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1.
Toxicol Lett ; 332: 42-55, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32629074

RESUMO

Obesity is associated with several female reproductive complications, such as polycystic ovary syndrome (PCOS). The exact mechanism of this relationship remains unclear. Few previous studies using diet containing refined carbohydrate (HCD) leading to obesity have been performed and it is unclear if HCD is linked with reproductive dysfunctions. In this investigation, we assessed whether subchronic HCD exposure results in reproductive and other irregularities. Female rats were fed with HCD for 15 days and metabolic outcomes and reproductive tract morphophysiology were assessed. We further assessed reproductive tract inflammation, oxidative stress (OS) and fibrosis. HCD rats displayed metabolic impairments, such as an increase in body weight/adiposity, adipocyte hypertrophic, abnormal lipid profile, glucose tolerance and insulin resistance (IR) and hyperleptinemia. Improper functioning of the HCD reproductive tract was observed. Specifically, irregular estrous cyclicity, high LH levels and abnormal ovarian morphology coupled with reduction in primordial and primary follicle numbers was observed, suggesting ovarian reserve depletion. Improper follicular development and a reduction in antral follicles, corpora lutea and granulosa layer area together with an increase in cystic follicles were apparent. Uterine atrophy and reduction in endometrial gland (GE) number was observed in HCD rats. Reproductive tract inflammation, OS and fibrosis were seen in HCD rats. Further, strong positive correlations were observed between body weight/adiposity and IR with estrous cycle length, cystic follicles, ovarian reserve, GE and other abnormalities. Thus, these data suggest that the subchronic HCD exposure led to PCOS-like features, impaired ovarian reserve, GE number, and other reproductive abnormalities in female rats.


Assuntos
Carboidratos da Dieta/toxicidade , Reserva Ovariana/efeitos dos fármacos , Ovário/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Adiposidade/efeitos dos fármacos , Animais , Peso Corporal , Dieta , Ciclo Estral/efeitos dos fármacos , Feminino , Fibrose , Intolerância à Glucose/sangue , Intolerância à Glucose/induzido quimicamente , Resistência à Insulina , Leptina/sangue , Metabolismo dos Lipídeos , Folículo Ovariano/efeitos dos fármacos , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Ratos , Ratos Wistar
2.
PLoS Med ; 17(6): e1003132, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32574161

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common, complex genetic disorder affecting up to 15% of reproductive-age women worldwide, depending on the diagnostic criteria applied. These diagnostic criteria are based on expert opinion and have been the subject of considerable controversy. The phenotypic variation observed in PCOS is suggestive of an underlying genetic heterogeneity, but a recent meta-analysis of European ancestry PCOS cases found that the genetic architecture of PCOS defined by different diagnostic criteria was generally similar, suggesting that the criteria do not identify biologically distinct disease subtypes. We performed this study to test the hypothesis that there are biologically relevant subtypes of PCOS. METHODS AND FINDINGS: Using biochemical and genotype data from a previously published PCOS genome-wide association study (GWAS), we investigated whether there were reproducible phenotypic subtypes of PCOS with subtype-specific genetic associations. Unsupervised hierarchical cluster analysis was performed on quantitative anthropometric, reproductive, and metabolic traits in a genotyped cohort of 893 PCOS cases (median and interquartile range [IQR]: age = 28 [25-32], body mass index [BMI] = 35.4 [28.2-41.5]). The clusters were replicated in an independent, ungenotyped cohort of 263 PCOS cases (median and IQR: age = 28 [24-33], BMI = 35.7 [28.4-42.3]). The clustering revealed 2 distinct PCOS subtypes: a "reproductive" group (21%-23%), characterized by higher luteinizing hormone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels, and a "metabolic" group (37%-39%), characterized by higher BMI, glucose, and insulin levels with lower SHBG and LH levels. We performed a GWAS on the genotyped cohort, limiting the cases to either the reproductive or metabolic subtypes. We identified alleles in 4 loci that were associated with the reproductive subtype at genome-wide significance (PRDM2/KAZN, P = 2.2 × 10-10; IQCA1, P = 2.8 × 10-9; BMPR1B/UNC5C, P = 9.7 × 10-9; CDH10, P = 1.2 × 10-8) and one locus that was significantly associated with the metabolic subtype (KCNH7/FIGN, P = 1.0 × 10-8). We developed a predictive model to classify a separate, family-based cohort of 73 women with PCOS (median and IQR: age = 28 [25-33], BMI = 34.3 [27.8-42.3]) and found that the subtypes tended to cluster in families and that carriers of previously reported rare variants in DENND1A, a gene that regulates androgen biosynthesis, were significantly more likely to have the reproductive subtype of PCOS. Limitations of our study were that only PCOS cases of European ancestry diagnosed by National Institutes of Health (NIH) criteria were included, the sample sizes for the subtype GWAS were small, and the GWAS findings were not replicated. CONCLUSIONS: In conclusion, we have found reproducible reproductive and metabolic subtypes of PCOS. Furthermore, these subtypes were associated with novel, to our knowledge, susceptibility loci. Our results suggest that these subtypes are biologically relevant because they appear to have distinct genetic architecture. This study demonstrates how phenotypic subtyping can be used to gain additional insights from GWAS data.


