Chemopreventive effects of metformin on obesity-associated endometrial proliferation

Qian Zhang, Joseph Celestino, Rosemarie Schmandt, Adrienne S. McCampbell, Diana L. Urbauer, Larissa A. Meyer, Jennifer K. Burzawa, Marilyn Huang, Melinda S. Yates, David Iglesias, Russell R. Broaddus, Karen H. Lu

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

OBJECTIVE: Obesity is a significant contributing factor to endometrial cancer risk. We previously demonstrated that estrogen-induced endometrial proliferation is enhanced in the context of hyperinsulinemia and insulin resistance. In this study, we investigate whether pharmacologic agents that modulate insulin sensitivity or normalize insulin levels will diminish the proliferative response to estrogen. STUDY DESIGN: Zucker fa/fa obese rats and lean controls were used as models of hyperinsulinemia and insulin resistance. Insulin levels were depleted in ovariectomized rats following treatment with streptozotocin, or modulated by metformin treatment. The number of BrdU-incorporated cells, estrogen-dependent proliferative and antiproliferative gene expression, and activation of mTOR and ERK1/2 MAPK signaling were studied. A rat normal endometrial cell line RENE1 was used to evaluate the direct effects of metformin on endometrial cell proliferation and gene expression in vitro. RESULTS: Streptozotocin lowered circulating insulin levels in obese rats and decreased the number of BrdU-labeled endometrial cells even in the presence of exogenous estrogen. Treatment with the insulinsensitizing drug metformin attenuated estrogen-dependent proliferative expression of c-myc and c-fos in the obese rat endometrium compared to untreated controls and was accompanied by inhibition of phosphorylation of the insulin and IGF1 receptors (IRb/IGF1R) and ERK1/2. In vitro studies indicated metformin inhibited RENE1 proliferation in a dose-dependent manner. CONCLUSION: These findings suggest that drugs that modulate insulin sensitivity, such as metformin, hinder estrogen-mediated endometrial proliferation. Therefore, these drugs may be clinically useful for the prevention of endometrial cancer in obese women.

Original languageEnglish (US)
Pages (from-to)24.e1-24.e12
JournalAmerican journal of obstetrics and gynecology
Volume209
Issue number1
DOIs
StatePublished - Jul 2013

Keywords

  • Estrogen
  • Insulin resistance
  • Obesity

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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