The hypothalamic-pituitary-thyroid axis plays a crucial role in the pathogenesis, diagnosis, risk stratification, effectiveness of radioiodine therapy, and treatment response evaluation in epithelial thyroid cancer. Supraphysiological doses of levothyroxine are used in patients with intermediate-risk and high-risk thyroid cancer to suppress thyroid-stimulating hormone (TSH) to prevent tumour progression. However, free thyroxine and tri-iodothyronine have also been found to promote tumour growth in thyroid cancer preclinical models. Moreover, current evidence remains inconclusive about the role of TSH suppression in improving survival outcomes and reveals an increased risk of cardiovascular and skeletal adverse events after long-term exposure to excess levothyroxine. Stimulation of the axis with either recombinant human TSH or thyroid hormone withdrawal has been proven equally effective for diagnostic purposes and for facilitating radioiodine uptake for thyroid remnant ablation, but evidence is insufficient for non-inferiority of recombinant human TSH-based vs thyroid hormone withdrawal-based stimulation before radioiodine therapy of distant metastases.

The deiodination of L-thyroxine (T4) by the three isoforms of selenium-containing iodothyronine deiodinases (DIOs) is an important process in the human body for the maintenance of the thyroid hormone homeostasis. The 5'-deiodination of T4 by DIO1 or DIO2 produces the biologically active hormone 3,5,3'-triiodo thyronine (T3) and 5-deiodination by DIO1 or DIO3 generates 3,3',5'-triiodo thyronine (rT3), which is considered to be biologically inactive. Selenium compounds are known to mimic the function of DIO3 by catalyzing the 5-deiodination of T4 and a co-operative halogen and chalcogen bonding is responsible for their activity. The substitution of 4'-OH group of T4 by an electron withdrawing group not only alters the reactivity but also changes the regioselectivity of deiodination. However, the effect of other halogen atoms (F, Cl or Br) in place of iodine in T4 on the regioselectivity has not been explored. In this paper, we describe simple synthetic methodologies toward various halogen analogues of T4. We also show that 2D NMR spectroscopy can be used as a powerful tool to identify the location of various halogen substitutions on the phenolic or tyrosyl rings. The deiodination experiments with peri-substituted naphthalene diselenol reveal that the regioselectivity or specificity towards iodine atom is not altered upon introduction of more electronegative halogen atoms (F, Cl and Br), reinforcing the concept of halogen bonding in the deiodination reactions.

Thyroid hormones (THs) play a crucial role in various biological functions, including metabolism, cell growth, and nervous system development, and any alteration involving the structure of the thyroid gland and TH secretion may result in thyroid disease. Growing evidence suggests that phthalate plasticizers, which are commonly used in a wide range of products (e.g., food packaging materials, children's toys, cosmetics, medical devices), can impact thyroid function, primarily affecting serum levels of THs and TH-related gene expression. Like phthalate compounds, recently introduced alternative plasticizers can leach from their source material into the environment, particularly into foods, although so far only a very limited number of studies have investigated their thyroid toxicity. This review aimed at summarizing the current knowledge on the role of phthalate and non-phthalate plasticizers in thyroid dysfunction and disease, describing the major biological mechanisms underlying this relationship. We will also focus on the food industry as one of the main players for the massive spread of such compounds in the human body, in turn conveyed by edible compounds. Given the increasing worldwide use of plasticizers and the essential role of THs in humans, novel strategies should be envisaged to reduce this burden on the thyroid and, in general, on human health.

Background: Abnormal platelet counts are frequently observed in patients with thyroid dysfunction; however, the direct impact of thyroid hormones on thrombopoiesis remains largely undefined. Methods: This study elucidates the dose-response effect of the thyroid hormone triiodothyronine (T3) on megakaryocyte (MK) development and thrombopoiesis using both a murine model of hyperthyroidism/hypothyroidism and in vitro cultures of human cord blood CD34+ cell-derived MKs. After the application of inhibitors to MKs, the examination of total and phosphorylated protein levels of the phosphoinositide 3-kinase (PI3K)/AKT pathway was utilized to assess the specific mechanisms of T3 action. The use of autophagy dual-staining lentivirus and transmission electron microscopy was employed to evaluate the impact of T3 on the autophagy flux in MKs. Mouse whole-body irradiation and bone marrow transplantation models are applied to assess the influence of T3 on the recovery of MKs/platelets in vivo. Results: We found that physiological or slightly elevated thyroid hormone levels are essential for sustaining MK development and thrombopoiesis, primarily through the TRα-PI3K/AKT signaling pathway. In contrast, supraphysiological thyroid hormone concentrations induce MK apoptosis via excessive autophagy, thereby reducing platelet production. Conclusions: Here, we present evidence that the thyroid hormone influences MK development and platelet production in a concentration-dependent manner, exhibiting a dualistic role. Our discoveries shed new light on the intricate relationship between thyroid hormones and platelet formation, offering novel perspectives on the pathophysiological consequences of thyroid disorders.

Free triiodothyronine (FT3) exerts a significant influence on glucose metabolism. The relationship between gestational diabetes mellitus (GDM) and FT3 during pregnancy is complex and inconsistently reported. Our study aims to explore the bidirectional association between FT3 during pregnancy and GDM, and to assess whether this association is causal.

The observational analysis included two clinical studies. Study 1 involved 6,221 pregnant women and applied multivariate logistic regression analysis to investigate the association between FT3 in early pregnancy and the subsequent risk of GDM. Study 2 comprised 387 pregnant women and employed linear regression analysis to examine the impact of GDM on FT3 in late pregnancy. Additionally, genome-wide association study (GWAS) summary statistics of FT3 and GDM were used to perform a bidirectional two-sample Mendelian randomization (MR) analysis to test for causal associations.

