Altered FoxO3 expression and apoptosis in granulosa cells of women with polycystic ovary syndrome

Mikaeili, Saideh; Rashidi, Batool Hossein; Safa, Majid; Najafi, Atabak; Sobhani, Aligholi; Asadi, Ebrahim; Abbasi, Mehdi

doi:10.1007/s00404-016-4068-z

Cited by 56 publications

(39 citation statements)

References 36 publications

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“…Although no "perfect" animal model currently exists for human PCOS due to its complex nature, the androgenized rat model has proven to be useful as it mimics many phenotypes of the human condition 20,22-24 . In the current studies, we used a DHT-induced rat model with a shorter (one month) duration of treatment and assessed its efficacy by examining ovary size, ovarian structural features, and granulosa cell apoptosis. Similar to the three-month DHT-induced rat model and human PCOS 20,25,26,29 , in one-month DHT-induced rat, we found an induction of early antral granulosa cell apoptosis, follicular growth arrest, disrupted folliculogenesis and anovulation, but without systemic changes (e.g. body weight changes and insulin sensitivity index).…”

Section: Discussionsupporting

confidence: 79%

“…Although the etiology of PCOS remains elusive due to its complex and heterogeneous nature, granulosa cell apoptosis has been suggested to play an important role in follicular growth arrest associated with the pathogenesis of PCOS 20,25,26 . We demonstrated, for the first time, the dysregulation of mitochondrial fission and fusion dynamics, and autophagy in a DHT-induced rat model that recapitulates many phenotypes of human PCOS.…”

Section: Discussionmentioning

confidence: 99%

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Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

Salehi

Mazier

Nivet

et al. 2020

Sci Rep

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In this study, we investigated in an androgenized rat model the involvement of autophagy and mitochondrial dynamics in granulosa cells in the pathogenesis of polycystic ovarian syndrome (PCOS) and its modulation by exogenous gonadotropin (eCG). We found 5α-dihydrotestosterone (DHT) treatment reduces ovarian length and weight with predominantly late antral and/or preovulatory stage follicles and no corpora lutea. DHT increased the population of large lysosomes (>50 micron) and macroautophagy, an event associated with granulosa cell apoptosis. Increased granulosa cell Dynamin Related Protein 1 (Drp1) content in the DHT group was accompanied by increased circular and constricted, but reduced rod-shaped, mitochondria. eCG eliminated all atypical follicles and increased the number of late antral and preovulatory follicles with less granulosa cell apoptosis. eCG-treated rats had a higher proportion of connected mitochondria, and in combination with DHT had a lower proportion of circular and constricted mitochondria than rats treated with DHT alone, suggesting that eCG induces mitochondrial fusion and attenuates fission in granulosa cells. In summary, we observed that DHT-induced up-regulation of Drp1 is associated with excessive mitochondrial fission, macroautophagy and apoptosis in granulosa cells at the antral stage of development in an androgenized rat model for PCOS, a response partially attenuated by exogenous gonadotropin.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

Salehi

Mazier

Nivet

et al. 2020

Sci Rep

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“…Mikaeili and cols. correlated FOX03 expression and activation in granulosa cells with apoptosis rates, and found a positive correlation between them, making this transcription factor a potential candidate target (20).…”

Section: Gonadotropin-independent Folliculogenesismentioning

confidence: 88%

An update of genetic basis of PCOS pathogenesis

Crespo¹,

Bachega²,

Mendonça³

et al. 2018

Archives of Endocrinology and Metabolism

101

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Polycystic ovary syndrome (PCOS) is a common and complex endocrine disorder that affects 5-20% of reproductive age women. PCOS clinical symptoms include hirsutism, menstrual dysfunction, infertility, obesity and metabolic syndrome. There is a wide heterogeneity in clinical manifestations and metabolic complications. The pathogenesis of PCOS is not fully elucidated, but four aspects seem to contribute to the syndrome to different degrees: increased ovarian and/or adrenal androgen secretion, partial folliculogenesis arrest, insulin resistance and neuroendocrine axis dysfunction. A definitive etiology remains to be elucidated, but PCOS has a strong heritable component indicated by familial clustering and twin studies. Genome Wide Association Studies (GWAS) have identified several new risk loci and candidate genes for PCOS. Despite these findings, the association studies have explained less than 10% of heritability. Therefore, we could speculate that different phenotypes and subphenotypes are caused by rare private genetic variants. Modern genetic studies, such as whole exome and genome sequencing, will help to clarify the contribution of these rare genetic variants on different PCOS phenotypes. Arch Endocrinol Metab. 2018;62(3):352-61.

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“…3 Its overexpression in GCs is associated with higher apoptosis in PCOS. 12 To date, the factors that up-regulate and activate FOXO3 in GCs of PCOS patients are still unclear. m 6 A is the most prevalent modification of mRNA in higher eukaryotes.…”

Section: Introductionmentioning

confidence: 99%

Altered m⁶A modification is involved in up‐regulated expression of FOXO3 in luteinized granulosa cells of non‐obese polycystic ovary syndrome patients

Zhang

Deng

Liu

et al. 2020

J Cellular Molecular Medi

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Altered FoxO3 expression and apoptosis in granulosa cells of women with polycystic ovary syndrome

Abstract: Activation and overexpression of FoxO3 in granulosa cells of PCOS women correlated with higher apoptosis levels in these cells suggesting that FoxO3 may be a candidate for the higher apoptosis in granulosa cells from women with PCOS.

Cited by 56 publications

References 36 publications

Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

An update of genetic basis of PCOS pathogenesis

Altered m⁶A modification is involved in up‐regulated expression of FOXO3 in luteinized granulosa cells of non‐obese polycystic ovary syndrome patients

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Altered FoxO3 expression and apoptosis in granulosa cells of women with polycystic ovary syndrome

Abstract: Activation and overexpression of FoxO3 in granulosa cells of PCOS women correlated with higher apoptosis levels in these cells suggesting that FoxO3 may be a candidate for the higher apoptosis in granulosa cells from women with PCOS.

Cited by 56 publications

References 36 publications

Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

Ovarian mitochondrial dynamics and cell fate regulation in an androgen-induced rat model of polycystic ovarian syndrome

An update of genetic basis of PCOS pathogenesis

Altered m6A modification is involved in up‐regulated expression of FOXO3 in luteinized granulosa cells of non‐obese polycystic ovary syndrome patients

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Altered m⁶A modification is involved in up‐regulated expression of FOXO3 in luteinized granulosa cells of non‐obese polycystic ovary syndrome patients