Assuntos
Síndrome do Ovário Policístico/genética , Adulto , Análise por Conglomerados , Feminino , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Síndrome do Ovário Policístico/classificação , Síndrome do Ovário Policístico/patologia
3.
DNA Cell Biol ; 39(8): 1458-1466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32513025

RESUMO

Polycystic ovary syndrome (PCOS) is a multifactorial disorder characterized by irregular menstrual problems, hyperandrogenism, and presence of polycystic ovaries. Till date, molecular mechanism underlying PCOS remains elusive. Recently mitochondrial displacement loop (D-loop) variants have been identified to be novel players in the pathogenesis of PCOS. At present, rare variants, besides common variants, are also the focus of research as it is believed to make essential contribution to the risk of complex diseases. However, rare and low hetroplasmic variants in mitochondrial D-loop are still not investigated in PCOS women. Furthermore, variants in light-strand origin of DNA replication (OriL) of mitochondrial DNA (mtDNA) have not been explored in PCOS. Hence, in this study, we investigated rare to common mitochondrial D-loop and OriL region variants obtained using mtDNA next-generation sequencing in women with PCOS. Furthermore, we also assessed mtDNA copy number, a biomarker of mitochondrial dysfunction (MD) in women with PCOS, as the variants in mtDNA are known to be associated with low mtDNA copy number in PCOS women. A total of 67 D-loop variants including 6 novel variants were identified in 30 PCOS women. Among 67 variants, 29 variants were reported in PCOS women. A single variant, 5746A was found in OriL region in two PCOS women. Both transition and transversion variants were found but transition variants occur at very high frequency compared with transversions (82.35% vs. 17.64%, respectively). As transition variants in mtDNA are known to arise because of polymerase γ errors, occurrence of high transition rates indicates that most mutation arises because of defect in replication errors that causes mtDNA damage leading to MD. Furthermore, mtDNA copy number was found to be low in women with PCOS compared with healthy control women suggesting that MD may be the contributing factor in the pathogenesis of PCOS.


Assuntos
Variações do Número de Cópias de DNA/genética , DNA Mitocondrial/genética , Mitocôndrias/genética , Síndrome do Ovário Policístico/genética , Adolescente , Adulto , Replicação do DNA/genética , DNA Mitocondrial/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Mitocôndrias/patologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/patologia , Testosterona/sangue , Tireotropina/sangue , Adulto Jovem
4.
Gene ; 754: 144903, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32540374

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among reproductive-age women. The circRNA-miRNA axis functions in various diseases progression have been partially revealed in the past two decades. However, little is known about the role of the circRNA-miRNA axis in PCOS progression. MicroRNA miR-760, which is characterized by tissue-specific, has been studied in several cancers. Firstly, we found that miR-760 expression was decreased in PCOS tissues insulin treated GCs, KGN and SVOG cells. Secondly, The CCK-8 and apoptosis experiment results suggested that downregulated miR-760 promoted cell proliferation ability and suppressed apoptosis activity in KGN and SVOG cells. Then, the bioinformatic analysis result indicated that circPUM1 was a potential sponge to miR-760. By performing AGO2-RIP, RNA pull-down, Luciferase reporter, and qRT-PCR experiments, we demonstrated that circPUM1 acted as a molecular sponge to miR-760, and decreased miR-760 expression. Moreover, it was found that the promotive effect of circPUM1 was mediated by regulating miR-760. Collectively, our findings suggest that circPUM1 promotes PCOS progression through sponging to miR-760. We may provide a promising therapeutic target for PCOS.


Assuntos
Regulação da Expressão Gênica , Células da Granulosa/patologia , MicroRNAs/genética , Síndrome do Ovário Policístico/patologia , RNA Circular/genética , Apoptose , Proliferação de Células , Células Cultivadas , Progressão da Doença , Feminino , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo
5.
Gene ; 741: 144560, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169631

RESUMO

SNV (single nucleotide variation) in estrogen receptor (ESR1 and ESR2) genes are susceptibility markers for complex diseases, such as cancer, metabolic disorders and women infertility. We explored six widely used SNVs in ESR1 (rs2234693, rs9340799, rs3798577, rs3020314) and ESR2 (rs1256049, rs4986938) in polycystic ovary syndrome (PCOS) in women from Tunisia (n = 254) compared to controls (n = 170). Genotyping was performed by RFLP-PCR or real-time PCR and analyzed in GoldenHelix statistical package. Logistic regression revealed association of rs2234693, rs3798577 and rs3020314 (ESR1) and rs1256049 (ESR2), the association of rs2234693 (C/T) being the strongest with P < 4.81 × 10-6, 2.88 × 10-5 after Bonferroni correction, OR 0.31, 95%CI (0.18-0.53)). Correlations were found with LH, LH/FSH or hyperandrogenism and even more significant with metabolic syndrome (rs9340799) and hyperglycemia (rs3798577). Among 14 haplotypes reconstructed in ESR1gene, four haplotypes (H1 to H4) were associated with PCOS the strongest being that of H1 (P < 0.002) supported by Bonferroni (P < 0.033) and permutation tests (P < 4 x10-4). In haplotype trend regression, concordant correlations were found with insulin resistance (P < 0.033) for H2 and with high blood pressure for H3 (P < 0.048). While these data revealed influential role on metabolic rather and hormonal features of PCOS, the association of rs2234693 was the strongest among all ethnic populations studied thus far giving a new insight on estrogen receptor gene variation in distant North African populations and their role in metabolic alteration of PCOS.


