Association between copy-number variation on metabolic phenotypes and HDL-C levels in patients with polycystic ovary syndrome.

Polygenic diseases with a broad phenotypic spectrum, such as polycystic ovary syndrome (PCOS), present a particular challenge in terms of identifying the underlying genetic mechanisms, nevertheless genetic variants have impact on the individual phenotype. We aimed to determine if next to genetic variations like SNPs further mechanisms might play a role in the pathogenesis of PCOS. We examined the effect of copy-number variations (CNVs) on metabolic phenotypes in PCOS.

A key role of GARP in the immune suppressive tumor microenvironment.

In melanoma patients, one of the main reasons for tumor immune escape and therapy failure is the immunosuppressive tumor microenvironment. Herein, suppressive immune cells and inhibitory factors secreted by the tumor itself play a central role.In the present study we show that the Treg activation marker GARP (glycoprotein A repetitions predominant), known to induce peripheral tolerance in a TGF-β dependent way, is also expressed on human primary melanoma.

How Soluble GARP Enhances TGFβ Activation.

GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFβ (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity.

Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network.

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors.

Translating Treg Therapy in Humanized Mice.

Regulatory T cells (Treg) control immune cell function as well as non-immunological processes. Their far-reaching regulatory activities suggest their functional manipulation as a means to sustainably and causally intervene with the course of diseases. Preclinical tools and strategies are however needed to further test and develop interventional strategies outside the human body.

Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo.

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2.

Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4⁺ T cells.

Glycoprotein A repetitions predominant (GARP) is expressed on the surface of activated human regulatory T cells (Treg) and regulates the bioavailability of transforming growth factor-β (TGF-β). GARP has been assumed to require membrane anchoring. To investigate the function of GARP in more detail, we generated a soluble GARP protein (sGARP) and analyzed its impact on differentiation and activation of human CD4⁺ T cells.

Genetic variants in central metabolic genes influence some but not all relations of inflammatory markers in a collective with polycystic ovary syndrome.

Patients with polycystic ovary syndrome (PCOS) suffer, in addition to reproductive disturbances, from symptoms of the metabolic syndrome like insulin resistance, elevated coronary risk and visceral obesity. Genes with confirmed associations to the metabolic syndrome are also candidate genes for a relationship to metabolic parameters of the PCOS syndrome. The study presented indicates that genetic variants of the transcription factors LXRα or PPARγ and the PON-1 or the IGF-2 cluster are associated with altered metabolic phenotypes in PCOS patients.

Genetic variations in SREBP-1 and LXRα are not directly associated to PCOS but contribute to the physiological specifics of the syndrome.

The polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder consisting of reproductive disturbances associated with all aspects of the metabolic syndrome and genetic components in the pathology of this complex disease is very likely. Accordingly, variations in single genes might affect specific features of PCOS and thereby help to define different subgroups. SREBP-1 or LXRα have been shown to be genetically linked to lipid metabolism or insulin sensitivity.

A functional GNAQ promoter haplotype is associated with altered Gq expression and with insulin resistance and obesity in women with polycystic ovary syndrome.

Objectives: The G-protein Gq, encoded by GNAQ, is involved in glucose metabolism. The GNAQ promoter harbours three polymorphisms. The TT(-695/-694)GC polymorphism was already shown to affect Gq transcription.

Regulation of the expression of inducible nitric oxide synthase.

Nitric oxide (NO) generated by the inducible isoform of nitric oxide synthase (iNOS) is involved in complex immunomodulatory and antitumoral mechanisms and has been described to have multiple beneficial microbicidal, antiviral and antiparasital effects. However, dysfunctional induction of iNOS expression seems to be involved in the pathophysiology of several human diseases. Therefore iNOS has to be regulated very tightly.

Maladaptive coping with illness in women with polycystic ovary syndrome.

Objective: To investigate associations between active and passive coping, psychiatric symptoms of depression and anxiety, and quality of life in women with polycystic ovary syndrome (PCOS). To assess the relative contribution of these coping strategies to reduced quality of life in an attempt to clarify the possible relevance of coping for impaired psychosocial well-being in PCOS.

Design: Internet-based survey.

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).

Background: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS.

Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome.

Background: Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH.

Medical treatment of hirsutism.

