scholarly journals Granulosa Cell Survival and Proliferation Are Altered in Polycystic Ovary Syndrome

2008 ◽  
Vol 93 (3) ◽  
pp. 881-887 ◽  
Author(s):  
M. Das ◽  
O. Djahanbakhch ◽  
B. Hacihanefioglu ◽  
E. Saridogan ◽  
M. Ikram ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary Syndrome ◽  
Cell Survival ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Ovary Syndrome ◽  
Survival Factor ◽  
Effector Caspase

Abstract Context: Polycystic ovary syndrome (PCOS) represents the most common endocrine abnormality in women of reproductive age. The cause of PCOS remains largely unknown, but studies suggest an intrinsic ovarian abnormality. Objective: The objective of the study was to test our hypothesis that differences in granulosa cell proliferation and apoptosis may underlie abnormalities that affect follicular development. Design: Granulosa cells were prepared from follicular fluid aspirated from 4- to 8-mm follicles of unstimulated ovaries during routine laparoscopy or laparotomy from women with anovulatory PCOS and those with regular ovulatory cycles. Setting: The study was conducted at a university hospital. Patients: Fourteen women with anovulatory PCOS and nine women with regular ovulatory cycles participated in the study. Main Outcome Measures: Immunocytochemistry on granulosa cells to investigate apoptotic and proliferation rates, together with real-time RT-PCR to analyze gene expression profiles of apoptotic regulators, was measured. Results: Significantly lower apoptotic rates were found in granulosa cells from patients with PCOS, compared with women with regular ovulatory cycles (P = 0.004). Lower apoptotic rates were associated with decreased levels of the apoptotic effector caspase-3 (P = 0.001) and increased levels of the anti-apoptotic survival factor cellular inhibitor of apoptosis proteins-2 in the PCOS group that were coupled to higher proliferation rates (P = 0.032). Gene expression profiling confirmed the immunocytochemical findings. Conclusions: Our findings indicate that there are significant differences in the rate of cell death and proliferation in granulosa cell populations in PCOS patients. These are associated with decreased expression of apoptotic effectors and increased expression of a cell survival factor. These results provide new insights that may be useful in developing specific therapeutic intervention strategies in PCOS.

scholarly journals Letrozole-Induced Polycystic Ovary Syndrome Attenuates Cystathionine-β Synthase Gene Expression in the Ovaries of Female Sprague Dawley Rats

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1244-1244
Author(s):  
Amanda Bries ◽  
Joe Webb ◽  
Brooke Vogel ◽  
Claudia Carrillo ◽  
Aileen Keating ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polycystic Ovary Syndrome ◽  
Mrna Expression ◽  
Polycystic Ovary ◽  
Elevated Serum ◽  
Reproductive Age ◽  
Sprague Dawley ◽  
Polycystic Ovaries ◽  
Ovary Syndrome ◽  
Sd Rats

