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

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.