Hirsutism is usually the result of an underlying adrenal, ovarian, or central endocrine abnormality mainly due to polycystic ovary syndrome but may also be idiopathic or drug induced. The aim of medical treatment of hirsutism is to rectify any causal hormonal balance, slow down or stop excessive hair growth, and improve the aesthetic appearance of hirsutism, thereby positively affecting the patient's quality of life. Today, for the majority of women, a monotherapy with oral contraceptives that have antiandrogenic activity is recommended as a first-line treatment for hirsutism.

Mood and sexual function in polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) fail to conform with societal norms for outer appearance. Many PCOS patients thus feel stigmatized in the sense of a loss of "feminine identity." In addition to somatic impairment, mood disturbances such as depression and limitations in emotional well-being, quality of life, and life satisfaction, the diagnosis of PCOS also has a negative impact on sexual self-worth and sexual satisfaction.

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance.

Objective: Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR.

Retinol-binding protein 4 levels are elevated in polycystic ovary syndrome women with obesity and impaired glucose metabolism.

Objective: Insulin resistance and obesity are common features of the polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4), a new fat-derived adipokine, has been described to be elevated in obesity and type 2 diabetes. The aim of the present study was to investigate whether serum RBP4 levels are correlated with metabolic parameters, indices of insulin resistance, and endocrine variables in German PCOS women.

Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome.

Background: One of the main criteria to establish a diagnosis of polycystic ovary syndrome (PCOS) is hyperandrogenemia. Recent observations suggest that total testosterone may not be a sensitive marker for the detection of androgen excess. The aim of the present study was to compare the value of different androgen determinations for diagnosis of PCOS.

Calpain-10 variants and haplotypes are associated with polycystic ovary syndrome in Caucasians.

PCOS is known to be associated with an increased risk of T2DM and has been proposed to share a common genetic background with T2DM. Recent studies suggest that the Calpain-10 gene (CAPN10) is an interesting candidate gene for PCOS susceptibility. However, contradictory results were reported concerning the contribution of certain CAPN10 variants, especially of UCSNP-44, to genetic predisposition to T2DM, hirsutism, and PCOS.

The CC genotype of the GNAS T393C polymorphism is associated with obesity and insulin resistance in women with polycystic ovary syndrome.

Objective: Variants in the Gs protein alpha subunit gene (GNAS1) are known to be involved in the pathogenesis of several endocrine and metabolic disorders. To understand genetic determinants of androgen excess, insulin resistance, and obesity in polycystic ovary syndrome (PCOS), we investigated the effect of the common GNAS1 T393C polymorphism on the phenotype of German PCOS women.

Design: Two hundred and seventy-eight PCOS women and 820 Caucasian controls were genotyped for the common T393C polymorphism in GNAS1.

Metformin treatment of polycystic ovary syndrome improves health-related quality-of-life, emotional distress and sexuality.

Background: In polycystic ovary syndrome (PCOS), changes in physical appearance, menstrual disturbances and infertility result in psychological distress and reduced quality-of-life. Metformin improves biochemical, clinical and reproductive parameters in PCOS women. In a prospective, observational study, we analysed the effects of metformin treatment on health-related quality-of-life (HRQL), emotional well-being and sexuality in PCOS.

Determinants of emotional distress in women with polycystic ovary syndrome.

Background: The goals were to analyse the incidence of mental distress in women with untreated polycystic ovary syndrome (PCOS) using self-report measures, to characterize PCOS patients at risk for psychiatric disease with regard to sociodemographic and clinical characteristics, and to assess the impact of emotional distress on quality of life.

Methods And Results: Complete metabolic, hormonal, clinical and self-report psychological data [emotional distress, Symptom Check List 90 (SCL-90-R); quality of life, Short-Form Health Survey 36 (SF-36); sexual satisfaction, visual analogue scales; sociodemographic data] were obtained from n = 143 untreated women with PCOS. Prior psychiatric diagnoses were exclusionary.

Decreased soluble leptin receptor levels in women with polycystic ovary syndrome.

Objective: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and a high incidence of obesity. Leptin, the product of the ob gene, is involved in the regulation of energy balance and obesity and circulates in both free and bound forms. The soluble leptin receptor (sOB-R) is the most important leptin-binding protein, thus influencing the biologically active free leptin level.