卵巢损伤有一定的保护作用。②血清抑制素B水平下降是反映卵巢储备功能下降的直接指标,较FSH水平升高更早期、更敏感。

Investigation on protective effects of leuprorelin and vitamin E on cisplatin induced reproductive toxicity and changes of serum inhibin B

Objective:To explore protective effects of leuprorelin and vitamin E on cisplatin induced reproductive toxicity (uterus and ovary) and value of inhibin B in prognosis of ovarian reserve function.Methods:64 female SD rats aged 12 weeks body mass (270±20) g] were divided into four groups,and 16 rats in each group: A group (control group),B group (cisplatin group),C group (enantone+cisplatin group) and D group (vitamin E+cisplatin group) .Rats in A group received intraperitoneal injection of normal saline for 10 days,2 mg/d;rats in B group received intraperitoneal injection of cisplatin for 10 days,2 mg/(kg·d);rats in C group received subcutaneous injection of leuprorelin for 10 days,0.25 mg per rat,then from the eleventh day,the rats received intraperitoneal injection of cisplatin for 10 days,2 mg/(kg·d);rats in D group received vitamin E,50 mg/(kg·d),and received intraperitoneal injection of cisplatin for 10 days,2 mg/(kg·d).Half rats in four groups were executed at the end of medication,and the residual rats in four groups were executed on the thirtieth day after medication.The serum levels of inhibin B and follicle stimulating hormone (FSH) in the four groups were detected,and pathologic examination of bilateral ovaries was conducted under light microscope,then the amount of follicles was calculated.Results:At the end of medication: compared to the other three groups,the amount of follicles and serum inhibin B level in B group were lower,but the serum level of FSH was higher,and interstitial fibrosis and necrosis of ovaries in B group were observed;the amount of primary follicles in C group was more than that in B group;the amount of follicles in D group was low,but was more than that in B group (P<0.05),and hemorrhage and necrosis of ovaries in D group were less than those in B group,the serum level of inhibin B in D group was lower than that in A group but higher than that in B group;the level of FSH in C group decreased.On the thirtieth day after medication,the amounts of follicles in B group and D group decreased,but more than those at the end of medication (P<0.05),mature follicles developed;the serum levels of inhibin B in the four group on the thirtieth day after medication were higher than those at the end of medication,but the serum level of inhibin B in B group was the lowest (P<0.05),there was no significant difference in FSH level among the four groups.Conclusion:Combined application of enantone+cisplatin or vitamin E+cisplatin play protective effects in prevention of ovary injury induced by chemotherapy.As a direct index,low level of inhibin B reflects the decline of ovarian reserve function,which is more quick and sensitive compared to the increase of FSH level.