Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats

J Endocrinol. 2018 May;237(2):123-137. doi: 10.1530/JOE-18-0086. Epub 2018 Mar 13.


Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2, two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions.

Keywords: MAPK/ERK/p38 signaling pathway; implantation; metformin; polycystic ovary syndrome; progesterone receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chorionic Gonadotropin / pharmacology
  • Disease Models, Animal
  • Embryo Implantation / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Insulin / pharmacology
  • Metformin / pharmacology*
  • Metformin / therapeutic use*
  • Polycystic Ovary Syndrome / drug therapy*
  • Polycystic Ovary Syndrome / metabolism
  • Polycystic Ovary Syndrome / pathology
  • Pregnancy
  • Progesterone / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Progesterone / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Uterus / drug effects*
  • Uterus / metabolism


  • Chorionic Gonadotropin
  • Insulin
  • Receptors, Progesterone
  • Progesterone
  • Metformin