Wang S Y, Xue Q, Zhou Y F, Yin L
Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing 100034, China.
Zhonghua Fu Chan Ke Za Zhi. 2019 Apr 25;54(4):249-254. doi: 10.3760/cma.j.issn.0529-567x.2019.04.007.
To elucidate whether metformin could regulate the mRNA expression level of estrogen synthetase and ER in human uterine leiomyoma tissues. (1) Seventeen pairs of uterine leiomyoma tissues and adjacent myometrium (>2 cm) were collected from patients underwent hysterectomy in Peking University First Hospital between December 2016 and January 2017. Real-time PCR was used to measure the mRNA expression level of estrogen synthetase [including cytochrome P450 cholesterol side chain cleavage enzyme (P450scc), cytochrome P450 17α-hydroxylase (P450c17), 3-beta-hydroxysteroid dehydrogenase type 2 (3β-HSD-2), 17-beta-hydroxysteroid dehydrogenase type 1 (17β-HSD-1) and aromatase cytochrome P450 (P450arom)] and ER (including ERα and ERβ) in the uterine leiomyoma tissues and adjacent myometrium. (2) Uterine leiomyoma cells derived from uterine leiomyoma tissues were identified by immunocytochemistry method and cultured to the third generation. The treatment groups were cultured with different concentrations of metformin (10, 50 and 100 μmol/L) for 48 hours, and the control group was cultured with deionized water for 48 hours. The mRNA expression level of estrogen synthetase and estrogen receptor subtypes were measured by real-time PCR. (1) P450scc, P450c17, 3β-HSD-2, 17β-HSD-1, P450arom mRNA median expression levels were 112, 4, 13, 42 and 194 in the uterine leiomyoma tissues, and were respectively 114, 5, 11, 32 and 6 in the myometrium. Compared to those of the myometrium, 3β-HSD-2 and P450arom mRNA expression levels in the uterine leiomyoma tissue were significantly higher (0.05), while there were no significant change of mRNA expression levels among P450scc, P450c17 and 17β-HSD-1 (0.05). ERα and ERβ mRNA median expression levels were 208 and 116 in the uterine leiomyoma tissues, and were 24 and 95 in the myometrium. Compared to that of the myometrium, ERα mRNA level in the uterine leiomyoma tissue was significantly higher (0.001), while there were no significant change of ERβ mRNA level (0.193). (2) After cultured with different concentrations of metformin (10, 50 and 100 μmol/L), the P450arom mRNA levels in the uterine leiomyoma tissues were 9±4, 8±5 and 8±3 respectively in the treatment groups and was 16±5 in the control group. Compared to that of the control group, P450arom mRNA expression levels in the treatment groups were significantly declined (0.05). There were no significant different change of mRNA expression levels among 3β-HSD-2, ERα and ERβ between the treatment groups and the control group (0.05). Metformin could down-regulate the mRNA expression level of aromatase in the uterine leiomyoma cells. These results indicate that metformin may inhibit the local estrogen synthesis and therefore suppress the development of uterine leiomyoma.
为阐明二甲双胍是否能调节人子宫平滑肌瘤组织中雌激素合成酶和雌激素受体（ER）的mRNA表达水平。（1）2016年12月至2017年1月期间，从北京大学第一医院接受子宫切除术的患者中收集了17对子宫平滑肌瘤组织及其相邻的肌层（>2 cm）。采用实时荧光定量PCR检测子宫平滑肌瘤组织及其相邻肌层中雌激素合成酶[包括细胞色素P450胆固醇侧链裂解酶（P450scc）、细胞色素P450 17α-羟化酶（P450c17）、2型3-β-羟类固醇脱氢酶（3β-HSD-2）、1型17-β-羟类固醇脱氢酶（17β-HSD-1）和芳香化酶细胞色素P450（P450arom）]和ER（包括ERα和ERβ）的mRNA表达水平。（2）采用免疫细胞化学方法鉴定从子宫平滑肌瘤组织中分离出的子宫平滑肌瘤细胞，并培养至第三代。处理组用不同浓度的二甲双胍（10、50和100 μmol/L）培养48小时，对照组用去离子水培养48小时。采用实时荧光定量PCR检测雌激素合成酶和雌激素受体亚型的mRNA表达水平。（1）子宫平滑肌瘤组织中P450scc、P450c17、3β-HSD-2、17β-HSD-1、P450arom mRNA的中位表达水平分别为112、4、13、42和194，肌层中分别为114、5、11、32和6。与肌层相比，子宫平滑肌瘤组织中3β-HSD-2和P450arom mRNA表达水平显著升高（P<0.05），而P450scc、P450c17和17β-HSD-1的mRNA表达水平无显著变化（P>0.05）。子宫平滑肌瘤组织中ERα和ERβ mRNA的中位表达水平分别为208和116，肌层中分别为24和95。与肌层相比，子宫平滑肌瘤组织中ERα mRNA水平显著升高（P<0.001），而ERβ mRNA水平无显著变化（P=0.193）。（2）用不同浓度的二甲双胍（10、50和100 μmol/L）培养后，处理组子宫平滑肌瘤组织中P450arom mRNA水平分别为9±4、8±5和8±3，对照组为16±5。与对照组相比，处理组P450arom mRNA表达水平显著降低（P<0.05）。处理组与对照组之间3β-HSD-2、ERα和ERβ的mRNA表达水平无显著差异（P>0.05）。二甲双胍可下调子宫平滑肌瘤细胞中芳香化酶的mRNA表达水平。这些结果表明，二甲双胍可能抑制局部雌激素合成，从而抑制子宫平滑肌瘤的发展。
