GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.
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SUBMITTER: Zhou W
PROVIDER: S-EPMC7414135 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC8677795 | biostudies-literature
Project description:We have shown recently that by acting on the thyroid-stimulating hormone (TSH) receptor (TSHR), TSH negatively regulates osteoclast differentiation. Both heterozygotic and homozygotic TSHR null mice are osteopenic with evidence of enhanced osteoclast differentiation. Here, we report that the accompanying elevation of TNFalpha, an osteoclastogenic cytokine, causes the increased osteoclast differentiation. This enhancement in TSHR-/- and TSHR+/- mice is abrogated in compound TSHR-/-/TNFalpha-/- and TSHR+/-/TNFalpha+/- mice, respectively. In parallel studies, we find that TSH directly inhibits TNFalpha production, reduces the number of TNFalpha-producing osteoclast precursors, and attenuates the induction of TNFalpha expression by IL-1, TNFalpha, and receptor activator of NF-kappaB ligand. TSH also suppresses osteoclast formation in murine macrophages and RAW-C3 cells. The suppression is more profound in cells that overexpress the TSHR than those transfected with empty vector. The overexpression of ligand-independent, constitutively active TSHR abrogates osteoclast formation even under basal conditions and in the absence of TSH. Finally, IL-1/TNFalpha and receptor activator of NF-kappaB ligand fail to stimulate AP-1 and NF-kappaB binding to DNA in cells transfected with TSHR or constitutively active TSHR. The results suggest that TNFalpha is the critical cytokine mediating the downstream antiresorptive effects of TSH on the skeleton.
| S-EPMC1568936 | biostudies-literature
Project description:BackgroundThe relationship between normal thyroid-stimulating hormone (TSH) levels and thyroid disease in adults remains controversial. This study aimed to investigate the correlation between serum TSH levels, particularly those falling within the normal range, and thyroid diseases in Chinese adults, including thyroid nodules (TN), goiter (GR), and thyroid antibody positivity.Materials and methodsThis research was a cross-sectional study conducted in an adult population in Tianjin, China. Thyroid volume (Tvol) and TN were assessed using thyroid ultrasonography. Fasting venous blood and spot urine samples were collected to evaluate thyroid function and iodine status.ResultsA total of 2460 subjects participated in the survey. The prevalence of thyroid dysfunction was 9.76%, and abnormal TSH levels were found to potentially increase the risk of GR and thyroid antibody positivity in adults. A total of 2220 subjects with TSH within the normal reference range were included in the further study. In these patients, Tvol decreased as TSH levels increased, in both men and women (P < 0.0001). Low TSH levels (0.27-1.41 IU/mL) were identified as a risk factor for TN (odds ratio [OR], 1.46; 95% CI: 1.14-1.87) and GR (OR 5.90, 95% CI 2.27-15.3). Upon stratification by sex and age, the risk of TN was found to be higher in women and elderly individuals (≥60 years old), while the risk of GR was found to be higher in men and younger individuals (<60 years old). High TSH levels (2.55-4.2 IU/mL) were identified as a risk factor for thyroid antibody positivity (OR, 1.53; 95% CI: 1.11-2.10). Men and younger individuals with high TSH levels exhibited a higher risk of thyroid antibody positivity.ConclusionIn adults with normal TSH levels, low TSH levels were associated with an increased risk of TN and GR, whereas high TSH levels were associated with thyroid antibody positivity. The research also suggests that adults whose TSH levels at upper or lower limits of the normal range should be reviewed regularly.