Assuntos
Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Adulto , Estrogênios/genética , Estrogênios/metabolismo , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Infertilidade Feminina/genética , Infertilidade Feminina/patologia , Modelos Logísticos , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/patologia , Polimorfismo de Fragmento de Restrição/genética , Polimorfismo de Nucleotídeo Único/genética , Tunísia
6.
Ann Endocrinol (Paris) ; 81(1): 18-27, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32127169

RESUMO

BACKGROUND: We aimed to identify key genes and microRNAs (miRNAs) associated with the development of polycystic ovary syndrome (PCOS). METHODS: GSE84376 mRNA microarray data (15 PCOS granulosa cells and 13 control granulosa cells) and GSE34526 mRNA microarray data (7 PCOS granulosa cells and 3 control granulosa cells) were downloaded from the Gene Expression Omnibus (GEO) database. First, differentially expressed gene (DEG) analysis, gene set enrichment analysis (GSEA) for differentially expressed mRNAs, and protein-protein interaction (PPI) network analysis were conducted. Next, miRNA-target genes were analyzed and functions predicted, and a competing endogenous RNA (ceRNA) network was constructed. Finally, the relationship between miR-486-5p and PRELID2 was experimentally validated. RESULTS: Spleen tyrosine kinase (SYK), major histocompatibility complex, class II, DR alpha (HLA-DRA), and interleukin 10 (IL-10) were important nodes in the PPI network. Interestingly, HLA-DRA was significantly enriched in phagosomes mediated by Staphylococcus aureus infection, and in IL-10 enriched during S. aureus infection. One miRNA (miR-486-5p) and a single target gene (PRELID2) were obtained from the ceRNA network. Further experiments showed that miR-486-5p is upregulated and PRELID2 is downregulated in PCOS patient granulosa cells, and that miR-486-5p targets the PRELID2 3'UTR. Topological property analysis showed that hsa-miR-4687-5p downregulation and hsa-miR-4651 upregulation determined the levels of most mRNAs. Levels of the hsa-miR-4651 target gene were significantly enriched in the leukocyte transendothelial migration pathway. CONCLUSIONS: Our results suggest that HLA-DRA and IL-10 may contribute to PCOS progression via phagosome enriched by S. aureus infection, while miR-486-5p may be implicated in follicular development in PCOS by targeting PRELID2. Besides, miR-4651 may be involved in inflammation via leukocyte transendothelial migration, by regulating its target gene. These findings may indicate new directions and constitute a breakthrough in studying the pathophysiology of PCOS.


Assuntos
MicroRNAs/genética , Síndrome do Ovário Policístico/genética , RNA Mensageiro/genética , Adulto , Estudos de Casos e Controles , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Células da Granulosa/metabolismo , Humanos , MicroRNAs/metabolismo , Análise em Microsséries , Síndrome do Ovário Policístico/patologia , RNA Mensageiro/metabolismo
7.
J Ovarian Res ; 13(1): 32, 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197626

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex reproduction and endocrine disorder of women in the reproductive age. Spearmint (Mentha spicata L.) has anti-androgenic activity and flaxseed (Linum usitatissimum L.) contains phytoestrogen and was reported to improve PCOS conditions. This study aimed to evaluate PCOS conditions following administration of a mixture of these two plants. METHODS: Twenty-four rats with regular cycles were randomly divided into four groups as control (C) and treatment-control (TC) received a combination of spearmint extract (SE) + flaxseed extract (FE). PCOS was induced in PCOS and treatment (T) groups by a single intramuscular injection of estradiol valerate. The treatment group received a combination of SE and FE for 30 days, 7 weeks after injection of estradiol valerate. Estrous cycles were monitored for 10 days and in the last day animals were sacrificed, ovaries were collected for the histomorphometric study and the serum levels of progesterone, testosterone, estradiol, and dehydroepiandrosterone (DHEA) were measured. RESULT: Significant rise in progesterone and a decrease in testosterone and estradiol with no significant change of DHEA in the T group, was observed in comparison with the PCOS group (P < 0.05). No significant difference noticed between T and control groups (C &CT) regarding evaluated hormones. A significant increase in primary, pre-antral and antral follicles noticed in the T group compared to the PCOS group. The number of cystic follicles decreased in the T group compared with the PCOS group. Granulosa layer thickness increased while the thickness of theca decreased significantly in the T group compared to the PCOS group (P < 0.05). No significant endocrine or histological differences noticed between C and TC groups. CONCLUSION: A combination of flaxseed and spearmint extract improved the endocrine profile and the histomorphometric features of the ovary in the T group compared to the PCOS group.


