Effects of metformin on mammalian target of rapamycin in a mouse model of endometrial hyperplasia

Eur J Obstet Gynecol Reprod Biol. 2009 Aug;145(2):195-9. doi: 10.1016/j.ejogrb.2009.04.034. Epub 2009 Jun 5.

Abstract

Objective: The effects of metformin on S6K1, which is a crucial effector of mTOR signaling, and on endometrium were studied in a mouse model of endometrial hyperplasia induced by unopposed estradiol or tamoxifen.

Study design: Forty-eight oophorectomized Balb/c mice were randomly assigned to receive saline, tamoxifen citrate (4 mg/kg), 17-beta estradiol hemihydrate (4 mg/kg), metformin (50 mg/kg), tamoxifen citrate (4 mg/kg) with metformin (50 mg/kg), or estradiol (4 mg/kg) with metformin (50 mg/kg) for 3 days. Histological markers of uterotrophy, including luminal epithelial cell height and density of endometrial glands were quantified for each slide. Immunohistochemical expression of PCNA and S6K1 was evaluated. H-score was used for S6K1 expression. Statistical analysis was performed using Student's t-test for comparison of two continous variables and one-way ANOVA for comparison of multiple variables.

Results: Mice treated either with tamoxifen or estradiol had significantly increased density of endometrial glands and epithelial heights compared to vehicle-only or metformin-only group (p<0.001). Addition of metformin to tamoxifen or estradiol treated mice significantly decreased the density of endometrial glands and epithelial cell heights (p<0.05). Addition of metformin to tamoxifen significantly decreased the H-score of S6K1 (p<0.05) and the immunohistochemical expression of PCNA (p<0.05) in uterine lining epithelium, glandular and stromal cells. Addition of metformin to estradiol significantly decreased the H-score of S6K1 (p<0.05) and the immunohistochemical expression of PCNA (p<0.05) in uterine lining epithelium, glandular and stromal cells.

Conclusion: Metformin seems to have possible antiproliferative effects on the endometrium of estradiol or tamoxifen treated mice via inhibiting the mTOR mediated S6K1 activation.

MeSH terms

  • Animals
  • Carrier Proteins / drug effects*
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Endometrial Hyperplasia / chemically induced
  • Endometrial Hyperplasia / metabolism*
  • Endometrial Hyperplasia / pathology
  • Endometrium / drug effects
  • Estradiol
  • Female
  • Metformin / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Phosphotransferases (Alcohol Group Acceptor) / drug effects*
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / drug effects
  • TOR Serine-Threonine Kinases
  • Tamoxifen

Substances

  • Carrier Proteins
  • Tamoxifen
  • Estradiol
  • Metformin
  • Phosphotransferases (Alcohol Group Acceptor)
  • mTOR protein, mouse
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka1 protein, mouse
  • TOR Serine-Threonine Kinases