| S-EPMC10577406 | biostudies-literature
Project description:High serum thyroid-stimulating hormone (TSH) levels are linked to many metabolic disorders, but the effects of TSH levels on the oral microbiota are still largely unknown. This study aimed to explore the association between the salivary microbiome in adults and serum TSH levels. Saliva and fasting blood samples were obtained from a health census conducted in Southeast China. All participants were divided according to serum TSH levels. The microbial genetic profiles and changes were acquired by 16S rDNA sequencing and bioinformatics analysis. Relevant anthropometric and biochemical measurements such as insulin resistance, blood lipids, and body composition were evaluated with laboratory tests and physical examinations. The salivary microbiome in individuals with higher TSH level showed significantly higher taxa diversity. Principal coordinates analysis and partial least squares discriminant analysis showed distinct clustering in the Abnormal and Normal Groups (Adonis, P=0.0320). Granulicatella was identified as a discriminative genus for comparison of the two groups. Fasting serum insulin, Homeostatic Model Assessment for Insulin Resistance, and hemoglobin A1 were elevated in the Abnormal Group (P<0.05), showing the presence of insulin resistance in individuals with abnormal higher serum TSH levels. Distance-based redundancy analysis revealed the association of this distinctive difference with salivary microbiome. In conclusion, shifts in microbial profile were observed in the saliva of individuals with different serum TSH levels, and insulin resistance may play an important role in the biochemical and microbial alteration.
| S-EPMC7952758 | biostudies-literature
Project description:BackgroundNormal brain development is dependent on maternal, fetal and neonatal thyroid function. Measuring neonatal thyroid-stimulating hormone (TSH) 48-72 hours after birth screens for congenital hypothyroidism, allowing early treatment to avoid serious impairment. However, even within sub-clinical ranges, disrupted thyroid homeostasis during brain development has been linked to adverse neurodevelopmental outcomes, including attention-deficit/hyperactivity disorder (ADHD).ObjectivesTo estimate the association between neonatal TSH below threshold for potential congenital hypothyroidism and subsequent ADHD diagnosis using a population-based birth cohort.MethodsChildren with a diagnosis of ADHD in the Norwegian Mother, Father and Child Cohort Study (MoBa) were identified through linkage with the Norwegian Patient Registry using ICD-10 codes for hyperkinetic disorders. The study included 405 ADHD cases and 1,092 controls (born 2003-2008) with available neonatal TSH concentrations below 10 mU/L (cut-off for potential congenital hypothyroidism) measured in dried blood spots sampled 48-72 hours after birth.ResultsIn multivariable, quintile models the relationship appeared to follow a U-shaped pattern with elevated odds ratios (OR) at lower and higher TSH levels. Among children with TSH in the lowest quintile, odds of ADHD was approximately 1.5-fold higher than children in the middle quintile (OR 1.60, 95% CI 1.09, 2.34), which was driven by substantially elevated risk among girls, with no association among boys (Pinteraction = 0.02; girls OR 3.10, 95% CI 1.53, 6.30; boys OR 1.16, 95% CI 0.73, 1.84).ConclusionsADHD risk appeared to be elevated among newborns with low TSH levels (i.e. with hyperthyroid status), and this association was mainly found among girls. Because our findings are suggestive of increased risk at very low TSH concentrations, where analytical accuracy is low, future studies should employ highly sensitive assays capable of accurate quantitation at very low concentrations. Also, larger studies are needed to investigate these associations at higher neonatal TSH concentrations where data are more widely distributed.
| S-EPMC7431377 | biostudies-literature
Project description:ObjectiveTo investigate the association between thyroid-stimulating hormone (TSH) and clinically relevant depression (CRD) in a population-based study.Patients and methodsAdult patients (≥18 years of age) who received care at Mayo Clinic in Rochester, Minnesota, and completed a TSH and Patient Health Questionnaire - 9 (PHQ-9) within 6 months of each other, between July 8, 2017, and August 31, 2021, were included. Demographics, medical comorbidities, thyroid function laboratory data, psychotropic medications, presence of primary thyroid disorder, thyroid hormone replacement (T4 and/or T3), and mood disorder diagnoses (using International Classification of Diseases, 10th version, Clinical Modifications codes) were extracted electronically. The primary outcome, CRD, was defined as a PHQ-9 score greater than or equal to 10. Logistic regression analysis was conducted to assess the association between TSH categories (low ≤0.3 mIU/L; normal >0.3-4.2 mIU/L; high >4.2 mIU/L) and CRD.ResultsThe cohort included 29,034 patients, mean age 51.4 years, 65% females, 89.9% White, and a mean body mass index of 29.9 kg/m2. The mean ± standard deviation for TSH was 3.0±8.5 mIU/L, and the mean PHQ-9 score was 6.3±6.2. After adjustment, the odds of CRD were significantly higher among the low TSH category (odds ratio, 1.37; 95% CI, 1.18-1.57; P<.001) compared with the normal TSH category, especially in people 70 years of age or younger compared with people older than 70 years of age. Subgroup analysis did not show an increase in odds of CRD among patients with subclinical/overt hypothyroidism/hyperthyroidism (after adjustment).ConclusionIn this large population-based cross-sectional study, we report that low TSH was associated with higher odds of depression. Future longitudinal cohort studies are needed to investigate the relationship between thyroid dysfunction and depression as well as sex differences.