Assuntos
Sistema Endócrino/efeitos dos fármacos , Linho/química , Mentha spicata/química , Ovário/metabolismo , Ovário/patologia , Extratos Vegetais/farmacologia , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/patologia , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Sinergismo Farmacológico , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios/sangue , Hormônios/metabolismo , Imuno-Histoquímica , Extratos Vegetais/química , Síndrome do Ovário Policístico/tratamento farmacológico , Ratos
8.
BMC Med Genet ; 21(1): 30, 2020 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-32050935

RESUMO

BACKGROUND: PCOS is a common disorder of women due to genetic, endocrine and environmental effects that manifests from puberty. The rs9939609 variant of fat mass and obesity associated (FTO) gene is linked to metabolic derangement in PCOS. We previously identified FTO (rs9939609) as a susceptibility locus for PCOS among Sri Lankan women and also explored the role of kisspeptin. Associated factors of the FTO candidate gene among South Asians with PCOS are unknown. METHODS: This study aimed to determine the association between FTO (rs9939609) polymorphism with clinical (BMI, acanthosis nigricans, hirsutism) and biochemical (serum kisspeptin and testosterone levels) characteristics of PCOS in a cohort of Sri Lankan women. Genetic and clinical data including serum kisspeptin and testosterone concentrations of our previously reported cases (n = 55) and controls (n = 110) were re-analyzed, specifically for an association with rs9939609 variant of FTO gene. RESULTS: Logistic regression analysis (AA - OR = 5.7, 95% CI = 2.41-13.63, p < 0.05) and genetic inheritance analysis (AA - OR = 5.49, 95%CI = 2.34-12.88, p < 0.05) showed that FTO (rs9939609) polymorphism is significantly associated with PCOS and its metabolic manifestations. Serum testosterone was significantly higher in affected women with mutant genotypes (AA+AT) than with the normal allele (TT) (p < 0.05). Although serum kisspeptin was higher in subjects with PCOS and mutant alleles than controls, this difference was not significant (p > 0.05). CONCLUSION: FTO gene variant rs9939609 is associated with hyperandrogenemia and metabolic manifestations of PCOS among women of Sri Lankan descent with the well-characterized phenotype. Serum kisspeptin and the FTO genotypes lack a significant association when adjusted for confounders.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome do Ovário Policístico/genética , Adolescente , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Feminino , Regulação da Expressão Gênica/genética , Genótipo , Humanos , Pessoa de Meia-Idade , Fenótipo , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único/genética , Sri Lanka
9.
PLoS One ; 15(2): e0229351, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32078641

RESUMO

Polycystic ovary syndrome (PCOS) affects around 10% of young women, with adverse consequences on fertility and cardiometabolic outcomes. PCOS appears to result from a genetic predisposition interacting with developmental events during fetal or perinatal life. We hypothesised that PCOS candidate genes might be expressed in the fetal ovary when the stroma develops; mechanistically linking the genetics, fetal origins and adult ovarian phenotype of PCOS. In bovine fetal ovaries (n = 37) of 18 PCOS candidate genes only SUMO1P1 was not expressed. Three patterns of expression were observed: early gestation (FBN3, GATA4, HMGA2, TOX3, DENND1A, LHCGR and FSHB), late gestation (INSR, FSHR, and LHCGR) and throughout gestation (THADA, ERBB4, RAD50, C8H9orf3, YAP1, RAB5B, SUOX and KRR1). A splice variant of FSHB exon 3 was also detected early in the bovine ovaries, but exon 2 was not detected. Three other genes, likely to be related to the PCOS aetiology (AMH, AR and TGFB1I1), were also expressed late in gestation. Significantly within each of the three gene groups, the mRNA levels of many genes were highly correlated with each other, despite, in some instances, being expressed in different cell types. TGFß is a well-known stimulator of stromal cell replication and collagen synthesis and TGFß treatment of cultured fetal ovarian stromal cells inhibited the expression of INSR, AR, C8H9orf3 and RAD50 and stimulated the expression of TGFB1I1. In human ovaries (n = 15, < 150 days gestation) many of the same genes as in bovine (FBN3, GATA4, HMGA2, FSHR, DENND1A and LHCGR but not TOX3 or FSHB) were expressed and correlated with each other. With so many relationships between PCOS candidate genes during development of the fetal ovary, including TGFß and androgen signalling, we suggest that future studies should determine if perturbations of these genes in the fetal ovary can lead to PCOS in later life.


Assuntos
Biomarcadores/análise , Desenvolvimento Fetal/genética , Regulação da Expressão Gênica no Desenvolvimento , Ovário/patologia , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único , Adulto , Animais , Bovinos , Feminino , Genes Reguladores , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Ovário/metabolismo , Síndrome do Ovário Policístico/genética , Gravidez , Células Estromais/metabolismo , Células Estromais/patologia
10.
DNA Cell Biol ; 39(8): 1401-1409, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32077751

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common female reproductive metabolisms. It is an endocrine disease that affects reproductive women and often exhibits with hyperandrogenemia, insulin resistance (IR), low inflammation, and an increased risk of type 2 diabetes mellitus, metabolic syndrome, and cardiovascular events such as hypertension and dyslipidemia in patients. However, the molecular mechanism of PCOS is still unclear. Recently, an increasing number of studies have shown that the oxidative stress induced by mitochondrial dysfunction has negative effects on IR, lipid metabolism, and follicular development, suggesting that mitochondrial dysfunction plays an essential role in the development of PCOS. Abnormal mitochondrial DNA copy number in patients with PCOS, and mitochondrial gene mutations, has been the focus of research in recent years, and functional mitochondrial diseases have been gradually accepted as a related factor in PCOS. This review is intended to summarize and discuss previous and recent studies and findings on the connections between mitochondrial dysfunction and PCOS.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Mitocôndrias/genética , Síndrome do Ovário Policístico/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/genética , Dislipidemias/patologia , Feminino , Humanos , Hiperandrogenismo/genética , Hiperandrogenismo/patologia , Hipertensão/genética , Hipertensão/patologia , Resistência à Insulina/genética , Mitocôndrias/patologia , Mutação/genética , Síndrome do Ovário Policístico/patologia
11.
BMC Med Genet ; 21(1): 14, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941453

