High Thyroid Stimulating Hormone Level Is Associated With Hyperandrogenism in Euthyroid Polycystic Ovary Syndrome (PCOS) Women, Independent of Age, BMI, and Thyroid Autoimmunity: A Cross-Sectional Analysis.
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ABSTRACT:
SUBMITTER: Cai J
PROVIDER: S-EPMC6467931 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Polycystic ovary syndrome (PCOS) is the commonest endocrine abnormality in women of reproductive age typically presenting with chronic oligo- or anovulation, clinical, or biochemical hyperandrogenism and polycystic ovarian morphology (PCOM). Restoring mono-ovulation is the ultimate goal of ovulation induction and most women do respond to ovulation inducing agents causing their Follicle-stimulating hormone (FSH) levels to rise. Familial clustering and the results from twin studies strongly support an underlying genetic basis for PCOS. Recent Genome wide association studies (GWAS) have identified several genetic variants being genome wide significantly associated with PCOS. Amongst those are variants in or near the Luteinizing hormone (LH) and FSH receptor genes as well as a variant in the FSH-β gene. The aim of this review is to summarize the available evidence as to whether single nucleotide polymorphisms are able to modify the PCOS phenotype or whether they constitute a risk factor for the syndrome. Data on the role of FSHR polymorphisms in PCOS are conflicting. It seems that in large Chinese studies FSHR polymorphisms are not associated with either PCOS risk or with PCOS treatment outcome. However, in large scale studies in Caucasians these polymorphisms seem to influence the risk of having PCOS. Moreover, these studies also showed that some polymorphisms might affect some clinical features of PCOS as well as treatment outcome. Although most research has focussed on the role of FSHR polymorphisms there seems to be also some evidence showing that single nucleotide polymorphisms (SNPs) in the LHCG-Receptor as well as those in FSH-β gene might also alter the phenotype of PCOS. In conclusion most studies confirm that FSHR polymorphisms do alter the phenotype of PCOS in that they either alter the response to exogenous FSH or hat they increase the risk of having PCOS.
| S-EPMC6379247 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) was hypothesized to result from functional ovarian hyperandrogenism (FOH) due to dysregulation of androgen secretion in 1989-1995. Subsequent studies have supported and amplified this hypothesis. When defined as otherwise unexplained hyperandrogenic oligoanovulation, two-thirds of PCOS cases have functionally typical FOH, characterized by 17-hydroxyprogesterone hyperresponsiveness to gonadotropin stimulation. Two-thirds of the remaining PCOS have FOH detectable by testosterone elevation after suppression of adrenal androgen production. About 3% of PCOS have a related isolated functional adrenal hyperandrogenism. The remaining PCOS cases are mild and lack evidence of steroid secretory abnormalities; most of these are obese, which we postulate to account for their atypical PCOS. Approximately half of normal women with polycystic ovarian morphology (PCOM) have subclinical FOH-related steroidogenic defects. Theca cells from polycystic ovaries of classic PCOS patients in long-term culture have an intrinsic steroidogenic dysregulation that can account for the steroidogenic abnormalities typical of FOH. These cells overexpress most steroidogenic enzymes, particularly cytochrome P450c17. Overexpression of a protein identified by genome-wide association screening, differentially expressed in normal and neoplastic development 1A.V2, in normal theca cells has reproduced this PCOS phenotype in vitro. A metabolic syndrome of obesity-related and/or intrinsic insulin resistance occurs in about half of PCOS patients, and the compensatory hyperinsulinism has tissue-selective effects, which include aggravation of hyperandrogenism. PCOS seems to arise as a complex trait that results from the interaction of diverse genetic and environmental factors. Heritable factors include PCOM, hyperandrogenemia, insulin resistance, and insulin secretory defects. Environmental factors include prenatal androgen exposure and poor fetal growth, whereas acquired obesity is a major postnatal factor. The variety of pathways involved and lack of a common thread attests to the multifactorial nature and heterogeneity of the syndrome. Further research into the fundamental basis of the disorder will be necessary to optimally correct androgen levels, ovulation, and metabolic homeostasis.
