Induction of apoptosis by metformin and progesterone in estrogen-induced endometrial hyperplasia in rats: involvement of the bcl-2 family proteins

Abstract

This study compared the antiproliferative effects of metformin and progesterone, via examination of the Bcl-2/Bax-caspase apoptotic pathway in estrogen-induced endometrial hyperplasia (EH) in 40 rats. Two rats died after bilateral oophorectomy, and 1 week after surgery, the remaining 38 were randomly divided into three groups: the first (control, n = 12) received 4 mg/kg 17β estradiol hemihydrate (E); the second (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 50 mg/kg metformin (E + M); and the third (n = 13) received 4 mg/kg 17β estradiol hemihydrate and 1 mg/day medroxiprogesterone acetate (E + MPA). Histological markers and Bcl-2, Bax and caspase 9 expression were analyzed. Luminal epithelial thickness, density of gland and epithelial height was significantly higher in group E than in groups E + M and E + MPA. Histopathologic parameters were similar between the E + M and E + MPA groups. Bcl-2/Bax ratio was significantly decreased in the E + M and E + MPA groups and caspase 9 expression levels were significantly increased in the E + M and E + MPA groups, compared with the control group. In addition, Bcl-2/Bax ratio and caspase 9 expression were similar between the E + M and E + MPA groups. The data indicate that metformin reduces estrogen-induced EH in rats, via activation of the caspase-dependent mitochondrial apoptotic pathway, to the same degree as progesterone.

Chinese abstract

本研究通过检测40只大鼠的雌激素诱导的子宫内膜增生细胞Bcl-2/Bax-caspase凋亡通路, 比较二甲双胍和孕酮的抗增殖作用。双侧卵巢切除后2只大鼠死亡, 手术后1周将剩余的38只大鼠随机分为3组：第一组（对照组, n = 12）接受4mg/kg 17β雌二醇半水合物（E）；第二组（n = 13）接受4mg/kg 17β雌二醇半水合物联合50mg/kg二甲双胍（E + M）；第三组（n = 13）接受4mg/kg 17β雌二醇半水合物联合1mg/day醋酸甲羟孕酮（E + MPA）。分析组织学标记物和Bcl-2, Bax and caspase 9的表达。E组的上皮厚度, 腺体密度和上皮高度明显高于E + M组和E + MPA组, 组织病理学参数与E + M组和E + MPA组相似。相对于对照组, E + M组和E + MPA组Bcl-2/Bax比例明显降低而caspase 9的表达明显增高。此外, E + M组和E + MPA组Bcl-2/Bax比例和caspase 9的表达相似。数据表明二甲双胍与孕酮一样通过caspase依赖的线粒体凋亡途径降低雌激素诱导的大鼠子宫内膜增生。

Keywords:

• Endometrial hyperplasia
• metformin
• progesterone
• caspase-dependent apoptosis
• Bcl-2 family

Disclosure statement

All authors declare that they have no conflicts of interest

Additional information

Funding

This study was supported by Erciyes University Scientific Research and Project center (Project No: 5591).