不同剂量来曲唑联合醋酸甲羟孕酮对大鼠子宫内膜异位症模型作用的研究

Study of Different Doses of Letrozole and Medroxyprogesterone Acetate Cotreating Endometriotic Rats

目的:探讨不同剂量来曲唑(LE)及醋酸甲羟孕酮(MPA)联合应用对大鼠子宫内膜异位症(EMT)模型的治疗效果及对肝、肾、骨以及生殖系统的影响,为LE临床治疗绝经前EMT提供实验基础。方法:应用自体子宫内膜移植方法建立大鼠EMT模型,将70只建模成功大鼠随机分为7组,每组10只:A^C组为LE 1 mg/(kg·d^(-1))+MPA[分别为8、4、2 mg/(kg·d^(-1))],D^F组为LE 0.5mg/(kg·d^(-1))+MPA[分别为8、4、2 mg/(kg·d^(-1))];G组为0.9%氯化钠液(对照组)。比较治疗前后大鼠EMT异位病灶体积的变化,检测异位病灶中细胞色素P450芳香化酶(P450arom)、Ki-67蛋白的表达及细胞凋亡情况,测定大鼠血清FSH、LH、E_2水平及肝、肾功能,取右侧股骨测量骨密度。结果:(1)除F组外,LE联合MPA各剂量组治疗后的异位病灶体积与G组比较均缩小(P<0.05),以A组和B组体积缩小最为显著(P<0.01)。(2)与G组相比,A^C组异位内膜中P450arom、Ki-67蛋白表达均低于G组(P<0.05或P<0.01),而异位内膜细胞凋亡率均高于G组(P<0.01),且以A、B两组最为明显(P<0.01)。(3)与G组相比,A、B、D组大鼠血清FSH、LH、E_2水平均降低(P<0.05或P<0.01),而且A组、B组的E_2水平更低。(4)与G组比较,C组大鼠卵巢质量明显增加(P<0.01),卵巢呈多囊改变;除F组外各治疗组子宫质量与G组比较均减轻(P<0.01),内膜均呈增生抑制或萎缩改变。(5)各剂量组的大鼠骨密度均无明显变化(P>0.05)。(6)仅A组治疗后出现肝功能异常,各组肾功能均未出现异常(P>0.05)。结论:LE 1 mg/(kg·d^(-1))联合MPA 4 mg/(kg·d^(-1))治疗效果最佳,且对肝肾功能无影响。其作用可能与通过协同降低大鼠血清E_2水平并减少异位内膜局部雌激素的分泌,抑制异位内膜增殖并促进凋亡有关。

Objective：To explore the treatment effect on EMT in rats using different doses of letrozole and Me- droxyprogesterone acetate （MPA） and their effects on liver, renal, skeletal and reproductive system. To provide lab evidence for treatment of EMT before menopause using letrozole. Methods：Endometriotic rat model was set up by surgical transplantation of autologous uterine tissues to ectopic site outside the uterus. 70 EM model rats were randomly divided into 7 groups,each with 10：A- C：LE 1 mg/（kg · d -1） and M PA [8 ,4,2 mg/（ kg · d -1 ） respectively] ;D- F：LE 0.5mg/（kg · d-1）and MPA[8,4,2 mg/（kg · d-1） respectively] ;G.0.9% saline （control group）. The volume of ectopic lesion in each group was compared before and after the treatment. The expression of P450arom and Ki-67 and cell apoptosis in the endometriotic tissues of the rat models were detected. The serum levels of FSH,LH and E2 were determined and liver and renal functions were detected. Bone mineral density（BMD） was measured in the right femur. Results.（1）Except for group F,the volume of the endometriotic tis- sues of the five groups reduced significantly compared with the G group（ P 〈 0.05）, and the greatest decrease in the volume were in group A and B （P〈0.01） ;（2）Compared with the G group,the expression of P450arom and Ki-67 protein decreased while the apoptotic rate increased in tissues of endometriosis （EM） on rat models among group A to group E （P〈0.05） ,in which group A and B were the most notable （ P〈0.01 ） ;（3）Compared with the G group,the level of FSH,LH and E2 reduced in group A,B and D （P〈0.05） ,moreover,the E2 level of group A and B was lower than that in group D （P〈0.05） ;（4）Compared with the G group,the ovarian weight in group C increased greatly,and the ovaries showed polycystic. The uterine weights decreased among group A to group E, and the endometrium presented atrophy or inhibition of proliferation;（5）There was no change on the bone density among each group（ P 〉 0. 05） ;（6）Abnormal liver function was only detected in group A after treatment, and no abnormal renal function detected in any group （P 〉 0. 05）. Conclusions：LE 1 mg/（ kg · d -1 ） associated with MPA 4mg/（kg · d -1 ） had the most effect on EM rat models. Moreover,it had no influence on liver or renal function. The mechanism may be decreasing the serum level of E2, reducing local estrogen along with increasing the apoptosis while decreasing the proliferation of the ectopic tissues.