In Study 1, after adjusting for potential confounding factors, increased FT3 levels in early pregnancy were associated with the subsequent risk of GDM [odds ratio (OR) 1.122; 95% confidence interval (CI) 1.004, 1.255; P = 0.043], and the restricted cubic spline analysis indicated a linear association (P for nonlinearity = 0.72). In Study 2, we didn't find association between GDM and FT3 levels in late pregnancy. MR analysis found a positive causal relationship of genetically predicted FT3 on the risk of GDM (OR 1.26; 95% CI 1.01, 1.57; P = 0.041), while in the reverse MR, there was no significant relationship of GDM on FT3. In addition, the sensitivity analysis illustrated the robustness of our MR results.

FT3 levels in early pregnancy were positively associated with the risk of GDM, and MR analysis provided evidence supporting a causal relationship. However, future studies are required to further investigate this association through larger-scale GWAS in diverse ethnic populations and to explore the underlying biological mechanisms.

At present, studies on tadpole nutrition and metabolism are scarce. This study aimed at comparing the influence of two protein sources, fishmeal (FM) and dried whole egg powder (DWEP), on tadpoles from the perspective of growth, the metamorphosis rate, lipid metabolism, antioxidant properties and the intestinal flora. In this experiment, the control diet was set to contain no FM or DWEP. Based on the control diet, 5% and 10% FM or DWEP were included, respectively. The results of the experiment indicated that FM or DWEP inclusion significantly enhanced the growth performance and metamorphosis rate (p < 0.05); activated hepatic lipid metabolism, as manifested by enhanced LPL and HL activity; upregulated lipid metabolism-related gene expression (fasn, acc, acadl and cpt1α) (p < 0.05); and distinctly elevated the activity of SOD, CAT and GPX (p < 0.05), suggesting improved antioxidant capabilities (p < 0.05). Moreover, the inclusion of FM or DWEP elevated the relative abundance of Actinobacteria and Actinomyces and reduced the relative abundance of Proteobacteria. Unexpectedly, no significant differences were observed between the FM and DWEP groups regarding the above detected indices. This indicates that using DWEP to replace FM is a viable option.

Selenium (Se) is a vital trace element for children, playing a crucial role in numerous physiological processes, including antioxidant defense, immune regulation, thyroid function, and bone metabolism. Emerging evidence highlights its potential impact on child development and growth while also underscoring the complexity of its mechanisms and the global variations in Se intake. The aim of this review is to comprehensively elucidate the significance of Se in various biological processes within the human body, with a focus on its role in child development and growth; its biochemical effects on the nervous system, thyroid function, immune system, and bone tissue; and the implications of Se deficiency and toxicity. This review integrates findings from experimental models, epidemiological studies, and clinical trials to explore Se's role in neurodevelopment, growth regulation, and immune competence in children. Selenoproteins, which regulate oxidative stress and thyroid hormone and bone metabolism, are essential for normal growth and cognitive development in children. Se deficiency and toxicity has been linked to impaired immune function, growth retardation, and decreased immune function. The findings underscore Se's influence on various biological pathways that are critical for healthy child development and its broader importance for child health. Public health strategies aimed at optimizing selenium intake may play a pivotal role in improving pediatric health outcomes worldwide.

Thyroid hormones (THs) are key modulators of energy metabolism and cross-talk with other endocrine and metabolic factors. Notably, leptin can increase hypothalamic control of TH synthesis as an adaptive metabolic response regulating body weight. In this study, we found that the TH signal is heightened in overweight humans and is lost with obesity. In mice, systemic and intracerebroventricular leptin injection induces the expression of type 2 deiodinase (D2), the TH-activating enzyme, in skeletal muscle. Mechanistically, leptin enhances the transcription of D2 by a STAT3- and α-melanocyte-stimulating hormone (α-MSH)/cyclic AMP (cAMP)-dependent regulation. Notably, mice lacking D2 or with a mutation in the TH receptor do not exhibit the metabolic effects of leptin, such as increased insulin sensitivity and oxygen consumption, indicating that leptin's peripheral metabolic effects in skeletal muscle are mediated by TH. These findings underscore the critical role of leptin in integrating the TH-induced metabolic activation, while also contributing to appetite suppression in response to perceived fat stores.

Stroke patients may exhibit low thyroid hormone (TH) levels and disease-related malnutrition, both potentially affecting clinical status; their relationships remain unexplored. This study aimed to evaluate TH concentrations in subacute stroke patients and investigate the relationships between TH levels, nutritional risk, and functional status.

Early subacute stroke patients admitted to a rehabilitation unit were assessed using various nutritional screening tools (Geriatric Nutritional Risk Index-GNRI, Prognostic Nutritional Index-PNI, and Controlling Nutritional Status-CONUT score) and with the Global Leadership Initiative on Malnutrition (GLIM) criteria. Thyroid-Stimulating Hormone (TSH), free Tetraiodothyronine-Thyroxine (fT4) and free Triiodothyronine (fT3) levels were determined. Functional and cognitive status was evaluated using different scales. Associations between altered THs and nutritional status were examined through univariate/multivariate analyses and ROC analyses. Among 264 patients (age 72.0 ± 10.5 yrs), significant correlations emerged between fT3 and nutritional risk and functional tests (mostly p < 0.001). The prevalence of high nutritional risk determined by GNRI, PNI and CONUT increased from higher to lower fT3 tertiles. Lower fT3 levels were observed in patients at high nutritional risk and with GLIM-based malnutrition. fT3 exhibited reasonable predictive power for high nutritional risk (particularly PNI: AUC 0.769, 95%CI 0.702-0.836, p < 0.001). Multivariate logistic regression identified nutritional risk (p < 0.001) and time from stroke onset as predictors of low fT3 values.

Altered fT3 levels in early subacute stroke patients correlate with high nutritional risk and poor functional status. Low fT3 values upon admission for stroke rehabilitation may serve as a further parameter to be considered in patients at high nutritional risk.