RESUMO

BACKGROUND: The DENND1A gene is one of the most important sites associated with polycystic ovary syndrome (PCOS). We attempted to analyze the correlation between five single nucleotide polymorphisms (SNPs) in the DENND1A gene and the development of PCOS. METHODS: A total of 346 PCOS patients and 225 normal ovulatory women were involved in the case-control study. Clinical variables and hormones were recorded. According to the Hap Map database, five tagging SNPs (rs2479106, rs2768819, rs2670139, rs2536951 and rs2479102) in the DENND1A gene were identified. The TaqMan probe and the PCR-RFLP (restriction fragment length polymorphism) methods were used for revealing these genotypes. TaqMan Genotype Software was used to analyze the alleles of the five SNPs. RESULTS: Linkage disequilibrium and the gene frequency analysis demonstrated that the CCGGG haplotype might increase the risk of PCOS (P = 0.038, OR = 1.89, 95% CI = 1.027-3.481). Significant differences were found in genotypic and allelic distributions at the rs2536951 and rs2479102 loci between PCOS women and controls (P <  0.001). The LH levels and LH/FSH ratios were higher in PCOS patients than in the control group. A detailed analysis revealed that for the rs2479106 locus, these two values were significantly different in the control subjects who had AA, AG and GG genotypes (P = 0.013 and P = 0.007, respectively), and for the rs2468819 locus, these two values were significantly different among the PCOS patients with AA, AG and GG genotypes (P = 0.013 and 0.002, respectively). CONCLUSIONS: The tagging SNPs rs2479106 and rs2468819 in the DENND1A gene are associated with PCOS in the Chinese population, whereas rs2670139, rs2536951 and rs2479102 are not correlated with PCOS in the same population.


Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Fatores de Troca do Nucleotídeo Guanina/genética , Síndrome do Ovário Policístico/genética , Adulto , Alelos , China/epidemiologia , Feminino , Genótipo , Haplótipos/genética , Humanos , Síndrome do Ovário Policístico/epidemiologia , Síndrome do Ovário Policístico/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
Mol Cell Biochem ; 465(1-2): 187-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894528

RESUMO

Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age. Although much is understood concerning the pathology of PCOS, further investigation into the influence of microribonucleic acids (miRNAs) on the proliferation of ovarian granulosa cells (GCs) is needed. This study investigated the role of specific miRNAs in ovarian dysfunction of PCOS and its effect on the proliferation of GCs. Initially, miRNA profiling was performed on the ovarian cortexes of 15 rats in which PCOS had been induced and 15 rats without PCOS (non-PCOS). This mechanical study was performed on ovarian GCs extracted from human chorionic gonadotrophin (hCG)-induced rats. Insulin was used to treat GCs to establish the PCOS cell model. Increased Equus caballus mir-9119 expression was observed and confirmed in the insulin-induced model of PCOS in GCs (GC-PCOS) as well as in the hCG-induced rats when compared to non-PCOS rats and cells. Observation and confirmation were carried out through both miRNA array and quantitative PCR. In contrast, downregulation of the nuclear factor kappa B (NFκB) p65 was observed in the PCOS cell model. Additionally, annexin V, FITC, and propidium iodide flow cytometry showed overexpression of miR-9119-induced apoptosis. In this study, we revealed that miR-9119 inhibition regulates p65 expression levels in insulin-treated GCs by binding to the 3'-untranslated of p65. Additionally, regulation of p65 expression was positively correlated with the expression of the double-stranded RNA endoribonuclease DICER. Moreover, RNA silencing/overexpression of p65 affected the functional role of miR-9119. In conclusion, GCs of PCOS, the expression of miR-9119, and targeted NFκB/p65-DICER axis are upregulated in order to maintain cell viability and prevent apoptosis, thereby promoting Anti-Müllerian hormone production in GCs. This study may provide a new understanding of the mechanism of GC dysfunction.


