Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome.
Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS) patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial-stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K-Akt-NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China; Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Yuehui
Y
Zhang
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Min
M
Hu
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Fanci
F
Meng
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Xiaoyan
X
Sun
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Hongfei
H
Xu
Department of Acupuncture and Moxibustion, Second Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150001 Harbin, China.
Jiao
J
Zhang
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College, Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University, 200032 Shanghai, China.
Peng
P
Cui
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Njomeza
N
Morina
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, 200011 Shanghai, China; Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, 200011 Shanghai, China.
Xin
X
Li
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Wei
W
Li
Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, 150040 Harbin, China.
Xiao-Ke
XK
Wu
Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden.
Mats
M
Brännström
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden. Electronic address: ruijin.shao@fysiologi.gu.se.
Ruijin
R
Shao
Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden.
Håkan
H
Billig
D000818:Animals; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D004195:Disease Models, Animal; D010064:Embryo Implantation / Q000187:drug effects; D004958:Estradiol / Q000097:blood; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D017588:Hyperandrogenism / Q000139:chemically induced / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000097:blood; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013739:Testosterone / Q000097:blood; D014599:Uterus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D060528:Wnt4 Protein / Q000235:genetics / Q000378:metabolism
D006063:Chorionic Gonadotropin; D007328:Insulin; D016328:NF-kappa B; D011944:Receptors, Androgen; D060528:Wnt4 Protein; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
Hyperandrogenism; Insulin resistance; Metformin; Molecular mechanism; PCOS; Rat uterus