| S-EPMC10554405 | biostudies-literature
Project description:BACKGROUND:Overt thyroid dysfunction has been associated with adverse obstetric outcomes. However, less is known regarding subclinical hypothyroidism or thyroid autoimmunity and their relationship to pregnancy complications. OBJECTIVE:The purpose of this study was to examine the association between prepregnancy anti-thyroid antibodies and subclinical hypothyroidism and preterm delivery, gestational diabetes mellitus, and preeclampsia. STUDY DESIGN:We conducted a secondary analysis of a prospective cohort of 18- to 40-year-old women with 1-2 previous pregnancy losses (n=1193) who participated in a multicenter randomized, placebo-controlled trial of low-dose aspirin. Prepregnancy levels of thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody were measured. Relative risks and 95% confidence intervals were estimated with the use of generalized linear models with adjustment for age and body mass index. RESULTS:Among women with an ongoing pregnancy of >20 weeks estimated gestational age, there was no association between prepregnancy thyroid-stimulating hormone level (>2.5 vs ?2.5 mIU/L) and preterm delivery (adjusted relative risk, 0.77; 95% confidence interval, 0.40-1.47), gestational diabetes mellitus (adjusted relative risk, 1.28; 95% confidence interval, 0.54-3.04), or preeclampsia (adjusted relative risk, 1.20; 95% confidence interval, 0.71-2.04). Similarly, among women with thyroid antibodies, there was no increase in the likelihood of preterm delivery (relative risk, 1.26; 95% confidence interval, 0.65-2.45), gestational diabetes mellitus (relative risk, 1.33; 95% confidence interval, 0.51-3.49), or preeclampsia (relative risk, 1.02; 95% confidence interval, 0.54-1.92), compared with women without these antibodies. CONCLUSION:Among women with 1-2 previous pregnancy losses, subclinical hypothyroidism and thyroid autoimmunity were not associated with an increased risk of preterm delivery, gestational diabetes mellitus, or preeclampsia. These data support current recommendations that low-risk asymptomatic women should not be screened routinely for thyroid dysfunction or autoimmunity.
| S-EPMC5712235 | biostudies-literature
Project description:Background: The effects of thyroid-stimulating hormone (TSH) and thyroid hormones on the development of human papillary thyroid cancer (PTC) remain poorly understood.Methods: The study population consisted of 741 (341 women, 400 men) histologically confirmed PTC cases and 741 matched controls with prediagnostic serum samples stored in the Department of Defense Serum Repository. Concentrations of TSH, total T3, total T4, and free T4 were measured in serum samples. Conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI).Results: The median time between blood draw and PTC diagnosis was 1,454 days. Compared with the middle tertile of TSH levels within the normal range, serum TSH levels below the normal range were associated with an elevated risk of PTC among women (OR, 3.74; 95% CI, 1.53-9.19) but not men. TSH levels above the normal range were associated with an increased risk of PTC among men (OR, 1.96; 95% CI, 1.04-3.66) but not women. The risk of PTC decreased with increasing TSH levels within the normal range among both men and women (Ptrend = 0.0005 and 0.041, respectively).Conclusions: We found a significantly increased risk of PTC associated with TSH levels below the normal range among women and with TSH levels above the normal range among men. An inverse association between PTC and TSH levels within the normal range was observed among both men and women.Impact: These results could have significant clinical implications for physicians who are managing patients with abnormal thyroid functions and those with thyroidectomy. Cancer Epidemiol Biomarkers Prev; 26(8); 1209-18. ©2017 AACR.
