Effects of androgen on embryo implantation in the mouse delayed-implantation model

Diao, Honglu; Su, Ren-Wei; Tan, Hui-Ning; Li, Shijie; Wei, Lei; Deng, Weng-Bo; Yang, Zeng‐Ming

doi:10.1016/j.fertnstert.2007.07.1341

Cited by 40 publications

(22 citation statements)

References 40 publications

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“…; Forcelledo & Croxatto, ; Diao et al . ; Hu et al . ), we injected pregnant rats with DHT and/or insulin from GD 7.5 (the time of completion of implantation) to GD 13.5 in the current study (Fig.…”

Section: Methodsmentioning

confidence: 99%

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

Zhang

Zhao

et al. 2019

The Journal of Physiology

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Key pointsr Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanisms remain unknown.r Herein, pregnant rats chronically treated with 5α-dihydrotestosterone (DHT) and insulin exhibited hyperandrogenism and insulin resistance, as well as increased fetal loss, and these features are strikingly similar to those observed in pregnant PCOS patients.r Fetal loss in our DHT+insulin-treated pregnant rats was associated with mitochondrial dysfunction, disturbed superoxide dismutase 1 and Keap1/Nrf2 antioxidant responses, over-production of reactive oxygen species (ROS) and impaired formation of the placenta.r Chronic treatment of pregnant rats with DHT or insulin alone indicated that DHT triggered many of the molecular pathways leading to placental abnormalities and fetal loss, whereas insulin often exerted distinct effects on placental gene expression compared to co-treatment with DHT and insulin.r Treatment of DHT+insulin-treated pregnant rats with the antioxidant N-acetylcysteine improved fetal survival but was deleterious in normal pregnant rats.r Our results provide insight into the fetal loss associated with hyperandrogenism and insulin resistance in women and suggest that physiological levels of ROS are required for normal placental formation and fetal survival during pregnancy.Yuehui Zhang is a professor and chief physician in the . She carried out postdoctoral research training in reproductive endocrinology at the University of Gothenburg, Sweden and obstetrics and gynaecology at the University of Pennsylvania, USA. Her research aims are to uncover the cellular and molecular mechanisms in aetiologies of polycystic ovary syndrome (PCOS) and other gynaecological diseases, as well as to develop an effective treatment for PCOS patients.Abstract Women with polycystic ovary syndrome (PCOS) commonly suffer from miscarriage, but the underlying mechanism of PCOS-induced fetal loss during pregnancy remains obscure and specific therapies are lacking. We used pregnant rats treated with 5α-dihydrotestosterone (DHT) and insulin to investigate the impact of hyperandrogenism and insulin resistance on fetal survival and to determine the molecular link between PCOS conditions and placental dysfunction during pregnancy. Our study shows that pregnant rats chronically treated with a combination of DHT and insulin exhibited endocrine aberrations such as hyperandrogenism and insulin resistance that are strikingly similar to those in pregnant PCOS patients. Of pathophysiological significance, DHT+insulin-treated pregnant rats had greater fetal loss and subsequently decreased litter sizes compared to normal pregnant rats. This negative effect was accompanied by impaired trophoblast differentiation, increased glycogen accumulation, and decreased angiogenesis in the placenta. Mechanistically, we report that over-production of reactive oxygen species (ROS) in the placenta, mitochondrial dysfunction, and disturbed superoxide dismutase 1 (SOD1) and Keap1/Nrf2 antioxidant responses constitute im...

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Section: Methodsmentioning

confidence: 99%

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

Zhang

Zhao

et al. 2019

The Journal of Physiology

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“…Injection of carbenoxolone -a broad gap junction blocker to mice causes a delay in the implantation of blastocysts [27]. In addition, in cultured primary human endometrial stromal cells treatment with the gap junction blocker results in impaired decidualization [28].…”

Section: Wwwbjbmsorgmentioning

confidence: 99%

Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review

Kamal

Ibrahim

Mokhtar

2019

Bosn J of Basic Med Sci

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The functions of androgen and connexin in the mammalian female reproductive system are suggested to be related. Previous research has shown that androgen affects connexin expression and localization in the female reproductive system, altering its function. However, no definitive conclusion on their cause-effect relationship has been drawn yet. In addition, a high prevalence of women with polycystic ovary syndrome (PCOS), who are characterized by elevated androgen levels and failure of ovulation, has prompted the studies on the relationship between androgen and connexin in the ovaries. This systematic review aims to investigate the effect of androgen on connexin expression in the mammalian female reproductive system. The literature search was conducted using the MEDLINE, EBSCOhost, and Scopus databases and the following keywords: “androgen” or “testosterone” or “androgen blocker” or “anti-androgen” or “androstenedione” or “dehydroepiandrosterone” or “flutamide AND connexin” or “gap junction” or “cell junction”. We only considered in vitro and in vivo studies that involved treatment by androgen or androgen receptor blockers and measured connexin expression as one of the parameters. Our review showed that the exposure to androgen or androgen blocker affects connexin expression but not its localization in the mammalian ovary. However, it is not clear whether androgen downregulates or upregulates connexin expression. Additionally, it is inconclusive whether the upregulation of connexin positively contributes to the ovarian function.

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“…In support of a role for androgens in regulation of establishment of pregnancy, it has been reported that androgens can have a direct impact on implantation in mice. Insufficient androgens may delay embryo implantation, whereas excess androgens lead to an aberrant gene expression in implantation sites in a mouse delayed-implantation model (Diao et al 2008). Similar mechanisms have only recently been explored in human cell systems.…”

Section: Implantationmentioning

confidence: 99%

Regulation of androgen action during establishment of pregnancy

Gibson¹,

Simitsidellis²,

Saunders³

2016

Journal of Molecular Endocrinology

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During the establishment of pregnancy, the ovarian-derived hormones progesterone and oestradiol regulate remodelling of the endometrium to promote an environment that is able to support and maintain a successful pregnancy. Decidualisation is characterised by differentiation of endometrial stromal cells that secrete growth factors and cytokines that regulate vascular remodelling and immune cell influx. This differentiation process is critical for reproduction, and inadequate decidualisation is implicated in the aetiology of pregnancy disorders such as foetal growth restriction and preeclampsia. In contrast to progesterone and oestradiol, the role of androgens in regulating endometrial function is poorly understood. Androgen receptors are expressed in the endometrium, and androgens are reported to regulate both the transcriptome and the secretome of endometrial stromal cells. In androgen-target tissues, circulating precursors are activated to mediate local effects, and recent studies report that steroid concentrations detected in endometrial tissue are distinct to those detected in the peripheral circulation. New evidence suggests that decidualisation results in dynamic changes in the expression of androgen biosynthetic enzymes, highlighting a role for pre-receptor regulation of androgen action during the establishment of pregnancy. These results suggest that such enzymes could be future therapeutic targets for the treatment of infertility associated with endometrial dysfunction. In conclusion, these data support the hypothesis that androgens play a beneficial role in regulating the establishment and maintenance of pregnancy. Future studies should be focussed on investigating the safety and efficacy of androgen supplementation with the potential for utilisation of novel therapeutics, such as selective androgen receptor modulators, to improve reproductive outcomes in women.

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Effects of androgen on embryo implantation in the mouse delayed-implantation model

Cited by 40 publications

References 40 publications

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

Hyperandrogenism and insulin resistance‐induced fetal loss: evidence for placental mitochondrial abnormalities and elevated reactive oxygen species production in pregnant rats that mimic the clinical features of polycystic ovary syndrome

Androgen effect on connexin expression in the mammalian female reproductive system: a systematic review

Regulation of androgen action during establishment of pregnancy

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