Abstract Objectives Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 10% of reproductive age women and leads to hyperandrogenism, abnormal menstrual cycles, and polycystic ovaries. Moreover, PCOS has been associated with elevated serum homocysteine; however, the characterization of one-carbon metabolism (OCM) in PCOS remains incomplete. The aim of our research was to examine OCM in a genetic and chemically-induced rodent model of PCOS: 1) viable yellow Agouti (Avy) mice; and 2) letrozole (Let)-induced Sprague Dawley (SD) rats. Methods Five wk old female Avy mice (N = 18), their lean controls (N = 18), and SD rats (N = 36) were acclimated for one wk. Following acclimation, the animals were placed on a modified standard AIN93G diet (energy, %: 50.4, carbohydrate; 17.3, protein; and 32.3, fat). Rats were randomly assigned to Let (1 g/kg BW) treatment or vehicle (carboxymethylcellulose) control that was administered via a subcutaneously implanted slow-release pellet every 30-d. For both models, 12 animals were randomly assigned to be euthanized during proestrus at one of the following ages: 8, 16 or 24 wk. Bodyweight and estrous cycles were measured daily. Ovaries were collected to assess gene expression of OCM. These data were analyzed using linear mixed models to determine the main effects of age and treatment at a significance level of P < 0.05. Results Letrozole significantly reduced the occurrence of proestrus and estrus stages (P = 0.0001 and P = 0.006, respectively). Additionally, Let-induced rats had increased BW compared to control rats, across all age groups (P < 0.0001). In contrast, Avy mice weighed less than their controls by 24 wk of age (P < 0.0001). Cystathionine-β synthase (CBS) mRNA expression was downregulated in the Let-induced vs. control rats at 16 (59%; P < 0.05) and 24 (77%; P < 0.01) wk of age. As expected, Cyp19A1, aromatase mRNA was downregulated in the Let-induced rats (P = 0.02). Interestingly, betaine-homocysteine s-methyltransferase (BHMT) mRNA increased as a function of age in Let-induced rats (P = 0.03). Conclusions These data demonstrate that Letrozole-induced PCOS temporally decreases ovarian CBS mRNA expression; whereas, BHMT mRNA is upregulated as a function of age. Funding Sources This work was supported by the National Institute of Child Health and Human Development.

Granulosa Cell Survival and Proliferation Are Altered in Polycystic Ovary Syndrome

2008 ◽  
Vol 63 (9) ◽  
pp. 579-580
Author(s):  
M Das ◽  
O Djahanbakhch ◽  
B Hacihanefioglu ◽  
E Saridogan ◽  
M Ikram ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Cell Survival ◽  
Granulosa Cell ◽  
Polycystic Ovary ◽  
Ovary Syndrome ◽  
Cell Survival And Proliferation

scholarly journals Multiomics Analysis Reveals Molecular Abnormalities in Granulosa Cells of Women With Polycystic Ovary Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Rusong Zhao ◽  
Yonghui Jiang ◽  
Shigang Zhao ◽  
Han Zhao
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Reproductive Age ◽  
Differentially Expressed ◽  
Steroid Biosynthesis ◽  
Expression Array ◽  
Ovary Syndrome ◽  
Molecular Abnormalities ◽  
Genome Wide

Polycystic ovary syndrome (PCOS) is the most common complex endocrine and metabolic disease in women of reproductive age. It is characterized by anovulatory infertility, hormone disorders, and polycystic ovarian morphology. Regarding the importance of granulosa cells (GCs) in the pathogenesis of PCOS, few studies have investigated the etiology at a single “omics” level, such as with an mRNA expression array or methylation profiling assay, but this can provide only limited insights into the biological mechanisms. Here, genome-wide DNA methylation together with lncRNA-miRNA-mRNA profiles were simultaneously detected in GCs of PCOS cases and controls. A total of 3579 lncRNAs, 49 miRNAs, 669 mRNAs, and 890 differentially methylated regions (DMR)-associated genes were differentially expressed between PCOS cases and controls. Pathway analysis indicated that these differentially expressed genes were commonly associated with steroid biosynthesis and metabolism-related signaling, such as glycolysis/gluconeogenesis. In addition, we constructed ceRNA networks and identified some known ceRNA axes, such as lncRNAs-miR-628-5p-CYP11A1/HSD17B7. We also identified many new ceRNA axes, such as lncRNAs-miR-483-5p-GOT2. Interestingly, most ceRNA axes were also closely related to steroid biosynthesis and metabolic pathways. These findings suggest that it is important to systematically consider the role of reproductive and metabolic genes in the pathogenesis of PCOS.

scholarly journals Chemerin regulates autophagy to participate in polycystic ovary syndrome

2021 ◽  
Vol 49 (11) ◽  
pp. 030006052110583
Author(s):  
Xiaodong Luo ◽  
Yangyang Gong ◽  
Liuyun Cai ◽  
Lei Zhang ◽  
Xiaojing Dong
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cells ◽  
Rat Model ◽  
Polycystic Ovary ◽  
Mammalian Target Of Rapamycin ◽  
Ectopic Expression ◽  
Reproductive Age ◽  
Ovary Syndrome ◽  
Phosphoinositide 3 Kinase