| S-EPMC6494475 | biostudies-literature
Project description:Less-intense TSH suppression strategies can be used for differentiated thyroid cancer (DTC) patients with a low recurrence risk, but their metabolic outcomes are not well known. We aimed to evaluate changes in the serum cholesterol levels and the risk of hypercholesterolemia according to postoperative TSH levels in 1092 female DTC patients receiving levothyroxine after total thyroidectomy. The preoperative-to-follow-up change in total cholesterol (TC) levels in the TSH level <0.03, 0.03-0.3, 0.3-2, and 2-5 mIU/L groups was -3.69 mg/dL (p = 0.006), +0.13 mg/dL (p = 0.926), +12.46 mg/dL (p < 0.001), and +16.46 mg/dL (p < 0.001), respectively. When compared with TSH levels of 0.03-0.3 mIU/L, those of 0.3-2 mIU/L were found to be associated with hypercholesterolemia (adjusted odds ratio (AOR) = 1.86 and 5.08 for TC 200-240 and ?240 vs. <200 mg/dL) and hyper-low-density lipoprotein (LDL)-cholesterolemia (AOR = 2.76 for LDL-cholesterol ?160 vs. <130 mg/dL). Additionally, TSH levels of 2-5 mIU/dL were associated with hypercholesterolemia (AOR = 2.85 and 6.95 for TC 200-240 and ?240 vs. <200 mg/dL) and hyper-LDL-cholesterolemia (AOR = 2.08 and 4.17 for LDL-cholesterol 130-159 and ?160 mg/dL vs. <130 mg/dL). In patients with normal TSH level maintenance following thyroidectomy, TC levels markedly increased, resulting in an increased hypercholesterolemia prevalence. Metabolic derangement risk due to insufficient levothyroxine replacement should be considered in the adoption of less-intense TSH suppression strategies, postoperatively, in DTC patients.
| S-EPMC6723726 | biostudies-literature
Project description:Human thyroid stimulating hormone (TSH) is a glycoprotein secreted by the anterior part of the pituitary gland. TSH plays an important physiological role in the regulation of hypothalamic-pituitary-thyroid axis by modulating the release of the thyroid hormones from the thyroid gland. It induces iodine uptake by the thyroid, promotes thyroid epithelial differentiation and growth, and protects thyroid cells from apoptosis. Impairment of TSH signal transduction pathway leads to thyroid disorders such as goitre, hypothyroidism and hyperthyroidism, which can have complex clinical manifestations. TSH signaling is largely effected through two separate pathways, the adenylate cyclase and the phospholipase C pathways. In spite of its biomedical importance, a concise signaling map of TSH pathway is not available in the public domain. Therefore, we have generated a detailed signaling map of TSH pathway by systematically cataloging the molecular reactions induced by TSH including protein-protein interactions, post-translational modifications, protein translocation events and activation/inhibition reactions. We have cataloged 40 molecular association events, 42 enzyme-substrate reactions and 16 protein translocation events in TSH signaling pathway resource. Additionally, we have documented 208 genes, which are differentially regulated by TSH. We have provided the details of TSH pathway through NetPath (http://www.netpath.org), which is a publicly available resource for human signaling pathways developed by our group. We have also depicted the map of TSH signaling using NetSlim criteria (http://www.netpath.org/netslim/) and provided pathway maps in Wikipathways (http://www.wikipathways.org/). We anticipate that the availability of TSH pathway as a community resource will enhance further biomedical investigations into the function and effects of this important hormone.
| S-EPMC3830942 | biostudies-literature