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Many per- and polyfluoralkyl substances (PFASs) may disrupt maternal thyroid hormone homeostasis in pregnancy. Concerns should be raised regarding the PFASs exposure in pregnant women because thyroid hormones are involved in the early development of the fetus. In this study, we measured the concentrations of 13 PFASs, including five novel short-chain PFASs, in serum from 123 pregnant women in Beijing, China. Linear regression models were used to investigate the association between thyroid-stimulating hormone (TSH) or free thyroxine (FT4) levels and PFASs concentrations under consideration of the impacts of pregnancy-induced physiological factors. We found that perfluorobutanoic acid (PFBA) (β=0.189, 95%CI=-0.039, 0.417, p=0.10) and perfluorodecanoic acid (PFDA) (β=-0.554, 95%CI=-1.16, 0.049, p=0.071) were suggestive of significant association with TSH in thyroid peroxidase antibody (TPOAb) negative women. No association was observed between all PFASs and FT4 levels after controlling for these confounding factors, such as BMI, gestational weight gain and maternal age. These findings suggest that it should pay more attention to the association between thyroid hormone levels and short-chain PFASs concentrations. Future studies could consider a greater sample and the inclusion of other clinical indicators of thyroid function, such as free T3 and total T3.

Context Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. Objective (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. Methods (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. Results (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. Conclusion We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Graves' orbitopathy (GO), an extrathyroidal manifestation of Graves' disease, can seriously threaten a patient's quality of life. Given that immunosuppressive treatment during the early active phase of GO has been found to reduce both disease activity and severity, sensitive screening tests are needed.The present study included 86 patients with GO, in whom serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine, thyroid-stimulating antibody, TSH receptor antibody, thyroid peroxidase antibody, thyroglobulin, and thyroglobulin antibody were measured within 2 months before magnetic resonance imaging (MRI) for orbit assessment.The thyroid-stimulating antibody/TSH receptor antibody ratio was able to distinguish MRI results with a correct classification rate of 81%. When focusing on patients without T3 predominant Graves' diseases, the ratio distinguished MRI results at a rate of 92%. Receiver operating characteristic curve analysis revealed a cutoff antibody ratio of 87, which yielded a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 91%, 95%, 18.2, and 0.0957, respectively, for distinguished MRI results.The thyroid-stimulating antibody/TSH receptor antibody ratio is a highly sensitive and specific indicator for active GO, especially in patients without T3 predominance, and serves as a good screening test for active GO in primary care settings.

Thyroid hormones are critical for the development of opsins involved in color vision. Hypothyroid mice show delayed M-opsin development and expanded distribution of S-opsin on the retina. However, the effects of maternal hypothyroidism on opsin development remain unknown. This study investigates the effects of congenital central hypothyroidism and maternal hypothyroidism on opsin development in thyrotropin-releasing hormone knockout (TRH−/−) mice. We examined the mRNA expression and protein distribution of S/M-opsin on postnatal days (P)12 and 17, as well as mRNA expression of type 2 and 3 iodothyronine deiodinase (DIO2 and DIO3, respectively) in the retina and type 1 iodothyronine deiodinase (DIO1) in the liver at P12 in TRH+/− mice born to TRH+/− or TRH−/− dams, and conducted S/M-opsin analysis in TRH+/+ or TRH−/− mice born to TRH+/− dams at P12, P17, and P30. M-opsin expression was lower in TRH+/− mice born to TRH−/− dams than in those born to TRH+/− dams, whereas S-opsin expression did not significantly differ between them. DIO1, DIO2, and DIO3 mRNA expression levels were not significantly different between the two groups; therefore, thyroid function in peripheral tissues in the pups was similar. S/M-opsin expression did not significantly differ between the TRH+/+ and TRH−/− mice born to TRH+/− dams on any postnatal day. These results demonstrate that maternal hypothyroidism causes M-opsin developmental delay during the early developmental stages of neonatal mice, and TRH−/− mice, a model of congenital central hypothyroidism, born to a euthyroid dam do not have delayed opsin development.

Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC

Purpose Vitamin A is an essential nutrient with vital biological functions. The present study investigated the effect of different doses of vitamin A palmitate at different time intervals on thyroid hormones and glycemic markers. Methods Male rats were administrated vitamin A palmitate at different doses (0, 0.7, 1.5, 3, 6, and 12 mg/kg, oral) and samples were collected at different time intervals of 2, 4, and 6 weeks. The levels of vitamin A, thyroid hormones (T3, T4, and TSH), deiodinases (Dio1 and Dio3), glycemic markers (blood insulin and fasting glucose levels, HOMA IR and HOMA β), retinol-binding protein 4 (RBP4) and the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) were measured. Results The findings demonstrated that long-term supplementation with high doses of vitamin A palmitate resulted in hypothyroidism (lower T3 and T4 levels and elevated TSH levels) as well as upregulation of Dio1 and Dio3 expression levels. This effect was associated with elevated glucose and insulin levels, enhanced HOMA IR, and decreased HOMA B index. In addition, prolonged vitamin A supplementation significantly increased RBP4 levels that upregulated the expression of PEPCK. Conclusion High doses of vitamin A supplementation increased the risk of hypothyroidism, modulated insulin sensitivity, and over a long period, increased the incidence of type 2 diabetes mellitus associated with oxidative stress and hepatitis.

