Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, affecting 5-10% of females of reproductive age. Currently, little is known about the changes in whole proteins between PCOS and normal ovaries. In the present study, a proteomic approach comprised two-dimensional gel electrophoresis (2DE) analysis and mass spectroscopy was used to identify proteins and examine expression patterns in three PCOS and normal ovaries. One hundred and ten protein spots were separated and showed different intensities between PCOS and normal ovaries. Sixty-nine proteins associated with cellular metabolism and physiological process were identified from 72 spots. Fifty-four proteins were up-regulated in PCOS ovaries and 15 other proteins were up-regulated in normal ovaries. These data demonstrate, for the first time, the complexity in the regulation of ovarian protein expression in human PCOS, and will provide important insight for a better understanding of the pathogenetic mechanisms underlying this clinical disorder.
Mol Hum Reprod 2007 Aug
PMID:Proteomic analysis of human ovaries from normal and polycystic ovarian syndrome. 1755 64

Polycystic ovarian syndrome (PCOS) is universally recognised as the commonest endocrinopathy of women. The definition and the aetiological hypotheses of PCOS are continuously evolving to accommodate expanding knowledge on the syndrome, which is now known to be more complex than purely a reproductive disorder. Increased androgen synthesis, disrupted folliculogenesis and insulin resistance lie at the pathophysiological core of PCOS. An intriguing concept involves the perpetuation of a vicious circle with endocrine/reproductive and metabolic components. An unfavourable metabolic environment may unmask genetic traits of ovarian dysfunction, and the unfolding endocrine derangement could further aggravate the metabolic disarray. This article reviews the molecular mechanisms known to underlie the ovarian and metabolic abnormalities characterising PCOS. The putative interdependence between reproductive and metabolic aspects of PCOS, and therapeutic implications for the management of PCOS, are also discussed.
Expert Rev Mol Med 2008 Jan 30
PMID:Polycystic ovarian syndrome: pathophysiology, molecular aspects and clinical implications. 1823 Jan 93

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age today. Women with PCOS often demonstrate defective ovarian steroid biosynthesis and present with hyperandrogenemia. Moreover, 50-70% of PCOS women are insulin resistant and hyperinsulinemic. Insulin acts on the ovary via its own receptor and interacts with gonadotrophins, modulating steroidogenesis. The precise role of insulin and the molecular mechanisms that take place are not yet completely explicated. This review will be focused on insulin's action on the ovary and other target tissues, describing the intracellular signaling pathways implicated in steroidogenesis and their defects in women with PCOS.
J Steroid Biochem Mol Biol 2008 Apr
PMID:Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS). 1844 Feb 23

Women with polycystic ovary syndrome (PCOS) are characterized by excess androgen secretion and anovulatory infertility as a cause of follicular maturation arrest, and they are also associated with insulin resistance and obesity. Recently, it was suggested that one of the etiologies for PCOS is an abnormality of steroid hormones, and excessive secretion of androgen. The endoplasmic reticular cytochrome P450, 17alpha-hydroxylase (CYP17A), plays a key role in the mechanism of steroid hormones such as adrenal and gonadal steroid biosynthesis. Therefore, we studied the association between single nucleotide polymorphisms (SNPs) of the A1 allelic variant of the CYP17 gene and PCOS in a Korean population. The study recruited 134 Korean women with PCOS and 100 healthy women as controls. Using the HapAnalyzer, the genotype of the CYP17A1 polymorphism in PCOS and control patients were analyzed. We considered a p-value lower than 0.05 to be statistically significant. After genotypic analysis, we found seven SNPs of the CYP17A1 gene in a large population of subjects. The frequency of seven SNPs had no significant association with PCOS. However, one haplotype (ht3) had a p-value of p=0.001, suggesting that it may be associated with the pathogenesis of PCOS in a Korean population.
Int J Mol Med 2008 Aug
PMID:Association study for single nucleotide polymorphisms in the CYP17A1 gene and polycystic ovary syndrome. 1863 81