Accurate identification of individuals at high risk for mild cognitive impairment (MCI) among chronic heart failure (CHF) patients is crucial for reducing rehospitalization and mortality rates. This study aimed to develop and validate a machine learning model to predict MCI risk in CHF patients. 602 CHF patients were included in this cross-sectional analysis. We constructed four machine learning models and assessed the models using the area under the receiver operating characteristic curve (AUC), calibration curve, and clinical decision curve. Results showed that scores of psychological and social adaptation management, age, free triiodothyronine, Self-rating Depression Scale scores, hemoglobin, sleep duration per night and gender were the best predictors and these factors were used to construct dynamic nomograms. Among all models, eXtreme Gradient Boosting (XGBoost) with an AUC of 0.940 performed the best in predicting the risk of MCI in CHF patients. Dynamic nomogram helps clinicians perform early screening in large populations.

Thyroid Hormones (THs) critically impact human cancer. Although endowed with both tumor-promoting and inhibiting effects in different cancer types, excess of THs has been linked to enhanced tumor growth and progression. Breast cancer depends on the interaction between bulk tumor cells and the surrounding microenvironment in which mesenchymal stem cells (MSCs) exert powerful pro-tumorigenic activities.

Primary human MSCs from healthy female donors were co-cultured with DIO2 knock out (D2KO) and wild type (WT) MCF7 breast cancer cells to assess cell growth, migration, invasion and the expression of known epithelial-mesenchymal transition (EMT)- and inflammation-related markers. Furthermore, a surgery-free intraductal delivery model, i.e., the Mouse-INtraDuctal (MIND) injection method, was used as a tool for in vivo characterization of breast tumor formation and progression.

In this study, we uncovered a novel role of THs in regulating the tumor-stroma crosstalk. MCF7 cells enhanced the intracellular activation of THs through the TH-activating enzyme, D2, fostering their EMT properties and the dialogue with MSCs. D2 inactivation reduced the invasiveness of MCF7 cells and their responsiveness to the pro-tumorigenic induction via MSCs, both in vivo and in vitro.

Thus, we argue that intracellular activation of THs via D2 is a critical requirement for invasive and metastatic conversion of breast cancer cells, advising the blocking of D2 as a potential therapeutic tool for cancer therapy.

Thyroxine, the main hormone product of the thyroid, is produced at multiple sites within its protein precursor thyroglobulin. Each site consists of two tyrosine residues which undergo iodination and coupling, resulting in the synthesis of thyroxine at the acceptor tyrosine, where the hormone synthesis is later completed by proteolysis. Within the structurally resolved sites, the role of an essential conserved acidic residue preceding the acceptor remains elusive. To elucidate the mechanism of thyroxine synthesis we engineered a single-site minimal protein precursor. First, by its in vitro iodination and site-directed mutagenesis we show that the presence of the acidic residue, preferably glutamate, favors thyroxine synthesis. Secondly, within the designed precursor, we computationally modeled the reaction of iodination and iodotyrosine coupling giving rise to thyroxine. Our results reveal that hormone formation is triggered by iodotyrosine deprotonation, facilitated by proximity to a carboxylic group, closer in the case of glutamate, in line with our experimental findings and sequence conservation. Hereafter, we surmise that in the natural precursor thyroglobulin, two evolutionary late and slower hormonogenic sites coexist with an early evolutionary and faster one. Indeed, the latter is overlapping with a proteolytic site, thereby allowing prompt thyroxine release from thyroglobulin.

Background/Objectives: The thyroid gland has an important influence on the heart. Long-term exposure to high levels of thyroid hormones may lead to cardiac hypertrophy and dysfunction. The aim of the study was to evaluate the morphological and functional changes in the left ventricle in patients with hyperthyroidism caused by Graves' disease (GD) in comparison with healthy individuals, as well as to investigate potential differences in these parameters in GD patients in relation to the presence of orbitopathy. Methods: The prospective study included 39 patients with clinical manifestations and laboratory confirmation of GD and 35 healthy controls. All participants underwent a detailed echocardiographic examination. The groups were compared according to demographic characteristics (age and gender), heart rate and echocardiographic characteristics. Results: The patients with hyperthyroidism caused by GD had significantly higher values of left ventricular diameter, left ventricular volume and left ventricular mass compared to the healthy controls. In addition, hyperthyroidism significantly influenced the left ventricular contractility and led to the deterioration of the systolic and diastolic function, as shown together by longitudinal strain, color Doppler and tissue Doppler imaging. However, the patients with GD and orbitopathy showed better left ventricular function than those without orbitopathy. Conclusions: Besides the confirmation of previously known findings, our study indicates possible differences in echocardiographic parameters in GD patients in relation to the presence of orbitopathy. Further investigation with larger samples and meta-analyses of data focused on the evaluation of echocardiographic findings in the context of detailed biochemical and molecular analyses is required to confirm our preliminary results and their clinical significance.

A 3D thyroid model was developed to address the limitations of 2D cultures and study the effects of compounds like 3-MNT on dehalogenase 1 (IYD) and metabolic activity. Morphology was assessed by TEM, and the expression of tissue-specific genes (TPO, TSHR, PAX8, TTF-1, NIS, IYD, TG) and metabolic features were analyzed using qRT-PCR, immunofluorescence, western blotting, ELISA, and LC-MS/MS, with and without TSH stimulus and 3-MNT treatment. Confocal and TEM analyses confirmed a follicle-like 3D structure. Expression of TPO, NIS, TG, TSH, and PAX markers was significantly higher (p < 0.05) in 3D versus 2D cultures, and ELISA showed increased TG protein production. 3-MNT treatment inhibited IYD activity, indicated by increased MIT and DIT in the media, and significantly altered (p < 0.05) NIS, TG, IYD, TSHR, and TPO expression. These findings suggest 3D thyroid cultures closely replicate tissue traits and functionality, providing a valuable tool for thyroid research.

