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Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant ROS production.

Journal article
Authors Min Hu
Yuehui Zhang
Xiaozhu Guo
Wenyan Jia
Guoqi Liu
Jiao Zhang
Juan Li
Peng Cui
Amanda Nancy Sferruzzi-Perri
Yanhua Han
Xiaoke Wu
Hongxia Ma
Mats Brännström
Linus Ruijin Shao
Håkan Billig
Published in American journal of physiology. Endocrinology and metabolism
Volume 316
Issue 5
Pages E794-E809
ISSN 1522-1555
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages E794-E809
Language en
Keywords Uterine decidualization, angiogenesis, mitochondrial homeostasis, reactive oxygen species, Nrf2 signaling, polycystic ovary syndrome
Subject categories Endocrinology, Obstetrics and women's diseases, Obstetrics, Gynecology and Reproductive Medicine


Women with polycystic ovary syndrome (PCOS) are at increased risk of miscarriage, which often accompanies the hyperandrogenism and insulin resistance seen in these patients. However, neither the combinatorial interaction between these two PCOS-related etiological factors nor the mechanisms of their actions in the uterus during pregnancy are well understood. We hypothesised that hyperandrogensim and insulin resistance exert a causative role in miscarriage by inducing defects in uterine function that are accompanied by mitochondrial-mediated oxidative stress, inflammation and perturbed gene expression. Here we tested this hypothesis by studying the metabolic, endocrine and uterine abnormalities in pregnant rats after exposure to daily injection of 5α-dihydrotestosterone (DHT, 1.66 mg/kg body weight/day) and/or insulin (6.0 IU/day) from gestational day 7.5 to 13.5. We showed that while DHT-exposed and insulin-exposed pregnant rats presented impaired insulin sensitivity, DHT+insulin-exposed pregnant rats exhibited hyperandrogenism and peripheral insulin resistance, which mirrors pregnant PCOS patients. Compared to controls, hyperandrogenism and insulin resistance in the dam was associated with alterations in uterine morphology and aberrant expression of genes responsible for decidualization, placentation, angiogenesis and insulin signaling. Moreover, we observed changes in uterine mitochondrial function and homeostasis and suppression of both oxidative and antioxidative defenses in response to the hyperandrogenism and insulin resistance. These findings demonstrate that hyperandrogenism and insulin resistance induce mitochondria-mediated damage and a resulting imbalance between oxidative and antioxidative stress responses in the gravid uterus.

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