Functional Investigation on Aromatase in Endometrial Hyperplasia in Polycystic Ovary Syndrome Cases

Zhao, Pan-Lin; Zhang, Qiufang; Yan, Liying; Huang, Shuo; Chen, Yuan; Qiao, Jie

doi:10.7314/apjcp.2014.15.20.8975

“…Common opinion holds that androgens are the primary regulators of AR expression and activation 11 ; however, previous studies show that the high levels of AR are associated with the proliferative phase of the menstrual cycle 12 - 16 and that AR expression is also regulated by estrogens in human endometrium 52 , 53 . While endogenous androgen levels 1 , 3 and endometrial P450 aromatase expression 54 are significantly increased in PCOS patients, it is likely that both androgen and estrogen contribute to increased endometrial AR expression in PCOS patients. However, under the estrogen-related hyperplasia condition we observed a significant increase in AR expression in PCOS patients compared to non-PCOS patients.…”

Section: Discussionmentioning

confidence: 98%

Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

Li¹,

Pishdari²,

Cui³

et al. 2015

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The failure of reproductive success in polycystic ovary syndrome (PCOS) patients could be in part due to endometrial dysfunction. However, no studies have investigated any causality between androgen, androgen receptor (AR) expression, and adenosine monophosphate activated protein kinase (AMPK) activation in the endometrium under physiological and pathological conditions. In the present study, we show that 1) endometrial AR expression levels fluctuate in non-PCOS and PCOS patients during the menstrual cycle; 2) the menstrual phase-dependent alteration of p-AMPKα expression occurs in non-PCOS patients but not in PCOS patients; 3) AR expression is higher in PCOS patients than non-PCOS patients during hyperplasia while AMPKα activation (indicated by the ratio of p-AMPKα to AMPKα); and 4) co-localization of AR and Ki-67 in epithelial cell nuclei is observed in endometrial hyperplasia. Importantly, using in vitro human tissue culture and an in vivo 5α-dihydrotestosterone-treated rat model, we show that the action of androgen on AMPKα activation is likely mediated through nuclear AR, especially in epithelial cells. Collectively, we present evidence that AR expression and AMPKα activation depend on menstrual cycle phase and the presence of PCOS, and the data suggest that AR-mediated regulation of AMPKα activation might play a role in the development of endometrial hyperplasia.

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“…Furthermore, as we demonstrated in this study, the effectiveness of flutamide on fertility is most clearly seen in pregnant rats co-exposed to DHT and INS. Because of increased P450 aromatase mRNA expression in the PCOS endometrium [ 63 ], our findings do not rule out the possibility that flutamide might affect decidualization and implantation through other mechanisms (e.g., through interactions with estrogen receptor) in vivo [ 64 ], and this requires future study.…”

Section: Discussionmentioning

confidence: 99%

Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance

Zhang

¹

,

Hu

²

,

Yang

³

et al. 2021

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In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility. Key messages The proper regulation of uterine androgen receptor (AR) contributes to a normal pregnancy process, whereas the aberrant regulation of uterine AR might be linked to polycystic ovary syndrome (PCOS)-induced pregnancy-related complications. In the current study, we found that during normal rat pregnancy there is a stage-dependent decrease in AR abundance in the gravid uterus and that this is correlated with the differential expression of the endometrial receptivity and decidualization genes Spp1, Prl, Igfbp1, and Hbegf. Pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin (INS) or to DHT alone show elevated uterine AR protein abundance and implantation failure related to the aberrant expression of genes involved in endometrial receptivity and decidualization in early to mid-gestation. Treatment with the anti-androgen flutamide, starting from pre-implantation, effectively prevents DHT + INS-induced defects in endometrial receptivity and decidualization gene expression, restores uterine mitochondrial homeostasis, and increases the pregnancy rate and the numbers of viable fetuses. This study adds to our understanding of the mechanisms underlying poor pregnancy outcomes in PCOS patients and the possible therapeutic use of anti-androgens, including flutamide, after spontaneous conception.

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“…Furthermore, as we demonstrated in this study, the effectiveness of utamide on fertility is most clearly seen in pregnant rats co-exposed to DHT and INS. Because of increased P450 aromatase mRNA expression in the PCOS endometrium [57], our ndings do not rule out the possibility that utamide might affect decidualization and implantation through other mechanisms (e.g., through interactions with estrogen receptor) in vivo [58], and this requires future study.…”

Section: Discussionmentioning

confidence: 83%

Increased Uterine Androgen Receptor Protein Abundance Results in Implantation and Mitochondrial Defects in Pregnant Rats with Hyperandrogenism and Insulin Resistance

Zhang

¹

,

Hu

²

,

Yang

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility.

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Functional Investigation on Aromatase in Endometrial Hyperplasia in Polycystic Ovary Syndrome Cases

Cited by 16 publications

References 21 publications

Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

Regulation of Androgen Receptor Expression Alters AMPK Phosphorylation in the Endometrium: In Vivo and In Vitro Studies in Women with Polycystic Ovary Syndrome

Increased uterine androgen receptor protein abundance results in implantation and mitochondrial defects in pregnant rats with hyperandrogenism and insulin resistance

Increased Uterine Androgen Receptor Protein Abundance Results in Implantation and Mitochondrial Defects in Pregnant Rats with Hyperandrogenism and Insulin Resistance

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