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

Polycystic ovary syndrome (PCOS) is a heterogeneous familial disorder characterized by chronic anovulation and hyperandrogenism. This multi-system, polygenic, multi-factorial disorder is associated with an increased risk for metabolic abnormalities such as type 2 diabetes mellitus. Signs and symptoms of PCOS often emerge during the peri-pubertal years with premature pubarche (PP) being the earliest manifestation for some girls. Insulin resistance and hyperinsulinemia are important pathophysiological features that are common to both PP and PCOS. Future investigations are needed to uncover the relevant genetic and hormonal factors and identify effective interventions.
Mol Cell Endocrinol 2006 Jul 25
PMID:Puberty and polycystic ovary syndrome. 1675 May 96

Depot gonadotropin releasing hormone (GnRH) agonist (GnRHa) therapy is the treatment of choice for patients with central precocious puberty (CPP). It is still unclear whether long-term exposure to GnRHa is associated with impaired reproductive function in adulthood. The present study was performed on 46 women, former CPP patients, 12.5+/-3.7 years after the discontinuation of treatment with depot GnRHa. In a structured interview, we assessed general health status, clinical signs possibly associated with hyperandrogenism, menstrual cycle, gynaecological diseases and reproductive function. It appears that long-term treatment with depot GnRHa is safe and does not impair reproductive function. The risk of former CPP patients to develop hirsutism and/or polycystic ovary syndrome does not seem to be increased compared to the normal population but this issue needs to be addressed in further long-term follow-up studies.
Mol Cell Endocrinol 2006 Jul 25
PMID:Long-term GnRH agonist treatment for female central precocious puberty does not impair reproductive function. 1675 4

Polycystic ovary syndrome (PCOS) is a common endocrinopathy of unknown aetiology that affects women of reproductive age. During the past ten years, defective insulin activity in PCOS has been demonstrated in target tissues and causes insulin resistance and hyperinsulinaemia. Furthermore, presence of insulin receptors in the ovarian tissue and overproduction of androgens by theca cells leads to characteristic hyperandrogenaemia. Recent data suggest a divergence in post-receptor signalling pathways for insulin in its target tissues (muscle, adipocytes and ovarian tissue), where the metabolic pathway of insulin activity is defective, whereas the activation of steroidogenesis is maintained. Investigators are still searching for clues to understand the cause of this enigmatic syndrome, despite great advances in molecular medicine and genetics.
Trends Mol Med 2006 Jul
PMID:Molecular mechanisms of insulin resistance in polycystic ovary syndrome. 1676 48

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.
Mol Hum Reprod 2006 Aug
PMID:The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice. 1680 78

The present study describes the development and optimization of a cell-based reporter assay for the determination of androgen bioactivity levels in human serum samples. Towards this end, human embryonic kidney (HEK) 293 cells were cotransfected with two plasmids, one encoding the mouse mammary tumor virus (MMTV)-driven luciferase reporter gene and the other the SV40 promoter-driven human androgen receptor (AR), and a stable cell line, expressing human AR and androgen-responsive luciferase was established by antibiotic selection. RT-PCR confirmed proper transcription and stable integration of AR in the cell line. On stimulation of the cells with testosterone (T) for 24h, luciferase activity was increased in dose-dependent fashion up to 15-fold, with the minimum effective concentration of T being 0.03 nmol/l. T-induced reporter gene expression of the cells was inhibited by the anti-androgens cyproterone acetate and hydroxyflutamide. Upon stimulation with non-androgenic steroids like estradiol, progesterone, dexamethasone and cortisol, the cells showed only marginal activity except for a weak glucocorticoid effect at high concentration. The cells also responded well to various chemicals (mostly pesticides, their metabolites and common industrial chemicals) with known androgenic activity. The cell line was further optimized by measuring the levels of androgens from male and female serum samples. Our data indicated that the cells can be used to estimate androgen bioactivity in serum of females suffering from polycystic ovary syndrome (PCOS) and males of different age groups. In conclusion, we demonstrate that the bioassay based on this cell line provides a reliable method to determine serum levels of androgen bioactivity from biological samples even at the low concentrations present in female circulation. The 96-well plate format makes the assay suitable for high throughput measurements.
J Steroid Biochem Mol Biol 2006 Sep
PMID:Determination of androgen bioactivity in human serum samples using a recombinant cell based in vitro bioassay. 1689 44