Baseline thyroid function, as measured by the fT3 to fT4 ratio, has been shown to influence the prognosis of advanced cancer patients receiving active treatments. Although immune checkpoint blockade can alter the balance of thyroid hormones, this interaction has not been thoroughly investigated. The present research sought to determine whether changes in the fT3/fT4 ratio could affect the survival outcomes of patients with advanced non-small cell lung cancer (NSCLC) who were undergoing pembrolizumab-based therapies. This study included patients with metastatic NSCLC who received pembrolizumab as upfront treatment, either alone or in combination with platinum-based chemotherapy. Relevant data were gathered before the start (time point 1) and after 12 weeks (time point 2) of treatment. From April 2018 to May 2023, we enrolled 258 eligible patients, 156 (60.5%) and 102 (39.5%) of whom were treated with single-agent or combination therapy, respectively. We stratified patients into two groups based on baseline fT3 and fT4 values [euthyroid cohort defined by fT3 and fT4 both within the normal range vs. euthyroid sick syndrome cohort defined by low fT3 and/or fT4 levels]. We examined the differences in progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analyses. After applying propensity-score matching, we considered 88 relevant cases in each cohort. Longitudinal comparison of fT3/fT4 ratios showed a significant increase in the median value after pembrolizumab-based therapy (p < 0.001). We computed ROC curves to analyze the correlation between fT3/fT4 ratios and survival outcomes. The relative AUC values were not viable in predicting a positive outcome at the first time point. Conversely, assessment at the second time point revealed a significant association with PFS [AUC 0.82 (95% CI 0.75-0.89), p < 0.001] and OS [AUC 0.81 (95% CI 0.75-0.88), p < 0.001]. After a median follow-up of 20.2 (95% CI 16.2-24.2) months, the median PFS for the low and high fT3/fT4 ratio groups was 4.1 (95% CI 3.0-5.1) and 15.3 (95% CI 10.3-20.1) months, respectively (p < 0.001). The median OS for the low and high fT3/fT4 ratio groups was 6.7 (95% CI 4.9-8.5) and 19.6 (95% CI 16.4-22.8) months, respectively (p < 0.001). The multivariate analysis revealed that a low fT3/fT4 ratio was independently associated with shorter PFS [HR 2.51 (1.66-3.78); p < 0.001] and OS [HR 2.18 (1.43-3.34); p < 0.001]. After the optimal weighting of prognostic factors according to thyroid function impairment, the fT3/fT4 ratio at baseline did not affect the survival of patients receiving immune checkpoint blockade for advanced NSCLC. Patients with an increased fT3/fT4 ratio experienced a significantly decreased risk of disease progression and mortality. The longitudinal assessment of fT3/fT4 ratio may play a predictive role in this specific therapeutic setting.

Liver dysfunction can occur in patients presenting with thyrotoxicosis, due to several different aetiologies. A 42-year-old man had mild liver dysfunction on presentation with hyperthyroidism due to Graves' disease (GD): ALT 65 (0-45 IU/L), fT4 41.2 (9-23 pmol/L), fT3 > 30.7 (2.4-6 pmol/L), and TSH < 0.01 (0.3-4.2 mIU/L). His liver dysfunction worsened following the initiation of the antithyroid drug (ATD) carbimazole (CBZ), with ALT reaching a zenith of 263 IU/L at 8 weeks following presentation. Consequently, CBZ was stopped, and he was managed with urgent radioiodine therapy. His liver function tests (LFTs) improved within 1 week of stopping carbimazole (ALT 74 IU/L). Thionamide-induced liver dysfunction is more typically associated with a 'cholestatic' pattern, although he had a 'hepatitic' pattern of liver dysfunction. The risk of liver dysfunction in GD increases with older age and higher titres of thyroid-stimulating hormone receptor antibody (TRAb). This review of the literature seeks to explore the possible causes of liver dysfunction in a patient presenting with hyperthyroidism, including thyrotoxicosis-induced liver dysfunction, ATD-related liver dysfunction, and the exacerbation of underlying unrelated liver disease.

The study aimed to assess whether thyroid hormone (TH) sensitivity is related to visceral fat area (VFA) and visceral obesity in euthyroid subjects with type 2 diabetes (T2D).

750 euthyroid patients with T2D were enrolled. A VFA of 80 cm2 or more was considered visceral obesity. Central TH sensitivity was conducted using thyrotrophic thyroxine resistance index (TT4RI), thyrotropin index (TSHI), and thyroid feedback quantile-based index (TFQI). Free triiodothyronine to free thyroxine (FT3/FT4) was utilized for assessing peripheral TH sensitivity.

The subjects had a mean age of 51.5 ± 11.1 years, and 540 (72.0%) of them were men. In multivariable regression analyses, there was a positive correlation of FT3/FT4 tertile with visceral obesity, after full adjustment for confounding variables (P < 0.05). The middle and highest FT3/FT4 tertiles were correlated with a 134% [95% CI (1.24, 4.44)] and 98% [95% CI (1.04, 3.78)] higher prevalence of visceral obesity than the lowest tertile, respectively. Conversely, elevated TFQI levels were linked to a decreased prevalence of visceral obesity. Stratified analysis revealed that these associations were particularly pronounced in participants who are neither overweight nor obese and those aged less than 60 years (all P < 0.05).

Higher TH sensitivity is correlated with visceral obesity and elevated VFA in euthyroid patients with T2D, particularly among those younger than 60 years and individuals who are neither overweight nor obese.

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Iodine, an essential trace element for the human body, plays a pivotal role in sustaining health. Malnutrition has emerged as a pressing public health concern, posing a significant threat to human well-being. Iodine deficiency poses a substantial threat to the development of children, potentially leading to neurological developmental disorders and mental retardation. Conversely, excessive iodine intake can result in structural and functional abnormalities in the thyroid gland. In this study, we selected children aged 3-6 years through a stratified cluster sampling approach in six regions across China to explore the correlation between iodine nutrition and their physical growth. A total of 5920 preschool children participated in this study, with a median urinary iodine concentration (UIC) of 177.33 [107.06, 269.92] μg/L. Among these children, 250 (4.2%) exhibited stunting, 180 (3.0%) were underweight, 198 (3.3%) experienced wasting, 787 (3.3%) were overweight and 414 (7.0%) were classified as obese. The multivariate linear regression revealed that UIC exhibited a positive correlation with body mass index z-Score (BMIZ) in overweight children (β = 0.038; 95% CI: 0.001, 0.075). In normally growing children, the associations between UIC and height-for-age z-score, weight-for-age z-score and BMIZ displayed nonlinear patterns. Our findings suggest that iodine nutrition is adequate for Chinese children aged 3-6 years. Furthermore, iodine nutrition is intricately linked to the growth and development of these children. Consequently, it is imperative to implement decisive measures to prevent both iodine deficiency and excess.

