亮丙瑞林对顺铂所致大鼠卵巢毒性保护的实验研究

The protective effect of gonadotropin-releasing hormone agonist(enantone) from cisplatin-induced ovary damage in rat model

目的:探讨亮丙瑞林(GnRH-a)对大鼠顺铂所致卵巢功能损伤的保护作用。方法:选择SPF级别12周龄SD雌鼠96只,随机分为4组,每组24只。A组为正常对照组,腹腔注射生理盐水2ml/d。B组为顺铂组,C组为亮丙瑞林(GnRHa)+顺铂组,D组为单用亮丙瑞林组。于间情期C、D组皮下注射亮丙瑞林0.25mg/只(单次给药)。B、C组腹腔注射顺铂2mg/(kg.d),连续用药10天。用药结束后及结束后30天分别每组处死8只;每组剩余的雌鼠按2:1与雄鼠交配,产仔后处死。称体重、卵巢及子宫重量,统计卵泡数量和各级卵泡直径,观察卵巢和子宫病理学变化。测雌二醇(E2)、卵泡刺激素(FSH)。观察孕鼠产仔数量及外观。结果:用药结束后B、C组大鼠精神及饮食状况差,体重及子宫重量下降(P<0.05),以B组最为明显(P<0.05)。用药结束后30天4组大鼠体重增加,B组体重恢复得最慢(P<0.05)。用药结束后B、D组子宫黏膜层变薄,纤维成分多,子宫腺体少。C组子宫黏膜层变薄,但腺上皮细胞比B组清晰,有顶浆分泌现象。C、D组原始卵泡较多,生长卵泡、成熟卵泡数减少,各级卵泡的粒细胞层明显减少(P<0.05)。B组成熟卵泡减少明显(P<0.05)。用药结束后30天,B、C、D组子宫内膜厚度及腺体量均有所改善。B组成熟卵泡数减少(P<0.05)。C组和D组成熟卵泡数增多(P<0.05)。用药结束后B、C、D组FSH升高,E2下降(P<0.05),B组与C、D组相比,FSH升高,E2下降更明显(P<0.05)。用药结束后30天,C、D组FSH降低,E2升高(P<0.05)。4组鼠仔未见畸形,B组产仔数减少。结论:顺铂对大鼠卵巢有毒性作用。亮丙瑞林可使原始卵泡数增多,卵泡处于静止期,降低顺铂对卵巢的毒性作用。

Objective：To explore the protectvive effect of enantone from cisplatin-induced ovary damage in rats. Methods： 12-week female rats in SPF level （n = 96） were randomly divided into A, B ,C and D groups （n = 24 ）. Group A was normal control group （i. p. NS 2ml/d x 10d ）. Group B was treated with cisplatin. Group C was treated with enantone ＋ cisplatin and group D with enantone only. Group C and D received enantone subcutaneously 0.25mg per rat in dioestrus. Group 13 and C received cisplatin 2mg/（kg·d） for i0 days. After being treated as mentioned above, and 30 days after the treatment, 8 rats from each group were executed respectively. Blood samples were collected from heart for FSH and E2 detecting. Weight and morphology of ovaries and uteruses were studied. The rest rats in each group mated by 2 ： 1, female to male respectively, and were then killed after childbirth. The characterics of their off-spring were observed. Results：Rats in group B and C after treatment, compared with group A,appeared to be more dispirited, yellow-haired and somnolent. The weight of rats in group A was significantly greater than that in other groups （P 〈 0.05 ）. The weight of group B was the lowest （ P 〈 0.05 ）. 30 days after treatment of cisplatin, rats in all groups appeared higher spirits. Rats in group C and D were still heavier than group B （ P 〈 0.05 ）. The mucous membrane of uterus of rats in group B and D became thinner, richer in fiber and had less gland. The mucous membrane of uterus of rats in group C also became thinner,but epithelial cells of gland were clearer and showed apocrine. 30 days after the cisplatin finished, the mucous membrane＇s thickness of group B, C and D all increased slightly. The number of primordial follicle cells in group C and D remained a lot, yet the number of growing and mature follicle cells decreased obviously, and the granular-cell layer of each kind of follicle cells also decreased apparently（ P 〈 0.05 ）. The number of growing and mature follicle cells in group B all remained a lot （ P 〈 0.05 ）. The number of mature follicle cells in group B decreased obviously, while in group C and D increased obviously （P 〈 0.05 ）. First day after finished cisplatin, compared with group A, the FSH in group B, C, D increased but E2 decreased （ P 〈 0.05 ）. Compared with group B, the FSH in both group C and D decreased, but E2 increased （ P 〈 0.05 ）. The offspring of all groups were not observed abnormal appearance, but the number of offsprings in group B was obviously less. Conclusion：Cispatin has obvious toxicity to ovary and uterus in rats. Enantone may interfere the process of small follicle development into big follicle of rats, and keep the follicles in stationary phase.