| S-EPMC5045492 | biostudies-literature
Project description:The impacts of thyroid hormones (TH) on lipid profile in euthyroid adults have gained much attention. It is currently unknown whether BMI influences such interaction. In the present study, we investigate the role of BMI in modulating the association between TH and lipid parameters in 1372 euthyroid healthy adults. Our results show that thyroid parameters are differentially associated with lipid profile. FT3 is positively correlated with total cholesterol (β = 0.176 ± 0.046, P < 0.001) and LDL cholesterol levels (β = 0.161 ± 0.040, P < 0.001). FT4 is negatively correlated with TG (β = -0.087 ± 0.029, P < 0.01) while positively correlated with HDL cholesterol levels (β = 0.013 ± 0.005, P < 0.01). TSH is positively associated with TG (β = 0.145 ± 0.056, P < 0.05) and total cholesterol levels (β = 0.094 ± 0.030, P < 0.01). Importantly, BMI modulates the effect of TH on lipid profile: the interaction of FT4 and BMI and the interaction of FT3 and BMI reach statistical significance in predicting TG and HDL cholesterol levels, respectively. Stratified according to BMI levels, most associations between TH and lipid profile are significant only in normal-weight group. In conclusion, in euthyroid adults, high normal FT3, TSH levels, and low normal FT4 levels are associated with unfavorable lipid profile. BMI mediates the effect of thyroid function on lipid profile in euthyroid adults.
| S-EPMC5572619 | biostudies-literature
Project description:Previous studies identified follicle-stimulating hormone receptor (FSHR) and luteinizing hormone/choriogonadotropin receptor (LHCGR) genes as polycystic ovary syndrome (PCOS) susceptibility loci, which was dependent on the racial/ethnic background of studied population. We investigated the association of genetic variants in FSHR and LHCGR with PCOS in Bahraini Arab women.A retrospective case-control study, involving 203 women with PCOS, and 211 age- and ethnically-matched control women. FSHR and LHCGR genotyping was done by allelic exclusion method (real-time PCR).Significantly lower frequencies of heterozygous LHCGR rs7371084 and FSHR rs11692782 genotype carriers were seen between women with PCOS vs. controls, and increased frequency of heterozygous homozygous LHCGR rs4953616 genotype carriers were detected between women with PCOS compared to control women. Limited linkage disequilibrium was noted among LHCGR and FSHR SNPs, and 2 blocks were constructed: the first (Block 1) spanning 61 kb contained the six tested LHCGR SNPs, and the second (Block 2) spanning 298 kb contained four of the five tested FSHR SNPs. Higher frequency of LHCGR GTCAAG haplotype was seen in women with PCOS compared to controls; the frequencies of the remaining LHCGR haplotypes, and all FSHR haplotypes were similar between cases and controls.This is the first study to confirm the association of novel LHCGR (rs7371084, rs4953616) and FSHR (rs11692782) SNPs with PCOS. The differential association of LHCGR and FSHR variants with PCOS confirms the racial/ethnic contribution to their association with PCOS.