Objective Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age. Chemerin has recently been discovered as a novel adipokine associated with obesity and metabolic syndrome. Excessive autophagy activity and overexpression of autophagy-related genes in follicular granulosa cells are important mechanisms of PCOS. This study aimed to investigate the effect of chemerin on autophagy in PCOS. Methods A rat model of PCOS was established by subcutaneous injection of testosterone propionate under a high-fat diet. Expression levels of chemerin and its receptor CMKLR1 were determined by real-time polymerase chain reaction and western blot. Proliferation and apoptosis of human granulosa cells in vitro and expression of autophagy-related genes were examined using bafilomycin A1 (autophagy inhibitor) and Torin1 (autophagy inducer). Results Chemerin and CMKLR1 expression were significantly increased in the ovary in a rat model of PCOS. Ectopic expression of chemerin promoted the proliferation and inhibited the apoptosis of COV434 cells. Ectopic expression of chemerin also induced autophagy by inhibiting the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Conclusions Chemerin and CMKLR1 were overexpressed in PCOS rats. Chemerin promoted autophagy through inhibiting the PI3K/Akt/mTOR pathway, and may provide a potential target and biomarker of PCOS.

scholarly journals miR-3188 Regulates proliferation and apoptosis of granulosa cells by targeting KCNA5 in the polycystic ovary syndrome

2021 ◽  
Author(s):  
Shan Zhou ◽  
Liang Xia ◽  
Yuanyuan Chen ◽  
Weiying Guo ◽  
Jinxing Hu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Polycystic Ovary Syndrome ◽  
Cell Viability ◽  
Granulosa Cell ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Healthy Controls ◽  
Ovarian Dysfunction ◽  
Ovary Syndrome

Abnormal proliferation of granulosa cells is implicated in ovarian dysfunction and dysregulated folliculogenesis in the polycystic ovary syndrome (PCOS). Aberrant microRNA (miRNA) expression might contribute to disordered folliculogenesis and granulosa cell proliferation in PCOS. This study aimed to investigate the roles of miR-3188 in ovarian dysfunction, as well as the mechanism involved in granulosa cell proliferation in PCOS. Firstly, peripheral blood samples were isolated from PCOS patients and healthy controls, and qRT-PCR analysis demonstrated a dramatic increase in miR-3188 in PCOS patients when compared to the healthy controls. Secondly, miR-3188 overexpression increased cell viability of the granulosa-like tumor cell line (KGN). However, cell viability of KGN was repressed by interference with miR-3188. MiR-3188 promoted cell cycle of KGN through increasing cyclinD1 and decreasing p21 levels. Moreover, cell apoptosis was suppressed by miR-3188 in KGN, indicated by enhanced Bcl-2, and reduced Bax and cleaved caspase-3 levels, whereas knockdown of miR-3188 resulted in opposite effects. Lastly, potassium voltage-gated channel subfamily A member 5 (KCNA5) was verified as a target of miR-3188. KCNA5 expression was decreased and displayed negative correlation with miR-3188 levels in PCOS patients. Overexpression of KCNA5 attenuated the promotive effects of miR-3188 on cell viability and cell cycle in KGN. In conclusion, miR-3188, a key miRNA enhanced in PCOS, promoted granulosa cell proliferation through down-regulation of KCNA5, providing a new therapeutic target for PCOS.

scholarly journals High-Throughput Sequencing Profiles About lncRNAs and mRNAs of Ovarian Granulosa Cells in Polycystic Ovary Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanjun Zheng ◽  
Yuehong Bian ◽  
Richao Wu ◽  
Wei Chen ◽  
Linlin Fu ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Expression Profiles ◽  
Reproductive Age ◽  
Endocrine Disorders ◽  
Clinical Parameters ◽  
Ovary Syndrome ◽  
Predictive Values ◽  
Ovarian Granulosa Cells

