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Context: Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear., Objective: This study aimed to investigate the association between thyroid function and anemia., Methods: This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants., Results: In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.06]), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes., Conclusion: While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status., Methods: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction., Results: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59)., Conclusions: Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk., (© 2021. The Author(s).)

Context: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM., Objective: This work aims to investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI., Methods: A mendelian randomization study was conducted of European-ancestry participants from the UK Biobank population. The present study involved 408 895 individuals (mean age 57.4 years [SD 8.0], 45.9% men), of whom 19 773 had DM. Genetic variants for circulatory TSH, free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. The main outcome measures included self-reported DM-stratified analyses by BMI. Analyses were repeated for nonfasting glucose and glycated hemoglobin A1c (HbA1c) among individuals without DM., Results: Genetically determined TSH and fT4 levels were not associated with risk of DM in the total UK Biobank population. However, in analyses stratified on genetically determined BMI, genetically determined higher TSH, and not fT4, was associated with a lower risk for DM only in the low BMI group (odds ratio 0.91; 95% CI, 0.85-0.98 in low BMI; P value for interaction = .06). Similar results were observed for glucose and HbA1c among individuals without DM., Conclusion: TSH, but not fT4, is a potential causal risk factor for DM in individuals with genetically determined low BMI highlighting potential protective effects of TSH only in low-risk populations., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Both thyroid dysfunction and levothyroxine (LT4) therapy have been associated with bone loss, but studies on the effect of LT4 for subclinical hypothyroidism (SHypo) on bone yielded conflicting results., Objective: To assess the effect of LT4 treatment on bone mineral density (BMD), Trabecular Bone Score (TBS), and bone turnover markers (BTMs) in older adults with SHypo., Design and Intervention: Planned nested substudy of the double-blind placebo-controlled TRUST trial. Participants with SHypo were randomized to LT4 with dose titration versus placebo with computerized mock titration., Setting and Participants: 196 community-dwelling adults over 65 years enrolled at the Swiss TRUST sites had baseline and 1-year follow-up bone examinations; 4 participants withdrew due to adverse events not related to treatment., Main Outcome Measures: One-year percentage changes of BMD, TBS, and 2 serum BTMs (serum CTX-1 [sCTX] and procollagen type 1 N-terminal polypeptide [P1NP]). Student's t-test for unadjusted analyses and linear regression adjusted for clinical center and sex were performed., Results: Mean age was 74.3 years ± 5.7, 45.4% were women, and 19.6% were osteoporotic. The unadjusted 1-year change in lumbar spine BMD was similar between LT4 (+0.8%) and placebo-treated groups (-0.6%; between-groups difference +1.4%: 95% confidence interval [CI] -0.1 to 2.9, P = .059). Likewise, there were no between-group differences in 1-year change in TBS (-1.3%: 95% CI -3.1 to 0.6, P = .19), total hip BMD (-0.2%: 95% CI -1.1 to 0.1, P = .61), or BTMs levels (sCTX +24.1%: 95% CI -7.9 to 56.2, P = .14), or after adjustment for clinical centers and sex., Conclusions: Over 1-year levothyroxine had no effect on bone health in older adults with SHypo., Registration: ClinicalTrial.gov NCT01660126 and NCT02491008., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (expression quantitative trait loci [eQTLs]) are associated with BMD. For both analyses, we used summary-level data of genomewide association studies (GWASs) investigating BMD of the femoral neck (n = 32,735) and the lumbar spine (n = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium. For the MR study, we selected 20 genetic variants that were previously identified for circulating TSH levels in a GWAS meta-analysis (n = 26,420). All independent genetic instruments for TSH were combined in analyses for both femoral neck and lumbar spine BMD. In these studies, we found no evidence that a genetically determined 1-standard deviation (SD) decrease in circulating TSH concentration was associated with femoral neck BMD (0.003 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.053 to 0.048; p = 0.92) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.069 to 0.049; p = 0.73). A total of 706 common genetic variants have been mapped to the TSHR locus and expression loci for TSHR. However, none of these genetic variants were associated with BMD at the femoral neck or lumbar spine. In conclusion, we found no evidence for a causal effect of circulating TSH on BMD, nor did we find any association between genetic variation at the TSHR locus or expression thereof and BMD. © 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc.)

The relationship between thyroid status and longevity has been investigated extensively. However, data on thyroid status and survival in old age is scarce. In this study we investigated associations of different parameters of thyroid status with mortality in nonagenarians, and whether these associations were different in nonagenarians from long-lived families than in nonagenarians from the general population. In total, 805 nonagenarians from the Leiden Longevity Study and 259 nonagenarians from the Leiden 85-plus Study were followed up to collect mortality data. At baseline, levels of thyrotropin (TSH), free thyroxine (fT4) and free triiodothyronine (fT3) were measured. In nonagenarians from long-lived families and from the general population, associations between thyroid parameters and mortality were similar. We found no interaction between study population and parameters of thyroid status on mortality (P-values>0.70). The results from both studies were combined to derive generalizable associations. Hazard ratios (HRs) for the highest compared to lowest tertiles were determined, resulting in TSH HR 0.91 (P=0.25), fT4 HR 1.22 (P=0.02), fT3 HR 0.74 (P=1.31e-4), and fT3/fT4 HR 0.66 (P=5.64e-7). In conclusion, higher fT3/fT4 ratios, higher levels of fT3, and lower levels of fT4 were associated with lower mortality rate in nonagenarians and independent of familial longevity status.