| S-EPMC4380895 | biostudies-literature
Project description:<p><b>PCOS</b> is a complex genetic disease reflecting the interplay of susceptibility genes and environmental factors. The cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the pathogenesis of the associated metabolic abnormalities. Male as well as female first-degree relatives have reproductive and metabolic phenotypes including increased prevalence rates of type 2 diabetes (T2D), metabolic syndrome (MBS) and other risk factors for cardiovascular disease (CVD). Northwestern University (NU) investigators lead a team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including genome-wide association study (GWAS). Together with an expert group of collaborators from the Hershey Medical Center, and The University of Chicago, we have conducted a GWAS to identify PCOS susceptibility alleles using a large cohort of extensively and consistently phenotyped PCOS cases. Population controls for this study come from the NUgene project described below.</p> <p><b>NUgene project</b>: In 2002, Northwestern committed to the development of a DNA repository to serve as a platform for the identification and validation of genotype-phenotype associations that will impact healthcare. The NUgene Project is a repository with longitudinal medical information from participating patients at affiliated hospitals and outpatient clinics from the Northwestern University Medical Center. Participants' DNA samples are coupled with data from a questionnaire (2 versions were used, 1 before and 1 after February 2006, both are included) and continuously updated data from our Electronic Medical Record (EMR) representing actual clinical care events. Northwestern has a state-of-the art, comprehensive inpatient and outpatient EMR system of over 2 million patients. NUgene has broad access to participant data for all outpatient visits as well as inpatient data via a consolidated data warehouse. NUgene participants consent to distribution and use of their coded DNA samples and data for a broad range of genetic research by third-party investigators.</p>
| phs000368.v1.p1 | EGA
Project description:Polycystic ovary syndrome (PCOS) is a common infertility disorder affecting a significant proportion of the global population. It is the main cause of anovulatory infertility in women and is the most common endocrinopathy affecting reproductive-aged women, with a prevalence of 8-13% depending on the criteria used and population studied. The disease is multifactorial and complex and, therefore, often difficult to diagnose due to overlapping symptoms. Multiple etiological factors have been implicated in PCOS. Due to the complex pathophysiology involving multiple pathways and proteins, single genetic diagnostic tests cannot be determined. Progress has been achieved in the management and diagnosis of PCOS; however, not much is known about the molecular players and signaling pathways underlying it. Conclusively PCOS is a polygenic and multifactorial syndromic disorder. Many genes have been associated with PCOS, which affect fertility either directly or indirectly. However, studies conducted on PCOS patients from multiple families failed to find a fully penetrant variant(s). The present study was designed to review the current genetic understanding of the disease. In the present review, we have discussed the clinical spectrum, the genetics, and the variants identified as being associated with PCOS. The mechanisms by which variants in the genes confer risk to PCOS and the nature of the physical and genetic interaction between the genetic elements underlying PCOS remain to be determined. Elucidation of genetic players and cellular pathways underlying PCOS will certainly increase our understanding of the pathophysiology of this syndrome. The study also discusses the current status of the treatment modalities for PCOS, which is important to find new ways of treatment.
| S-EPMC6935309 | biostudies-literature
Project description:The thyroid-stimulating hormone receptor (TSHR) is a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR). Autoimmune hyperthyroidism, commonly known as Graves' disease (GD), is caused by stimulating autoantibodies to the TSHR. We previously described TSHR-specific antibodies (TSHR-Abs) in GD that recognize linear epitopes in the cleavage region of the TSHR ectodomain (C-TSHR-Abs) and induce thyroid cell apoptosis instead of stimulating the TSHR. We found that C-TSHR-Abs entered the cell through clathrin-mediated endocytosis but did not trigger endosomal maturation and failed to undergo normal vesicular sorting and trafficking. We found that stimulating TSHR-Abs (S-TSHR-Abs) activated G?s and, to a lesser extent, G?q but that C-TSHR-Abs failed to activate any of the G proteins normally activated in response to TSH. Furthermore, specific inhibition of G proteins in the presence of S-TSHR-mAbs or TSH resulted in a similar failure of endosomal maturation as that caused by C-TSHR-mAbs. Hence, whereas S-TSHR-mAbs and TSH contributed to normal vesicular trafficking of TSHR through the activation of major G proteins, the C-TSHR-Abs resulted in GRK2- and ?-arrestin-1-dependent biased signaling, which is interpreted as a danger signal by the cell. Our observations suggest that the binding of antibodies to different TSHR epitopes may decrease cell survival. Antibody-induced cell injury and the response to cell death amplify the loss of self-tolerance, which most likely helps to perpetuate GPCR-mediated autoimmunity.