Conflicting associations have been noted between thyroid function and gestational diabetes mellitus (GDM), with indications that pre-pregnancy BMI might influence these relationships. This study aims to examine the effect of thyroid hormone indices and their mediation role on the risk of GDM.

Pregnant women in our study were recruited from the Zhoushan Pregnant Women Cohort, Zhejiang Province, China. Participants who had their first prenatal follow-up and measured thyroid biomarkers in the first trimester, and oral glucose tolerance test (OGTT) records in the second trimester were eligible for inclusion in this study. The data were extracted from the Electronic Medical Record System database, at Zhoushan Maternal and Child Care Hospital. Maternal information about sociodemographic and health-related characteristics was extracted from the dataset. A unique personal identification number was provided to link both datasets. Multivariate logistic regression models were applied to investigate the correlations between thyroid hormone indices with GDM. The interaction effects of first-trimester thyroid hormone indices with pre-pregnancy BMI on GDM risk using a generalized linear regression model. Furthermore, the mediation analysis was used to explore the potential mediating effects of thyroid hormone indices on the relationship between pre-pregnancy BMI and GDM.

Overall, 5895 pregnant women were included in this study. The first-trimester FT4, thyroid feedback quantile-based index (TFQI), thyrotropin index (TSHI) and thyrotroph thyroxine resistance index (TT4RI) levels were negatively associated with fasting blood glucose (FBG) and postprandial blood glucose (PBG2H) in the second trimester (all P<0.05); FT3 and the FT3-to-FT4 ratio levels were positively associated with PBG1H and PBG2H in the second trimester (all P<0.05). Moreover, there were significant correlations between the highest quartile FT4, FT3, FT3-to-FT4 ratio, TSHI, and TFQI with GDM (all P < 0.05). The mediating effect of thyroid hormone parameters was 24.9% on the association between pre-pregnancy BMI and GDM.

In conclusion, the low FT4, high FT3-to-FT4 ratio, and low TFQI in the first trimester significantly increase the risk of GDM and should be given more attention. Furthermore, increased pre-pregnancy BMI might partially increase the risk of GDM by influencing the body's thyroid function.

It has been shown that monochromatic green light and blue light promote skeletal muscle development in early (P0-P26) and later growth stages (P27-P42), respectively. This study further investigated the effects of monochromatic light combinations on myogenesis and myofiber types transformation in broilers. Here, a total of 252 chicks were exposed to monochromatic light [red (R), green (G), blue (B), or white light (W)], and monochromatic light combination [green and blue light combination (GB), blue and green light combination (BG), red and blue combination (RB)] until P42. Compared with other groups, GB significantly increased body weight, and muscle organ index, both proportions of larger-size myofibers and oxidative myofibers in the pectoralis major (PM) and gastrocnemius muscle (GAS). Meanwhile, GB up-regulated the abundance of oxidative genes MYH7B and MYH1B, transcription factors PAX7 and Myf5, antioxidant proteins Nrf2, HO-1, and GPX4, and the activities of antioxidant enzymes CAT, GPx, and T-AOC, but down-regulated the abundance of glycolytic related genes MYH 1A, MyoD, MyoG, Mstn, Keap1, TNFa, and MDA levels. Consistent with the change of myofiber pattern, GB significantly reduced serum thyroid hormone (TH) levels, up-regulated skeletal muscle deiodinase DIO3 expression and down-regulated deiodinase DIO2 expression, which may directly lead to the reduction of intramuscular TH levels to affect myofiber types transformation. In contrast, the proportion of fast glycolytic muscle fibers increased in the RR with increasing TH levels. After thyroidectomy, the above parameters were inversed and resulted in no significant difference of each color light treatment group. These data suggested that GB significantly increased the proportion of oxidative muscle fibers and antioxidant capacity in skeletal muscle of broilers, which was regulated by TH-DIO2/DIO3 signaling pathway.

Hashimoto thyroiditis and Graves' disease are autoimmune thyroid disorders that are common in women of reproductive age and have a complex relationship with female fertility and health of the maternal-fetal dyad. Both hyperthyroidism and hypothyroidism, whether subclinical or overt in severity, directly or indirectly affect nearly every level of the hypothalamic-pituitary-ovary axis, uterine and ovarian function, as well as fetal development from implantation through delivery. Autoimmunity itself also appears to negatively impact both spontaneous and assisted fertility, as well as miscarriage risk, although the mechanism remains unclear, and the presence and magnitude of risk is variable in published literature. While treatment of overt hyperthyroidism and hypothyroidism is unequivocally recommended by professional societies, the impact of treatment on fertility outcomes, and the role of treatment in subclinical thyroid disease is more controversial. Unfortunately, levothyroxine has not been shown to abrogate the risk of subfertility and miscarriage observed in euthyroid thyroid autoantibody positive women.

Regardless of the cause, hypothyroidism should be treated with levothyroxine. The objectives of management are the normalization of TSH levels and the relief of symptoms. In general, the vast majority of patients who achieve normalization of TSH levels show a resolution of symptoms; however, for a small number of individuals, symptoms persist (despite adequate control of TSH). This scenario generates a dilemma in the therapeutic approach to these patients, because even when excluding other causes or concomitant diseases that can explain the persistence of symptoms, pharmacological management strategies are scarce. Consequently, the efficacy of some less conventional approaches to therapy, such as the use of LT3 monotherapy, desiccated thyroid extracts, and LT4/LT3 combinations, in addressing persistent hypothyroid symptoms have been evaluated in multiple studies. The majority of these studies did not observe a significant benefit from these "nonconventional" therapies in comparison to results with LT4 monotherapy alone. Nevertheless, some studies report that a significant proportion of patients prefer an alternative to monotherapy with LT4. The most common approach has been to prescribe a combination of LT4 and LT3, and this review describes and analyzes the current evidence of the efficacy of LT4/LT3 combination therapy vs. LT4 monotherapy in addressing persistent hypothyroidism symptoms to provide suggested guidelines for clinicians in the management of these patients.

