Effects of metformin on the expression of estrogen synthetase and ER mRNA in uterine leiomyoma tissues

Abstract

Objective: To elucidate whether metformin could regulate the mRNA expression level of estrogen synthetase and ER in human uterine leiomyoma tissues. Methods: (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. Results: (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 (P<0.05), while there were no significant change of mRNA expression levels among P450scc, P450c17 and 17β-HSD-1 (P>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 (P=0.001), while there were no significant change of ERβ mRNA level (P=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 (P<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 (P>0.05). Conclusions: 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.