Urine based gonadotropin assays provide a practical means of analyzing hormone secretion patterns. While research protocols have revealed pulsatile patterns of gonadotropins such as LH in the blood, these assays are of limited clinical use since daily venipuncture sampling is not feasible outside of a research environment. However, collection of several urine samples provides a method to achieve the same visualization of gonadotropin patterns in patients using a convenient and generally applicable technique based on analysis of the highly stable hLHbetacf for monitoring LH and hCGbetacf for monitoring pituitary hCG. We demonstrated that two different sampling techniques for analyzing these gonadotropin metabolites yielded the same information on their excretory patterns, either sampling of spot urines or collecting first morning void urines for several days. Next, we studied the core excretory patterns in several populations: menstruating and postmenopausal women from the general population, and two populations of women from a fertility center, one of which had polycystic ovaries (PCO). The PCO population was also subdivided into those with and without insulin resistance (IR). It was found that our hLHbetacf assay did not measure the form of the LH core (v-hLHbetacf) produced in subjects who were homozygous for a variant form of LH (v-LH). None of our patients tested were homozygous for the variant form of LH. It was also found that in most non-PCO (NPCO) patients, the hLHbetacf peak lasted for 7-9 days while among the PCO patients this peak frequently lasted for less than 7 days and an erratic pattern tended to appear. The overall differences in patterns between the PCO and NPCO patients were confirmed by spectral statistical methods. The prevalence of certain characteristic hLHbetacf patterns may be higher among women with PCO with a more severe clinical presentation. Use of urinary analysis of gonadotropin metabolites, especially hLHbetacf, may supplement subjective ultrasound studies with more sensitive biochemical measurements.
Mol Cell Endocrinol 2007 Jan 02
PMID:Patterns of LHbetacf among women in health and disease. 1708 20

Thiazolidinediones (TZDs) such as pioglitazone and rosiglitazone are widely used as insulin sensitizers in the treatment of type 2 diabetes. In diabetic women with polycystic ovary syndrome, treatment with pioglitazone or rosiglitazone improves insulin resistance and hyperandrogenism, but the mechanism by which TZDs down-regulate androgen production is unknown. Androgens are synthesized in the human gonads as well as the adrenals. We studied the regulation of androgen production by analyzing the effect of pioglitazone and rosiglitazone on steroidogenesis in human adrenal NCI-H295R cells, an established in vitro model of steroidogenesis of the human adrenal cortex. Both TZDs changed the steroid profile of the NCI-H295R cells and inhibited the activities of P450c17 and 3betaHSDII, key enzymes of androgen biosynthesis. Pioglitazone but not rosiglitazone inhibited the expression of the CYP17 and HSD3B2 genes. Likewise, pioglitazone repressed basal and 8-bromo-cAMP-stimulated activities of CYP17 and HSD3B2 promoter reporters in NCI-H295R cells. However, pioglitazone did not change the activity of a cAMP-responsive luciferase reporter, indicating that it does not influence cAMP/protein kinase A/cAMP response element-binding protein pathway signaling. Although peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor for TZDs, suppression of PPARgamma by small interfering RNA technique did not alter the inhibitory effect of pioglitazone on CYP17 and HSD3B2 expression, suggesting that the action of pioglitazone is independent of PPARgamma. On the other hand, treatment of NCI-H295R cells with mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) enhanced promoter activity and expression of CYP17. This effect was reversed by pioglitazone treatment, indicating that the MEK/ERK signaling pathway plays a role in regulating androgen biosynthesis by pioglitazone.
Mol Pharmacol 2007 Mar
PMID:Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2. 1713 41