| S-EPMC5812361 | biostudies-literature
Project description:Context:A majority of women with polycystic ovary syndrome (PCOS) have metabolic abnormalities that result in an increased risk of developing type 2 diabetes and heart disease. Correlative studies have shown an association between changes in the gut microbiome and metabolic disorders. Two recent studies reported a decrease in α diversity of the gut microbiome in women with PCOS compared with healthy women. Objective:We investigated whether changes in the gut microbiome correlated with specific clinical parameters in women with PCOS compared with healthy women. We also investigated whether there were changes in the gut microbiome in women with polycystic ovarian morphology (PCOM) who lacked the other diagnostic criteria of PCOS. Participants:Subjects were recruited at the Poznan University of Medical Sciences. Fecal microbial diversity profiles of healthy women (n = 48), women with PCOM (n = 42), and women diagnosed with PCOS using the Rotterdam criteria (n = 73) were analyzed using 16S ribosomal RNA gene sequencing. Results:Lower α diversity was observed in women with PCOS compared with healthy women. Women with PCOM had a change in α diversity that was intermediate between that of the other two groups. Regression analyses showed that hyperandrogenism, total testosterone, and hirsutism were negatively correlated with α diversity. Permutational multivariate analysis of variance in UniFrac distances showed that hyperandrogenism was also correlated with β diversity. A random forest identified bacteria that discriminated between healthy women and women with PCOS. Conclusion:These results suggest that hyperandrogenism may play a critical role in altering the gut microbiome in women with PCOS.
| S-EPMC6276580 | biostudies-literature
Project description:Polycystic ovary syndrome (PCOS) is a heterogeneous condition which is related to an endocrine reproductive disorder of females. It affects females of 18-44 age. The persistent hormonal disbalance leads to the complexities such as numerous cysts, an irregular menstrual cycle that ultimately leads to infertility among females. Many candidate genes have been identified to be one of the causes of PCOS. Different studies have been carried out to find the genetic correlation of PCOS. It is essential to carry out such studies that identify the clear cause of PCOS and its genetic association and hormonal disbalance. This review has highlighted different genes and their correlation with PCOS that leads to hormonal disbalance. Yet not in-depth but an attempt to study the genetic predisposition of PCOS.
| S-EPMC6687436 | biostudies-literature
Project description:BackgroundWomen with anovulatory polycystic ovary syndrome (PCOS) are generally insulin-resistant and as a consequence are often treated with the biguanide metformin. Results with metformin have, however, been variable with some studies demonstrating induction of regular cycles and an increase in ovulation, whereas others do not. Hence more understanding is needed regarding the mechanism of metformin's actions in ovarian granulosa cells especially in light of previous demonstrations of direct actions.ObjectiveThe aim of this study was to investigate metformin's interaction with the FSH/cAMP/protein kinase A pathway, which is the primary signaling pathway controlling CYP19A1 (aromatase) expression in the ovary.MethodsThe effect of metformin on FSH and forskolin-stimulated aromatase expression in human granulosa cells was measured by quantitative real-time PCR. Activity was assessed after transfection with a promoter II-luciferase construct, and by an RIA measuring conversion of androgen to estrogens. The effect on FSH receptor (FSHR) mRNA was assessed by quantitative PCR. Levels of phosphorylated cAMP response element binding protein (CREB) and CREB-regulated transcription coactivator 2 (CRTC2) were measured by Western blotting and cAMP by a bioluminescent assay.ResultsMetformin markedly reduced FSH but not forskolin-stimulated aromatase expression and activity. This effect was exerted by inhibition of basal and ligand-induced up-regulation of FSHR expression. Metformin also reduced FSH-induced phosphorylation of CREB and hence CRE activity, which could potentially disrupt the CREB-CREB-binding protein-CRTC2 coactivator complex that binds to CRE in promoter II of the aromatase gene. This is mediated in an AMP-activated protein kinase-independent manner, and does not involve alteration of cAMP levels.ConclusionThese finding have implications for the use of metformin in the treatment of anovulation in women with PCOS.
| S-EPMC3784648 | biostudies-literature