Thyroid Hormones (THs) play a central role in the development, cell growth, differentiation, and metabolic homeostasis of neurosensory systems, including the retina. The coordinated activity of various components of TH signaling, such as TH receptors (THRs) and the TH processing enzymes deiodinases 2 and 3 (DIO2, DIO3), is required for proper retinal maturation and function of the adult photoreceptors, Müller glial cells, and pigmented epithelial cells. Alterations of TH homeostasis, as observed both in frank or subclinical thyroid disorders, have been associated with sight-threatening diseases leading to irreversible vision loss i.e., diabetic retinopathy (DR), and age-related macular degeneration (AMD). Although observational studies do not allow causal inference, emerging data from preclinical models suggest a possible correlation between TH signaling imbalance and the development of retina disease. In this review, we analyze the most important features of TH signaling relevant to retinal development and function and its possible implication in DR and AMD etiology. A better understanding of TH pathways in these pathological settings might help identify novel targets and therapeutic strategies for the prevention and management of retinal disease.

Determining how internal and external stimuli interact to determine developmental trajectories of traits is a challenge that requires the integration of different subfields of biology. Internal stimuli, such as hormones, control developmental patterns of phenotypic changes, which might be modified by external environmental cues (e.g. plasticity). Thyroid hormone (TH) modulates the timing of opsin gene expression in developing Midas cichlid fish (Amphilophus citrinellus). Moreover, fish reared in red light accelerate this developmental timing compared to fish reared in white light. Hence, we hypothesized that plasticity caused by variation in light conditions has coopted the TH signaling pathway to induce changes in opsin gene expression. We treated Midas cichlids with TH and crossed this treatment with two light conditions, white and red. We observed that not only opsin expression responded similarly to TH and red light but also that, at high TH levels, there is limited capacity for light-induced plasticity. Transcriptomic analysis of the eye showed that genes in the TH pathway were affected by TH, but not by light treatments. Coexpression network analyses further suggested that response to light was independent of the response to TH manipulations. Taken together, our results suggest independent mechanisms mediating development and plasticity during development of opsin gene expression, and that responses to environmental stimuli may vary depending on internal stimuli. This conditional developmental response to external factors depending on internal ones (e.g. hormones) might play a fundamental role in the patterns of phenotypic divergence observed in Midas cichlids and potentially other organisms.

Mitochondria are highly plastic and dynamic organelles long known as the powerhouse of cellular bioenergetics, but also endowed with a critical role in stress responses and homeostasis maintenance, supporting and integrating activities across multifaced cellular processes. As a such, mitochondria dysfunctions are leading causes of a wide range of diseases and pathologies. Thyroid hormones (THs) are endocrine regulators of cellular metabolism, regulating intracellular nutrients fueling of sugars, amino acids and fatty acids. For instance, THs regulate the balance between the anabolism and catabolism of all the macro-molecules, influencing energy homeostasis during different nutritional conditions. Noteworthy, not only most of the TH-dependent metabolic modulations act via the mitochondria, but also THs have been proved to regulate the mitochondrial biosynthesis, dynamics and function. The significance of such an interplay is different in the context of specific tissues and strongly impacts on cellular homeostasis. Thus, a comprehensive understanding of THs-dependent mitochondrial functions and dynamics is required to develop more precise strategies for targeting mitochondrial function. Herein, we describe the mechanisms of TH-dependent metabolic regulation with a focus on mitochondrial action, in different tissue contexts, thus providing new insights for targeted modulation of mitochondrial dynamics.

Thyroid hormones, thyroxin (T4) and the biologically active triiodothyronine (T3), play important roles in liver metabolic regulation, including fatty acid biosynthesis, beta-oxidation, and cholesterol homeostasis. These functions position TH signaling as a potential target for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Elevated T3 levels in the circulation are associated with increased hepatic lipid turnover, which is also under the control of the circadian clock system. In this study, we developed a cell system to study the impact of hepatocyte circadian rhythms on the metabolic response to T3 treatment under control and steatotic conditions. Synchronized AML-12 circadian reporter hepatocytes were treated with T3 at different circadian phases and metabolic conditions. T3 treatment increased metabolic activity in a dose-independent fashion and had no significant effect on circadian rhythms in AML-12 cells. T3 had marked time-of-treatment-dependent effects on metabolic transcript expression. Steatosis induction altered metabolic transcript expression in AML-12 cells. In this condition, the circadian rhythm period was lengthened, and this effect was independent of T3. Under steatotic conditions, T3 had marked time-of-treatment dependent effects on metabolic transcript expression, which differed from those observed under control conditions. These findings reveal a time-of-day-dependent response of hepatocytes to T3, which is further modulated by the metabolic state. Our data suggest that time has a strong influence on liver TH action, which might be considered when treating MASLD.

Ischemic stroke, which accounts for 87% of cerebrovascular accidents, is responsible for massive global burden both in terms of economic cost and personal hardship. Many stroke survivors face long-term disability-a phenotype associated with an increasing number of genetic variants. While clinical variables such as stroke severity greatly impact recovery, genetic polymorphisms linked to functional outcome may offer physicians a unique opportunity to deliver personalized care based on their patient's genetic makeup, leading to improved outcomes. A comprehensive catalogue of the variants at play is required for such an approach. In this review, we compile and describe the polymorphisms associated with outcome scores such as modified Rankin Scale and Barthel Index. Our search identified 74 known genetic polymorphisms spread across 48 features associated with various poststroke disability metrics. The known variants span diverse biological systems and are related to inflammation, vascular homeostasis, growth factors, metabolism, the p53 regulatory pathway, and mitochondrial variation. Understanding how these variants influence functional outcome may be helpful in maximizing poststroke recovery.