Conventional estrogen receptor alpha knockout (neo-ERalphaKO, neo-ERalpha(-/-)) mice contain a truncated and chimeric ERalpha fusion protein that retains 35% estrogen-dependent transactivation activity, and therefore the in vivo ERalpha function is difficult to study thoroughly. Furthermore, these neo-ERalpha(-/-) mice cannot be used for tissue and temporal specific ERalpha deletion. Therefore, there is a clear need to establish a floxed ERalpha mouse line that can knockout ERalpha specifically and completely in each selected cell type. Here we generated floxed ERalpha mice using a self-excising ACN (tACE-Cre/Neo) cassette. Mating the floxed ERalpha mice with ACTB-Cre mice produces a deletion of the floxed allele disrupting the reading frame of the ERalpha transcript so that no ERalpha protein is detected in the ACTB-Cre/ERalpha(-/-) mice. Expression of ERalpha target genes, such as G-6-PD and lactoferrin, is diminished by over 90% in the ACTB-Cre/ERalpha(-/-) uterus, but not in the neo-ERalpha(-/-) uterus. Furthermore, we also validated that ACTB-Cre/ERalpha(-/-) females have a hypoplastic internal genital tract, polycystic ovaries with hemorrhagic follicles, infertility, and higher body weight. Together, our data clearly demonstrate that the newly established floxed ERalpha mouse is a reliable mouse model for future studies of ERalpha roles in vivo in the selective estrogen target tissues. The complete knockout of ERalpha in the ACTB-Cre/ERalpha(-/-) mice will also provide an improved mouse model to study the role of ERalpha in vivo.
Mol Cell Biochem 2009 Jan
PMID:Generation and characterization of a complete null estrogen receptor alpha mouse using Cre/LoxP technology. 1895 38

Polycystic ovary syndrome (PCOS) is a heterogeneous condition with unknown etiology and is considered to be the most common endocrine disorder in women of reproductive age. Two meta-analyses are presented here concerning the association of Plasminogen Activator Inhibitor 1 (PAI-1) 4G/5G polymorphism and the methylene-tetrahydrofolate reductase (MTHFR) C677T polymorphism with the risk of developing PCOS. Seven studies were included concerning PAI-1 (1538 cases, 710 controls) and six studies concerning MTHFR C677T (223 cases, 392 controls). Overall, a significant association was found for PAI-1, with the odds ratio (OR) for 4G carriers versus 5G homozygotes being equal to 1.600 (95% CI 1.052, 2.434) with strong evidence for dominant inheritance. There was however a large between-studies variability (I(2) = 67.3%). No evidence was found for association of MTHFR C677T polymorphism with PCOS (OR for the TT+CT versus CC comparison equal to 0.940 with 95% CI 0.561, 1.575). No evidence of publication bias was found in these meta-analyses. PAI-1 4G/5G polymorphism seems to be associated with the risk of developing PCOS. Further studies are needed in order to investigate the etiologic mechanism behind this association, as well as the interrelations with other components of the metabolic syndrome (hypertension, diabetes, etc.).
Mol Hum Reprod 2009 Jan
PMID:Plasminogen activator inhibitor-1 4G/5G and 5,10-methylene-tetrahydrofolate reductase C677T polymorphisms in polycystic ovary syndrome. 2270 71

Although subclinical inflammation and oxidative stress are implicated in the aetiology of diabetes, there are hardly any studies in prediabetes. Therefore, we made an attempt to study the gene expression pattern of certain inflammatory/oxidative genes using lymphocytes from Type 2 diabetic patients, impaired glucose tolerance (IGT), and normal glucose tolerance (NGT) subjects. Compared to NGT group, interleukin-6, tumor necrosis factor-alpha (TNF-alpha), p(22)Phox NADPH oxidase, and thioredoxin interacting protein (TXNIP) mRNA levels were higher and suppressor of cytokine signaling (SOCS-3) mRNA was lower in subjects with IGT and diabetes. The mean (+/-SE) levels of thiobarbituric acid reactive substances and protein carbonyl content were also elevated in glucose intolerant subjects. In multiple linear regression analysis, TXNIP and TNF-alpha showed a significant association with HbA1c even after adjusting for TBARS and PCO (TXNIP: beta = 1.70, P < 0.01; TNF-alpha: beta = 1.86, P < 0.01). Increased subclinical inflammation/oxidation is seen in Asian Indians with not only Type 2 diabetes but also IGT.
Mol Cell Biochem 2009 Apr
PMID:Subclinical inflammation/oxidation as revealed by altered gene expression profiles in subjects with impaired glucose tolerance and Type 2 diabetes patients. 1911 8