Assuntos
Regulação Enzimológica da Expressão Gênica , Células da Granulosa/metabolismo , MicroRNAs/metabolismo , Síndrome do Ovário Policístico/metabolismo , Ribonuclease III/biossíntese , Animais , Hormônio Antimülleriano/metabolismo , Sobrevivência Celular , Feminino , Células da Granulosa/patologia , Cavalos , Humanos , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/patologia , Ratos , Fator de Transcrição RelA/metabolismo
13.
Arch Gynecol Obstet ; 301(3): 809-816, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31927625

RESUMO

PURPOSE: To investigate the prevalence of type 2 diabetes mellitus (T2DM) at the 5-year follow-up after polycystic ovarian syndrome (PCOS) diagnosis compared between lean and overweight/obese groups. METHODS: This retrospective cohort study included 400 prediabetes PCOS women who attended our clinic. Participants were divided into either the lean group (body mass index [BMI]: < 23 kg/m2) or the overweight/obese group (BMI: ≥ 23 kg/m2). Patient demographic, clinical characteristics, metabolic profiles, and laboratory values were collected and compared between groups at baseline and during follow-up for 5 years. RESULTS: At the end of the follow-up, overweight/obese group had a higher risk for developing T2DM than lean group (11.5% vs. 0.5%, p < 0.001). Lean group had a lower incidence of hypertension (3% vs. 38.5%, p < 0.001) and dyslipidemia (35% vs. 53.5%, p < 0.001) than overweight/obese group. The factors found to be independently associated with increased risk for developing T2DM were BMI ≥ 23 kg/m2 (odds ratio [OR]: 1.075, p = 0.047), non-use of oral combined contraceptive pills (OR: 0.312, p = 0.028), and impaired fasting glucose at baseline (OR: 38.167, p < 0.001). CONCLUSIONS: Overweight/obese PCOS patients were found to be at significantly higher risk for developing T2DM than lean PCOS patients. Higher BMI, IFG at baseline, and non-use of oral contraceptive pills found to be independent predictors of T2DM in PCOS.


Assuntos
Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade/complicações , Sobrepeso/complicações , Síndrome do Ovário Policístico/etiologia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Incidência , Síndrome do Ovário Policístico/patologia , Prevalência , Estudos Retrospectivos , Adulto Jovem
14.
Arch Physiol Biochem ; 126(2): 183-186, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-30450993

RESUMO

Polycystic Ovary Syndrome is a multifactorial reproductive problem and a leading cause of female infertility worldwide. Evidences have shown that Oxidative Stress and decreased antioxidant status are often linked with PCOS. Insulin Resistance in PCOS patients ranges from 50% to 70% and may encourage OS by production of reactive oxygen species.Objective: Our study determines serum MDA levels along with plasma glucose, serum insulin, and insulin resistance in obese and nonobese PCOS subjects.Materials and methods: A case control study was conducted on diagnosed 100 PCOS patients and 100 controls. Fasting plasma glucose was measured by enzymatic method. Insulin was estimated by chemiluminescent microparticle immunoassay using Abott Architect i 2000 SR analyser. Insulin resistance was calculated by HOMA-IR. Malonaldehyde is determined as Thiobarbituric acid reactive substances.Results: CRP and serum MDA levels were increased in women with PCOS irrespective of obesity compared to their respective controls with a p value of < .001. However, though fasting glucose, serum insulin, and IR were increased in both obese and nonobese women with PCOS compared to their BMI adjusted controls with p value of < .001, the values were within reference range in nonobese women.Conclusion: Our study suggests that women with PCOS have oxidative stress and elevated CRP irrespective of obesity. However, hyperinsulinemia and Insulin resistance are seen only in obese women with PCOS, indicating that these women are at high risk for developing low grade inflammation and cardiovascular diseases.


Assuntos
Proteína C-Reativa/metabolismo , Hiperinsulinismo/sangue , Resistência à Insulina , Malondialdeído/sangue , Obesidade/sangue , Síndrome do Ovário Policístico/sangue , Adolescente , Adulto , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Estudos de Casos e Controles , Jejum/sangue , Feminino , Humanos , Hiperinsulinismo/diagnóstico , Hiperinsulinismo/patologia , Insulina/sangue , Obesidade/diagnóstico , Obesidade/patologia , Ovário/metabolismo , Ovário/patologia , Estresse Oxidativo , Síndrome do Ovário Policístico/diagnóstico , Síndrome do Ovário Policístico/patologia , Fatores de Risco
15.
Artif Cells Nanomed Biotechnol ; 48(1): 197-205, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31851829

RESUMO

Polycystic ovarian syndrome (PCOS) is a typical disease of female endocrine and metabolic abnormalities. miR-155, famous as a multifunctional miRNA, promotes the proliferation, migration and invasion of human cancer cells. Therefore, we aimed to explore its regulation mechanism in PCOS. BrdU incorporation and apoptosis assay were used to test KGN cell survival. Luciferase activity experiment was employed to test targeting link between miR-155 and programmed cell death 4 (PDCD4). Migration and invasion assay were operated to examine the influence of miR-155 and PDCD4 in migration and invasion of KGN cells. In addition, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay and western blot analysis were utilized to measure expression of miR-155 and other relative factors. We found that expression of miR-155 was high in PCOS patients' tissues and it promoted proliferation, migration and invasion in KGN cells. Further studies found that PDCD4 was down-regulated by miR-155 and was a target of miR-155. Overexpression of PDCD4 promoted cell apoptosis to mitigate PCOS. Besides, up-regulation of PDCD4 suppressed PI3K/AKT and JNK signal pathways. To sum up, miR-155 promoted proliferation, migration, invasion and the activation of PI3K/AKT and JNK pathways in KGN cells through negatively regulating PDCD4.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Movimento Celular/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Síndrome do Ovário Policístico/patologia , Proteínas de Ligação a RNA/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Síndrome do Ovário Policístico/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética
16.
J Ethnopharmacol ; 248: 112300, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31606536