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age, which is characterized by ovulatory dysfunction, clinical and/or biochemical androgen excess, polycystic ovaries on ultrasound and genetic heterogeneity. It was well-accepted that many lncRNAs and mRNAs were associated with PCOS, however, remain unclear. Therefore, the purpose of our study was to examine different expression profiles of lncRNAs and mRNAs in ovarian granulosa cells (GCs) in PCOS and Controls, and identify the correlation between lncRNAs, mRNAs and clinical parameters. Sixty five PCOS patients and 65 Controls were enrolled in this study and adopted standard long agonist protocols or GnRH antagonist protocols. Then 6 GCs samples in each group were subjected to high-thoughput sequencing and the remaining samples were used for the further verification by quantitative real-time PCR (qRT-PCR). Gene Oncology (GO), Kyoto Encyclopedia Genes and Genomes (KEGG) enrichment analysis were performed. We predicted the relationship between lncRNAs and mRNAs by Cytoscape software. According to the expression level of lncRNAs, mRNAs and the clinical parameters, we also explored their relationship and evaluate their predictive values for embryos quality and PCOS. We identified 1,049 differential expressed lncRNAs and 3,246 mRNAs (fold-change ≥2, p-value < 0.05). Seven lncRNAs (NONHSAT101926.2, NONHSAT136825.2, NONHSAT227177.1, NONHSAT010538.2, NONHSAT191377.1, NONHSAT230904.1, ENST00000607307) and 3 mRNAs (EREG, ENTPD6, YAP1) were validated consistent with sequence profile. Seven lncRNAs were related to hormone level and follicle counts, 3 mRNAs had connections with lipid metabolism. The area under curve (AUC) of 7 lncRNAs were valuable in distinguishing patients with PCOS from Controls. The AUC of NONHSAT230904.1 and NONHSAT227177.1 were 0.6807 and 0.6410, respectively, for distinguishing whether the rate of high-quality embryos exceeds 50%. Our study showed that the GCs lncRNAs and mRNAs were involved in the occurrence and development of PCOS, which contribute to clarify the pathogenesis mechanism of PCOS.

scholarly journals Role of RAB5A in FSHR-mediated signal transduction in human granulosa cells

Reproduction ◽  
2018 ◽  
Vol 155 (6) ◽  
pp. 505-514 ◽  
Author(s):  
Kai Zhu ◽  
Shang Li ◽  
Jiansheng Liu ◽  
Yan Hong ◽  
Zi-Jiang Chen ◽  
...  
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Granulosa Cells ◽  
Polycystic Ovary ◽  
Small Gtpase ◽  
Reproductive Age ◽  
Mrna Levels ◽  
Obese Patients ◽  
Ovary Syndrome ◽  
Human Granulosa Cells ◽  
A Genome

Polycystic ovary syndrome, a common condition characterized by endocrine dysfunction, menstrual irregularity, anovulation and polycystic ovaries, affects 5–7% of reproductive-age women. RAB5B, which is identified by a genome-wide association study as a risk locus for this syndrome, encodes a small GTPase involved in control of receptor internalization and early endosome fusion. We found that RAB5A mRNA levels in luteinized granulosa cells of obese patients with polycystic ovary syndrome were lower than in those of obese women without the syndrome. RAB5A regulated follicle-stimulating hormone (FSH)-mediated translocation of the FSH receptor (FSHR) from the membrane to the cytoplasm and the subsequent FSH–FSHR signaling pathway. We showed that RAB5A negatively regulated aromatase expression and estradiol synthesis in human granulosa cells in association with changes in FSHR levels by way of the cAMP/PKA/CREB pathway. The regulation of FSHR by RAB5A may have been associated with two transcription factors, USF1 and USF2. In conclusion, RAB5A gene was abnormally expressed in luteinized granulosa cells of obese patients with polycystic ovary syndrome, which may help explain high FSHR levels found in this syndrome.

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