Polycystic ovary syndrome mouse model by prenatal exposure to high anti-Müllerian hormone

Abstract Polycystic ovary syndrome (PCOS) is a complex disorder characterised by endocrine, reproductive and metabolic abnormalities. Despite PCOS being the most common endocrinopathy affecting women of reproductive age, its etiology is poorly understood so there is no cure and symptom-oriented treatment is suboptimal. Elucidation of the underlying mechanisms involved in the pathogenesis of PCOS would pave the way for the development of new interventions for PCOS. Hyperandrogenism is the most consistent feature observed in PCOS patients, and recently aberrant neuroendocrine signalling and adipose tissue function have been proposed as playing a pathogenic role in the development of experimental PCOS. To investigate the role of adipose tissue and the brain as potential key sites for androgen receptor (AR)-mediated development of PCOS, we combined an adipocyte and brain-specific ARKO knockout (AdBARKO) mouse model with a dihydrotestosterone (DHT)-induced mouse model of PCOS. Wildtype (WT) and AdBARKO prepubertal mice were implanted with a blank or DHT implant and examined after 12 weeks. In WT control females, DHT exposure induced the PCOS reproductive traits of cycle irregularity, ovulatory dysfunction and reduced follicle health. In contrast, these reproductive features of PCOS were absent in DHT-treated AdBARKO females. The PCOS metabolic characteristics of increased adiposity, adipocyte hypertrophy and hepatic steatosis were induced by DHT in WT females. Despite DHT treatment, AdBARKO females displayed normal white adipose tissue weight, and adipocyte hypertrophy and hepatic steatosis were not evident. However, as with WT mice, DHT treatment induced increased fasting glucose levels in AdBARKO females. These results demonstrate that adipose tissue and the brain are key loci for androgen-mediated actions involved in the developmental origins of PCOS. These findings support targeting adipocyte and neuroendocrine AR-driven pathways in the future development of novel therapeutic strategies for PCOS.

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Retinoic acid and fibroblast growth factor-2 play a key role on modulation of sex hormones and apoptosis in a mouse model of polycystic ovary syndrome induced by estradiol valerate

Taiwanese Journal of Obstetrics and Gynecology ◽

10.1016/j.tjog.2020.08.004 ◽

2020 ◽

Vol 59 (6) ◽

pp. 882-890 ◽

Cited By ~ 1

Author(s):

Ardeshir Moayeri ◽

Ayoob Rostamzadeh ◽

Amir Raoofi ◽

Mohammad Jafar Rezaie ◽

Zahra Abasian ◽

...

Keyword(s):

Retinoic Acid ◽

Growth Factor ◽

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Fibroblast Growth Factor ◽

Polycystic Ovary ◽

Fibroblast Growth Factor 2 ◽

Estradiol Valerate ◽

Fibroblast Growth ◽

Ovary Syndrome

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NLRP3 expression is upregulated in ovarian granulosa cells in a mouse model of polycystic ovary syndrome

10.26226/morressier.5af300b3738ab10027aa99f4 ◽

2018 ◽

Author(s):

Bo Wang

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Granulosa Cells ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

Ovarian Granulosa Cells ◽

Nlrp3 Expression

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Demethylation of LHR in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gap089 ◽

2009 ◽

Vol 16 (4) ◽

pp. 260-266 ◽

Cited By ~ 30

Author(s):

J.-Q. Zhu ◽

L. Zhu ◽

X.-W. Liang ◽

F.-Q. Xing ◽

H. Schatten ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Polycystic Ovary ◽

Ovary Syndrome

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Androgens impair β-cell function in a mouse model of polycystic ovary syndrome by activating endoplasmic reticulum stress

Endocrine Connections ◽

10.1530/ec-20-0608 ◽

2021 ◽

Author(s):

Bo Zhu ◽

Yumei Chen ◽

Fang Xu ◽

Xiaolu Shen ◽

Xuanyu Chen ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Er Stress ◽

Cell Function ◽

Polycystic Ovary ◽

Β Cells ◽

Β Cell ◽

Ovary Syndrome ◽

Β Cell Function

Background: Androgens excess results in endoplasmic reticulum (ER) stress, which is an important cause of β cells dysfunction. Here, we investigated the molecular regulation of androgens excess, ER stress, and β-cell function in polycystic ovary syndrome (PCOS). Methods: PCOS mouse model was established by injection of dehydroepiandrosterone (DHEA). Primary cultured mouse islets were used to detect testosterone (TE)-induced ER stress. The response of ER stress, apoptosis, and hyperinsulinemia were analyzed in INS-1 cells with or without TE exposure. Androgen receptor (AR) antagonist and ER stress inhibitor treatment was performed to evaluate the role of TE in ER stress and proinsulin secretion of PCOS mice. Results: PCOS mice had higher ER stress in islets. TE exposure induced ER stress and apoptosis significantly through sustaining insulin overexpression in β cells, which in turn impaired proinsulin maturation and secretion. Blocking this process could significantly relieve ER stress and apoptosis and improve insulin homeostasis. Conclusion: ER stress activated by androgens excess in PCOS contributes to β cell dysfunction and hyperinsulinemia.

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Effect of berberine on hyperandrogenemia, ovulation dysfunction and inflammation in a mouse model of polycystic ovary syndrome

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i9.23 ◽

2020 ◽

Vol 19 (9) ◽

pp. 1963-1968

Author(s):

Kena Lu ◽

Hanmei Lin

Keyword(s):

Polycystic Ovary Syndrome ◽

Mouse Model ◽

Polycystic Ovary ◽

Inflammatory Factors ◽

Control Group ◽

High Dose ◽

Model Group ◽

Blank Control Group ◽

Ovary Syndrome ◽

Stage Of Development

Purpose: To study the effect of berberine (BBR) on hyperandrogenemia (HA), ovulation dysfunction and inflammation in a mouse model of polycystic ovary syndrome (PCOS).Methods: Forty-five female Kunming mice were randomly divided into control group (9 mice), and mice injected with dehydroepiandrosterone (n = 36) for establishment of PCOS model. The PCOS mice were randomly divided into model group, low-dose BBR (0.25 g/kg), medium-dose BBR (0.5 g/kg) and highdose (1.0 g/kg) groups, with 9 mice in each group. Changes in ovarian morphology were monitored, and sex hormone levels i.e. testosterone (T) and luteinizing hormone (LH)), and inflammatory factors were determined.Results: The model group levels of T and LH were significantly higher than those of the blank control group (p < 0.05), but T and LH levels were significantly lower in middle- and high-dose BBR groups than in the model mice. There were marked increases in IL-6 and TNF-α levels in model mice, when compared to blank control mice, but reduced in the mice treated at the 3 doses of BBR, relative to model mice (p < 0.05). In contrast, the number of follicles was higher at each stage of development in mice for each BBR dose than in the model mice, with increase in corpus luteum.Conclusion: Berberine lowers the weight of PCOS mice, mitigates hyperandrogenemia and inflammatory state, and enhances recovery of ovulation. However, there is need for further studies on its clinic applicability. Keywords: Berberine, Polycystic ovary syndrome, Hyperandrogenemia, Ovulation dysfunction, Inflammatory

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