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Mahuang-Tang (MHT) has traditionally been used in Asia to treat a variety of diseases, such as fever without sweating, joint pain, lower back pain, asthma, and gynecological conditions. Polycystic ovary syndrome (PCOS) is a kind of gynecological disease that causes amenorrhea, infertility, and menopausal and urogenital disorders that could benefit from MHT treatment. AIM OF THE STUDY: In this study, we examined the effects of MHT on ovarian hormones and steroidogenic enzymes in female PCOS rats. METHODS AND RESULTS: The PCOS rat model was induced by Letrozole, and an in vivo evaluation of whether the dietary consumption of MHT improved the PCOS-like symptoms was conducted. The luteinizing hormone (LH) level and luteinizing hormone/follicular-stimulating hormone (LH/FSH) ratio increased in PCOS rats but decreased following MHT treatment. In the PCOS rats, the reduced estrogen level was restored to that of normal controls with MHT treatment in serum. The transcription level(s) of gonadotropin receptors (Fshr and Lhr), steroid receptors (Pgr, and Esr1) and steroidogenic enzymes (Cyp19a1, Hsd3b1, Hsd17a1, and Cyp11a1) changed under the PCOS condition, and were regulated by MHT treatment in the ovaries of PCOS rats. The reproductive tissues of Letrozole-induced PCOS rats were restored into estrogenic condition from androgen environments. CONCLUSION: These results suggest that MHT ameliorates the symptoms of PCOS by improving the dysregulation of ovarian steroids and steroidogenic enzymes in PCOS rats.


Assuntos
Medicina Tradicional Coreana , Síndrome do Ovário Policístico/tratamento farmacológico , Animais , Feminino , Hormônios/sangue , Letrozol , Medicina Tradicional , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/patologia , Ratos Sprague-Dawley , Receptores da Gonadotropina/genética , Receptores de Esteroides/genética , Esteroide Hidroxilases/genética
17.
J Clin Endocrinol Metab ; 105(1)2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31529097

RESUMO

CONTEXT: Women with polycystic ovarian syndrome (PCOS) have decreased growth hormone (GH), which can result in increased visceral adiposity (VAT) and impaired vascular function. GH-releasing hormone, a dipeptidyl peptidase-4 (DPP4) substrate, stimulates GH secretion. OBJECTIVE: We tested the hypothesis that DPP4 inhibition increases GH and improves glucose levels and vascular function in women with PCOS. METHODS: Eighteen women with PCOS participated in a double-blind, crossover study. They received sitagliptin either 100 mg or placebo daily for 1 month, with crossover treatments separated by an 8-week washout. During each treatment, women underwent a 75-gram oral glucose tolerance test (OGTT) and assessments of vascular function and body composition. Overnight GH secretion was assessed via venous sampling every 10 minutes for 12 hours and analyzed using an automated deconvolution algorithm. RESULTS: During OGTT, sitagliptin increased glucagon-like peptide-1 (P < 0.001), early insulin secretion (from mean [± SD] insulinogenic index 1.9 ± 1.2 to 3.2 ± 3.1; P = 0.02), and decreased peak glucose (mean -17.2 mg/dL [95% CI, -27.7 to -6.6]; P < 0.01). At 1 month, sitagliptin decreased VAT (from 1141.9 ± 700.7 to 1055.1 ± 710.1 g; P = 0.02) but did not affect vascular function. Sitagliptin increased GH half-life (from 13.9 ± 3.6 to 17.0 ± 6.8 min, N = 16; P = 0.04) and interpulse interval (from 53.2 ± 20.0 to 77.3 ± 38.2 min, N = 16; P < 0.05) but did not increase mean overnight GH (P = 0.92 vs placebo). CONCLUSIONS: Sitagliptin decreased the maximal glucose response to OGTT and VAT. Sitagliptin did not increase overnight GH but increased GH half-life and the interpulse interval. CLINICAL TRIAL REGISTRATION: This study was registered at www.clinicaltrials.gov as NCT02122380 prior to enrollment of the first participant.


Assuntos
Glicemia/metabolismo , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Gordura Intra-Abdominal/efeitos dos fármacos , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Adolescente , Adulto , Biomarcadores/análise , Glicemia/análise , Glicemia/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Seguimentos , Teste de Tolerância a Glucose , Hormônio do Crescimento Humano/metabolismo , Humanos , Pessoa de Meia-Idade , Síndrome do Ovário Policístico/patologia , Prognóstico , Adulto Jovem
18.
J Cell Physiol ; 235(2): 1339-1348, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31256441