Previous studies have shown that freshwater turtle shells can accumulate lactate during periods of anoxic submergence. Our objective in this study was to determine lactate uptake in other parts of the turtle's skeleton. We measured lactate concentration of 7 skeletal elements and 4 shell samples of red-eared slider turtles, Trachemys scripta, in control animals (N=12) and in animals following submergence for 4-5 days in N(2)-equilibrated water at 10 degrees C (N=8). We also collected blood samples and measured blood pH, PCO(2), and PO(2), and plasma lactate. Contralateral bone samples from 6 control turtles were analyzed for % water and mineral composition; bone from the other 6 were equilibrated with lactate solution in vitro. Anoxic submergence resulted in a combined respiratory/non-respiratory (lactic) acidosis and plasma lactate of 45.6+/-2.5 mmol l(-1). Shell and skeletal lactates all increased significantly in the anoxic animals (30.1-43.9 mmol kg(-1)) with limb bones having the highest levels and skull the least. Skeletal samples equilibrated in lactate solution in vitro for 2 days accumulated lactate in similar fashion with limb bones, except for fibula, higher, and skull significantly less than other bones. We conclude that the entire skeleton of the red-eared slider, like its shell, sequesters lactate and contributes thereby to lactic acid buffering.
Comp Biochem Physiol A Mol Integr Physiol 2007 Mar
PMID:Lactate uptake by skeletal bone in anoxic turtles, Trachemys scripta. 1718 12

SHBG (sex hormone-binding globulin) is a transport protein specific for dihydrotestosterone, testosterone and estradiol. The missense mutation in exon 8 (GAC-->AAC) causing the amino acid exchange Asp-->Asn in codon 327 (D327N) correlates according to the published data with increased SHBG levels. We studied possible association of this polymorphism with polycystic ovary syndrome (PCOS) and anthropometric and biochemical parameters in 248 PCOS patients and 109 healthy control women. The D327N polymorphism (wild-type and variant allele) was detected using PCR-RFLP method (restriction enzyme Bbs-I). For statistical evaluation chi(2) test, Mann-Whitney test, ANCOVA, ANOVA (NCSS 2004, Statgraphics Plus v.5.1, USA) were used. There was no significant difference in genotype distribution between PCOS and controls (chi(2)=1.03, p=0.59). Moreover, we did not find an association of the variant allele with plasma SHBG level, steroid hormones, or screened parameters of lipid and glucose metabolism. In conclusion, the D327N polymorphism of the SHBG gene does not influence susceptibility to PCOS.
J Steroid Biochem Mol Biol 2007 Apr
PMID:Role of D327N sex hormone-binding globulin gene polymorphism in the pathogenesis of polycystic ovary syndrome. 1725 3

Follistatin has been reported as a candidate gene for polycystic ovary syndrome (PCOS) from linkage and association studies. Acting to regulate the development of ovarian follicles and as an antagonist to aromatase activity, alterations in follistatin function or expression may result in key features of PCOS such as reduced serum FSH, impaired ovarian follicle development and augmented ovarian androgen production. We investigated polymorphisms in the FST gene to determine if genetic variation is associated with susceptibility to PCOS or key phenotypic features of PCOS patients in a case-control association study. One hundred and seventy-three PCOS patients of Caucasian descent (mean age 30.0 +/- 4.8 years), conforming to the NIH diagnostic criteria, were recruited from a clinical practice database and 107 normal ovulating women (mean age 38.8 +/- 13.4 years) were recruited from the general community as control subjects. Morphometric data, biochemistry and genomic DNA were collected from study subjects and genotyping was performed on seven Single nucleotide polymorphisms (SNPs) in the FST gene region. Allele frequencies of the SNPs were rs1423560 G/C (0.99/0.01), rs3797297 C/A (0.80/0.20), rs11745088 C/G (0.98/0.02), rs3203788 A/T (0.98/0.02) and rs1062809 G/C (1.00/-), rs1127760 A/T (0.98/0.02) and rs1127761 A/T (0.98/0.02), and these were not significantly different between the PCOS and control groups (P < 0.05). Statistical analysis revealed significant associations between the SNP rs3797297 and sex hormone-binding globulin (P = 0.04) and free androgen index (FAI) (P < 0.01). We conclude that FST is not a susceptibility locus for PCOS; however, the SNP rs3797297 from FST gene was associated with androgenic markers for PCOS and may be of importance in the hyperandrogenaemia of the disease.
Mol Hum Reprod 2007 Apr
PMID:Polymorphism of the follistatin gene in polycystic ovary syndrome. 1728 12


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>