The kynurenine pathway (KP) of tryptophan degradation includes several compounds that reveal immunomodulatory properties. The present study aimed to investigate the alteration in KP metabolites in young women with autoimmune thyroiditis (AIT) and their associations with thyroid function. The thyroid function tests, antithyroid antibodies measurement and ultrasonography of the thyroid gland have been performed in 57 young women with AIT and 38 age-matched healthy controls. The serum levels of tryptophan, kynurenine (KYN) and its metabolites were determined, and the activity of KP enzymes was calculated indirectly as product-to-substrate ratios. KP was activated and dysregulated in AIT, along with significantly elevated levels of KYN and anthranilic acid (AA), at the expense of the reduction of kynurenic acid (KYNA), which was reflected by the increase in the AA/KYNA ratio (p < 0.001). In univariate and multiple regression analyses, peripheral deiodinase (SPINA-GD) activity in AIT was positively associated with KYNA, AA, and quinolinic acid (QA). The merger of AA, AA/KYNA ratio, QA and SPINA-GD exhibited the highest sensitivity and specificity to predict AIT (p < 0.001) in receiver operating characteristic (ROC) analysis. In conclusion, the serum KYN metabolite profile is dysregulated in young women with AIT and could serve as a new predictor of AIT risk.

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-β. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-β, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

Autoimmune thyroid diseases (AITDs) include a wide spectrum of thyroid diseases affecting more commonly women than men. The most frequent forms are Graves' Disease (GD) and Hashimoto's thyroiditis / Autoimmune Thyroiditis (AIT), but there are also other immunogenic destructive forms of thyroiditis, that is, silent and postpartum thyroiditis. In the last decade, AITDs and other inflammatory thyroid diseases related to anti-tumor molecular drugs are more frequently seen due to the widespread use of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICPIs). Autoimmune thyroiditis related to SARS-CoV-2 infection has been a novel entity in recent years. Graves' Disease and AIT may shift from hyperthyroidism to hypothyroidism, which may complicate the differential diagnosis and further treatment strategy. Moreover, all AITDs may manifest with thyrotoxicosis (a clinical condition marked with high serum levels of thyroid hormones) which has to be distinguished from hyperthyroidism (increased thyroid hormone production and secretion as a result of hyperfunctioning thyroid gland) due to different therapeutic approaches. Nuclear medicine techniques, such as radioiodine uptake (RAIU) and thyroid scintigraphy, using 99mTc- pertechnetate (Na[99mTc]TcO4) or 123-Iodine (Na[123I]I), have a crucial role in the differential diagnosis. Measurement of thyroid antibodies, e.g. thyroid peroxidase antibodies (TPO) and thyrotropin receptor antibodies (TRAb), as well as thyroid ultrasound, are complementary methods in the evaluation of thyroid disorders.

The US Environmental Protection Agency is evaluating the ecological and toxicological effects of per- and polyfluorinated chemicals. A number of perfluorinated chemicals have been shown to impact the thyroid axis in vivo suggesting that the thyroid hormone system is a target of these chemicals. The objective of this study was to evaluate the activity of 136 perfluorinated chemicals at seven key molecular initiating events (MIE) within the thyroid axis using nine in vitro assays. The potential MIE targets investigated are Human Iodothyronine Deiodinase 1 (hDIO1), Human Iodothyronine Deiodinase 2 (hDIO2), Human Iodothyronine Deiodinase 3 (hDIO3), Xenopus Iodothyronine Deiodinase (xDIO3); Human Iodotyrosine Deiodinase (hIYD), Xenopus Iodotyrosine Deiodinase (xIYD), Human Thyroid Peroxidase (hTPO); and the serum binding proteins Human Transthyretin (hTTR) and Human Thyroxine Binding Globulin (hTBG). Of the 136 PFAS chemicals tested, 85 had sufficient activity to produce a half-maximal effect concentration (EC50) in at least one of the nine assays. In general, most of these PFAS chemicals did not have strong potency towards the seven MIEs examined, apart from transthyretin binding, for which several PFAS had potency similar to the respective model inhibitor. These data sets identify potentially active PFAS chemicals to prioritize for further testing in orthogonal in vitro assays and at higher levels of biological organization to evaluate their capacity for altering the thyroid hormone system and causing potential adverse health and ecological effects.

To explore the nature and extent of possible residual complaints among Dutch hypothyroid patients using thyroid replacement therapy, we initiated a comprehensive study measuring health-related quality of life (QoL), daily functioning, and hypothyroidism-associated symptoms in patients and control persons.

An online survey measuring thyroid-specific QoL (ThyPRO), daily functioning, and hypothyroidism-associated symptoms (ThySHI) was distributed among treated hypothyroid patients and control individuals. The advertising text was formulated in an open-ended manner. Patients also provided their most recent thyroid blood values and their thyroid medication.

There was a large-sized impairment of QoL (Cohen's d = 1.04, +93 % ThyPRO score) in hypothyroid patients on thyroid replacement therapy (n = 1195) as compared to controls (n = 236). Daily functioning was significantly reduced i.e., general health (-38 %), problems with vigorous- (+64 %) and moderate activities (+77 %). Almost 80 % of patients reported having complaints despite thyroid medication and in-range thyroid blood values, with 75 % expressing a desire for improved treatment options for hypothyroidism (total n = 1194). Hypothyroid patients experienced 2.8 times more intense hypothyroidism-associated symptoms than controls (n = 865, n = 203 resp). Patients' median reported serum concentrations were: TSH 0.90 mU/L, FT4 17.0 pmol/L, and FT3 2.67 pmol/L, with 52 % having low T3 levels (<3.1 pmol/L). The QoL was not found to be related to age, sex, BMI, menopausal status, stress, serum thyroid parameters, the origin and duration of hypothyroidism, the type of thyroid medication, or the LT4 dose used.

Our study revealed major reductions in quality of life and daily functioning, and nearly three times more intense hypothyroidism-associated symptoms in treated hypothyroid patients as compared to controls, despite treatment and largely in-range serum TSH/FT4 concentrations. The QoL was not associated with serum thyroid parameters. We recommend future research into the origin of persisting complaints and the development of improved treatment modalities for hypothyroidism.