The aim of this work was to study gene expression patterns of cultured cumulus cells from lean and overweight-obese polycystic ovary syndrome (PCOS) patients using genome-wide oligonucleotide microarray. The study included 25 patients undergoing in vitro fertilization and intra-cytoplasmic sperm injection: 12 diagnosed with PCOS and 13 matching controls. Each of the groups was subdivided into lean (body mass index (BMI) < 24) and overweight (BMI > 27) subgroups. The following comparisons of gene expression data were made: lean PCOS versus lean controls, lean PCOS versus overweight PCOS, all PCOS versus all controls, overweight PCOS versus overweight controls, overweight controls versus lean controls and all overweight versus all lean. The largest number of differentially expressed genes (DEGs), with fold change (FC) |FC| >or= 1.5 and P-value < 0.01, was found in the lean PCOS versus lean controls comparison (487) with most of these genes being down-regulated in PCOS. The second largest group of DEGs originated from the comparison of lean PCOS versus overweight PCOS (305). The other comparisons resulted in a much smaller number of DEGs (174, 109, 125 and 12, respectively). In the comparison of lean PCOS with lean controls, most DEGs were transcription factors and components of the extracellular matrix and two pathways, Wnt/beta-catenin and mitogen-activated protein kinase. When comparing overweight PCOS with overweight controls, most DEGs were of pathways related to insulin signaling, metabolism and energy production. The finding of unique gene expression patterns in cumulus cells from the two PCOS subtypes is in agreement with other studies that have found the two to be separate entities with potentially different pathophysiologies.
Mol Hum Reprod 2009 Feb
PMID:Gene expression microarray profiles of cumulus cells in lean and overweight-obese polycystic ovary syndrome patients. 1914 87

Unlike the well-established roles of androgen and androgen receptor (AR) in males, the functions of this steroid and its receptor in the ovary are still unclear. For decades, androgen and AR have long been considered to play a negative (at least not a positive) role in mammalian oocyte maturation. However, recent studies by us and others showed their positive influence in promoting meiotic maturation. On the other hand, rapid non-genomic effects of androgens have been observed and are now generally accepted as contributing to the physiological effects of the steroids and their related receptors in somatic cells, and this has stimulated us to explore the complex roles of AR in the ovary. Based on the classic dogma and new findings, we collected evidence to propose that the expression of AR shifts from the oocytes to the theca cells and finally disappears in the oocytes during evolution. It is suggested that the non-genomic pathway involving androgen and AR in the mammalian oocytes, unlike somatic cells, cells will undergo elimination. The function of androgen and AR in promoting meiotic maturation may have been replaced gradually by gonadotrophins. Moreover, a possible relationship between AR and polycystic ovary syndrome is also discussed, which might provide a clue for the pathology of the disease.
Mol Hum Reprod 2009 Mar
PMID:Androgen receptor's destiny in mammalian oocytes: a new hypothesis. 1919 57

Polycystic ovary syndrome (PCOS) is characterized by excessive theca cell androgen secretion, dependent upon LH, which acts through the intermediacy of 3',5'-cyclic adenosine monophosphate (cAMP). cAMP signaling pathways are controlled through regulation of its synthesis by adenylyl cyclases, and cAMP degradation by phosphodiesterases (PDEs). PDE8A, a high-affinity cAMP-specific PDE is expressed in the ovary and testis. Leydig cells from mice with a targeted mutation in the Pde8a gene are sensitized to the action of LH in terms of testosterone production. These observations led us to evaluate the human PDE8A gene as a PCOS candidate gene, and the hypothesis that reduced PDE8A activity or expression would contribute to excessive ovarian androgen production. We identified a rare variant (R136Q; NM_002605.2 c.407G > A) and studied another known single nucleotide polymorphism (SNP) (rs62019510, N401S) in the PDE8A coding sequence causing non-synonymous amino acid substitutions, and a new SNP in the promoter region (NT_010274.16:g.490155G > A). Although PDE8A kinetics were consistent with reduced activity in theca cell lysates, study of the expressed variants did not confirm reduced activity in cell-free assays. Sub-cellular localization of the enzyme was also not different among the coding sequence variants. The PDE8A promoter SNP and a previously described promoter SNP did not affect promoter activity in in vitro assays. The more common coding sequence SNP (N401S), and the promoter SNPs were not associated with PCOS in our transmission/disequilibrium test-based analysis, nor where they associated with total testosterone or dehydroepiandrosterone sulfate levels. These findings exclude a significant role for PDE8A as a PCOS candidate gene, and as a Las major determinant of androgen levels in women.
Mol Hum Reprod 2009 Aug
PMID:PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women. 1948 4


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