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

Journal article
Authors Min Hu
Yuehui Zhang
Jiaxing Feng
Xue Xu
Jiao Zhang
Wei Zhao
Xiaozhu Guo
Juan Li
Edvin Vestin
Peng Cui
Xin Li
Xiao-Ke Wu
Mats Brännström
Linus Ruijin Shao
Håkan Billig
Published in The Journal of endocrinology
Volume 237
Issue 2
Pages 123-137
ISSN 1479-6805
Publication year 2018
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages 123-137
Language en
Links dx.doi.org/10.1530/JOE-18-0086
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Endocrinology and Diabetes, Basic Medicine

Abstract

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.

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