Surgical removal of the thyroid gland (TG) for treating thyroid disorders leaves the patients on lifelong hormone replacement that partially compensates the physiological needs, but regenerating TG is challenging. Here, an approach is reported to regenerate TG within the spleen for fully restoring the thyroid's functions in mice, by transplanting thyroid tissue blocks to the spleen. Within 48 h, the transplanted tissue efficiently revascularizes, forming thyroid follicles similar to the native gland after 4 weeks. Structurally, the ectopically generated thyroid integrates with the surrounding splenic tissue while maintaining its integrity, separate from the lymphatic tissue. Functionally, it fully restores the native functions of the TG in hormone regulation in response to physiological stimuli, outperforming the established method of oral levothyroxine therapy in maintaining systemic homeostasis. The study demonstrates the full restoration of thyroid functions post-thyroidectomy by intrasplenic TG regeneration, providing fresh insights for designing novel therapies for thyroid-related disorders.

Malaria parasites have a devastating effect on the infected host. However, there is a paucity of data on the effect of Plasmodium falciparum on thyroid hormones.

This case-control study (1:1) involved children <16 years of age with uncomplicated malaria. Hematological parameters were determined using the URIT-5380 hematology analyzer (China). Later, levels of thyroid hormones, namely free triiodothyronine (fT3), free tetraiodothyronine (fT4), and thyroid-stimulating hormone (TSH), were determined using human ELISA kits (DiaSino ELISA kit, Zhengzhou, China).

Ninety children with malaria and ninety matched control group were studied. Overall, compared to the control group, lower TSH (3.43 ± 1.25 vs. 3.84 ± 1.34, p = 0.035) and elevated levels of fT3 levels (5.85 ± 1.79 vs. 3.89 ± 1.19, p < 0.001) were observed in patients with malaria. However, fT4 levels were comparable between cases and control group (16.37 ± 2.81 vs 17.06 ± 3.5, p = 0.150). Free T3 levels were significantly higher in children <10 years (p < 0.001) and higher among male children with malaria (p < 0.001). Overall, there was a significant positive relationship between parasite counts and fT3 (R = 0.95, p < 0.001). Furthermore, body temperature was positively correlated with fT3 (R = 0.97, p < 0.001).

Isolated fT3 thyrotoxicosis was observed in falciparum malaria, especially in children <10 years and male malaria patients, independent of TSH. This observation could explain the severity of malaria in children.

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. We explored these genes and created an expression panel that assesses liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH action under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state.

Thyroid hormones have vital roles in development, growth and energy metabolism. Within the past two decades, disturbances in thyroid hormone action have been implicated in ageing and the development of age-related diseases. This Review will consider results from biomedical studies that have identified the importance of precise temporospatial regulation of thyroid hormone action for local tissue maintenance and repair. Age-related disturbances in the maintenance of tissue homeostasis are thought to be important drivers of age-related disease. In most iodine-proficient human populations without thyroid disease, the mean, median and 97.5 centile for circulating concentrations of thyroid-stimulating hormone are progressively higher in adults over 80 years of age compared with middle-aged (50-59 years) and younger (20-29 years) adults. This trend has been shown to extend into advanced ages (over 100 years). Here, potential causes and consequences of the altered thyroid status observed in old age and its association with longevity will be discussed. In about 5-20% of adults at least 65 years of age, thyroid-stimulating hormone concentrations are elevated but circulating concentrations of thyroid hormone are within the population reference range, a condition referred to as subclinical hypothyroidism. Results from randomized clinical trials that have tested the clinical benefit of thyroid hormone replacement therapy in older adults with mild subclinical hypothyroidism will be discussed, as well as the implications of these findings for screening and treatment of subclinical hypothyroidism in older adults.

Thyroid hormones are critical modulators in the physiological processes necessary to virtually all tissues, with exceptionally fundamental roles in brain development and maintenance. These hormones regulate essential neurodevelopment events, including neuronal migration, synaptogenesis, and myelination. Additionally, thyroid hormones are crucial for maintaining brain homeostasis and cognitive function in adulthood. This chapter aims to offer a comprehensive understanding of thyroid hormone biosynthesis and its intricate role in brain physiology. Here, we described the mechanisms underlying the biosynthesis of thyroid hormones, their influence on various aspects of brain development and ongoing maintenance, and the proteins in the brain that are responsive to these hormones. This chapter was geared towards broadening our understanding of thyroid hormone action in the brain, shedding light on potential therapeutic targets for neurodevelopmental and neurodegenerative disorders.

Accumulated evidence showed that thyroid diseases induced cognitive decline. However, the relationship between thyroid hormones (THs) and cognition in older euthyroid people is still unclear. Our study aimed to estimate the association between THs within the euthyroid range and cognition in community-dwelling older adults in China. Data were extracted from a cohort study on the health status of rural older adults from the Guizhou province in China (HSRO). Serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) were measured using the electrochemiluminescence immunoassay. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE). Linear regression and a binary logistic regression model were used to explore the relationship between THs and cognition in euthyroidism (TSH level of 0.27 ~ 4.20mIU/L). A total of 957 euthyroidism individuals were included in this study, with a mean (SD) age of 71.34 (6.35) years. In individuals with euthyroidism, serum TSH and FT3 levels were positively associated with cognition (TSH:β = 0.06, 95% CI  0.01 ~ 0.11, P = 0.03; FT3:β = 0.07, 95% CI  0.01 ~ 0.12, P = 0.01); and serum FT3 and TSH levels were significantly associated with cognitive domains (P < 0.05). Further, euthyroid individuals in the lowest serum FT3(OR = 1.96; 95% CI 1.27 ~ 3.03) quartile had a twofold increased risk of cognitive impairment compared to those in the highest quartile after adjusting for potential confounding factors. These findings suggested that low levels of FT3 could be an independent risk factor for cognitive impairment in older euthyroid adults. Additionally, a positive linear association exists between serum FT3 levels and cognitive domains (such as immediate memory, language, and attention). Further studies are needed to determine the underlying mechanisms and the community significance of these findings.