RESUMO

This study aimed to investigate the molecular mechanisms underlying the roles of metformin (MET) and Sorafenib (SOR) in the treatment of endometrial hyperplasia (EH) in polycystic ovary syndrome (PCOS). Effects of MET and SOR on the area of endometrium and myometrium were detected. Western blot analysis and immunohistochemistry assays were carried out to detect the levels of mammalian target of rapamycin complex 1 (mTORC1), mTORC2, LC3-II, P62, and Caspase-3 in rats and cultured cells. Furthermore, cell counting kit-8 assay and flow cytometry analysis was carried out to determine the apoptotic profiles of treated cells. MET and SOR could apparently decrease the areas of endometrium and myometrium in PCOS. MET notably enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC1 and P62. Similarly, SOR also enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC2 and P62. Treatment with MET and SOR significantly inhibited the proliferation of HCC-94 and HEC-1-A cells while promoting their apoptosis by upregulating the expression of Caspase-3. In cells treated with MET, the expression of mTORC1 and LC3-II was upregulated while the expression of P62 was downregulated. Similarly, in cells treated with SOR, the expression of mTORC2 and LC3-II was also upregulated while the expression of P62 was also downregulated. Furthermore, MET showed no effect on mTORC2 expression, while SOR showed no effect on mTORC1 expression. In this study, we suggested that MET and SOR alleviated the risk of EH in PCOS via the mTORC1/autophagy/apoptosis axis and mTORC2/autophagy/apoptosis axis, respectively.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hiperplasia Endometrial/patologia , Metformina/farmacologia , Síndrome do Ovário Policístico/patologia , Sorafenibe/farmacologia , Animais , Proteínas Reguladoras de Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Sinergismo Farmacológico , Hiperplasia Endometrial/metabolismo , Feminino , Síndrome do Ovário Policístico/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Biomed Res Int ; 2019: 9193236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31828146

RESUMO

Polycystic ovary syndrome (PCOS) is a chronic metabolic disease that is associated with obesity and adipose tissue dysfunction. This study aimed to explore the roles of Dicer (an enzyme that processes primary microRNAs) and microRNAs in PCOS. Protein levels were detected by western blotting, and mRNA and microRNA levels were detected by RT-PCR. Dicer-deficient pre-adipocytes were established by lentiviral transfection, and an miR-223 mimic and miR-223 inhibitor were used to overexpress and inhibit miR-223, respectively. 3T3-L1 cells were induced to differentiate into mature adipocytes by IBMX, insulin, and dexamethasone. The degree of differentiation was determined by oil red O staining. An insulin resistance model was established by exposing mature adipocytes to excessive glucose and insulin. The protein levels of Dicer and Ago2 in adipose tissues of PCOS patients were significantly lower than those in control females. A Dicer-deficient 3T3-L1 cell model was successfully established, whose proliferation was inhibited significantly. Insulin-resistant mature adipocytes expressed significantly less Dicer protein than control cells. The differentiation of Dicer-deficient 3T3-L1 cells and their expression of miR-223 and marker genes associated with adipose differentiation were reduced significantly. Furthermore, 3T3-L1 cells showed a weaker ability to develop into mature adipocytes when miR-223 expression was inhibited. An miR-223 mimic was used to recover the differentiation block induced by Dicer deficiency. This rescued the expression of genes associated with adipose differentiation, although the differentiation block was not efficiently rescued. It is concluded that insulin resistance may contribute to the decreased levels of Dicer protein in adipose tissue of PCOS patients. This suggests that dysfunction of Dicer plays a significant role in obesity of PCOS patients. miR-223 is a key factor in Dicer-regulated adipose differentiation, and other microRNAs may be involved in the process.


Assuntos
RNA Helicases DEAD-box/genética , Resistência à Insulina/genética , MicroRNAs/genética , Síndrome do Ovário Policístico/genética , Ribonuclease III/genética , Células 3T3-L1 , Adipogenia/genética , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/patologia , Adulto , Animais , Proteínas Argonauta/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Feminino , Fertilização In Vitro , Líquido Folicular/metabolismo , Regulação da Expressão Gênica/genética , Células da Granulosa/metabolismo , Humanos , Camundongos , Síndrome do Ovário Policístico/patologia , Adulto Jovem
20.
Oxid Med Cell Longev ; 2019: 8218650, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772710

RESUMO

Background/Aims: Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by abnormal hormone levels in peripheral blood and poor-quality oocytes. PCOS is a pathophysiological syndrome caused by chronic inflammation and oxidative stress. The aim of this study was to investigate the mechanism of melatonin regulation on androgen production and antioxidative damage in granulosa cells from PCOS patients with hypoestrogenia and hyperandrogenia. Methods: Cumulus-oocyte complexes were collected from PCOS patients who had low levels of estrogen in follicular fluids. Results: Melatonin triggered upregulation of cytochrome P450 family 19 subfamily A member 1 (CYP19A1) expression via the extracellular signal-regulated kinase pathway in luteinized granulosa cells. As a result, conversion of androgen to 17ß-estradiol was accelerated. We also found that melatonin significantly reduced the levels of inducible nitric oxide (NO) synthetase and NO in luteinized granulosa cells. Levels of transcripts encoding NF-E2-related factor-2 and its downstream target heme oxygenase-1 were also increased, leading to anti-inflammatory and antioxidant effects. We also found that melatonin could improve oocyte development potential. Conclusion: Our preliminary results showed that melatonin had a positive impact on oocyte quality in PCOS patients with hypoestrogenia and hyperandrogenia.


Assuntos
Androgênios/sangue , Antioxidantes/uso terapêutico , Estrogênios/metabolismo , Células da Granulosa/metabolismo , Heme Oxigenase-1/metabolismo , Hiperandrogenismo/tratamento farmacológico , Melatonina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Antioxidantes/farmacologia , Feminino , Humanos , Melatonina/farmacologia , Síndrome do Ovário Policístico/patologia , Regulação para Cima
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