Vitamin D and myo-inositol reduce thyroid antibody titers in subjects with autoimmune thyroiditis. No previous study has investigated interactions between these agents. The aim of the current study was to determine whether the impact of exogenous vitamin D on thyroid autoimmunity and thyroid function in women with Hashimoto's thyroiditis depends on myo-inositol supplementation.The study population consisted of three thyroid antibody- and insulin sensitivity-matched groups of women with autoimmune thyroiditis and high-normal or slightly elevated TSH levels. Forty-one women (21 in group A and 20 in group C) had been treated for at least 6 months with myo-inositol (group A), while 21 women (group B) had not received myo-inositol preparations. Over the entire study period (6 months), groups A and C continued treatment with myo-inositol (2 g daily), while groups A and B received exogenous vitamin D (4000 IU daily). Plasma titers of thyroid peroxidase and thyroglobulin antibodies, as well as plasma concentrations of glucose, insulin, TSH, free thyroid hormones, prolactin, and 25-hydroxyvitamin D (25-OH-D) were assessed at entry and 6 months later. Moreover, baseline and follow-up values of the structure parameters of thyroid homeostasis were calculated RESULTS AND DISCUSSION: In groups A and B, vitamin D improved insulin sensitivity and increased 25-OH-D levels. Although follow-up antibody titers in both these groups were lower than baseline ones, the impact of vitamin D on thyroid peroxidase and thyroglobulin antibodies was stronger in group A than in group B. Only in group A, vitamin D decreased TSH levels and increased SPINA-GT. There were no differences between baseline and follow-up free values of glucose, thyroid hormones, prolactin, Jostel's index, and SPINA-GD. The impact of vitamin D treatment on antibody titers correlated with treatment-induced changes in 25-OH-D levels and the degree of improvement in insulin sensitivity. In group C, glucose homeostasis markers, antibody titers and hormone levels remained at a similar level throughout the study period.The obtained results suggest that the impact of vitamin D on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity in subjects with autoimmune thyroiditis is more pronounced if they receive myo-inositol.

Insulin resistance impairs the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity. Both metformin and myo-inositol were found to improve insulin sensitivity and to reduce thyrotropin levels in individuals with hypothyroidism. The aim of the present study was to compare the effect of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity between women receiving metformin and myo-inositol.The study included two groups of women with autoimmune hypothyroidism, treated for at least 6 months with either metformin (group A; n = 25) or myo-inositol (group B; n = 25). Both groups were matched for age, insulin sensitivity, hormone levels and antibody titers. For the following 6 months, all women received levothyroxine. Plasma levels of glucose, insulin, thyrotropin, free thyroid hormones, prolactin, 25-hydroxyvitamin D and high-sensitivity C-reactive protein (hsCRP), as well as titers of thyroid peroxidase and thyroglobulin antibodies were assessed at the beginning and at the end of the study.At baseline there were not differences between the study groups. Although levothyroxine reduced thyrotropin levels, increased free thyroid hormone levels and decreased antibody titers in both study groups, these effects were more pronounced in group A than group B. Only in group A, levothyroxine increased 25-hydroxyvitamin D, decreased hsCRP and improved insulin sensitivity. The impact of levothyroxine on thyrotropin and free thyroid hormones correlated with treatment-induced changes in insulin sensitivity, antibody titers, 25-hydroxyvitamin D and hsCRP.The present study suggests that the impact of levothyroxine on thyroid autoimmunity and hypothalamic-pituitary-thyroid axis activity is stronger in women receiving metformin than in women treated with myo-inositol.

The core neuroendocrine pathways regulating seasonal reproduction in vertebrates were characterized over a decade ago. This has led to the development of a “consensus” model of seasonal reproduction that appears to be largely conserved across mammals, birds, amphibians, reptile and fish. This model centers around the photoinduced increase in TSHβ expression in the pars tuberalis of the anterior pituitary gland as the key transducer of photic information from sensory cells to the critical switch in hypothalamic deiodinase enzyme expression that drives changes in localized thyroid hormone signaling. These changes in localized thyroid hormone signaling in the medial basal hypothalamus ultimately activate the reproductive axis. This model has in turn, been consistently supported by studies in a variety of taxa. As such, it has become the standard against which subsequent work is compared, particularly in the non-mammalian literature. However, as new studies move away from the handful of canonical model systems and begin to explore the effects of naturalistic rather than artificial photoperiod manipulations, a more nuanced picture has begun to emerge. Yet, progress in elucidating the detailed events of reproductive photostimulation has been uneven across the research community. In this perspective, I draw on emerging data from studies in free living animals that challenges some of the established assumptions of the avian consensus model of reproduction. Specifically, the role of TSHβ and its dissociation from deiodinase signaling. I then discuss how these apparently surprising findings can be contextualized within the context of the mammalian seasonal literature. In turn, this ability to contextualize from the mammalian literature highlights the breadth of the current gap versus our understanding of the molecular neuroendocrine mechanisms of seasonality in mammals versus birds and other non-mammalian seasonal breeders.

Maternal overweight or obesity during early pregnancy can increase the subsequent risk of gestational diabetes mellitus (GDM). However, whether these associations are mediated by thyroid hormones and their effect sizes is still unknown. This study aimed to identify the mediating effects of thyroid parameters between prepregnancy body mass index (BMI) or maternal weight gain during early pregnancy on the subsequent risk of GDM.This prospective mother-infant cohort study was conducted from 2018 to 2019. A total of 2772 singleton pregnant women were included in the analysis. A questionnaire survey, anthropometric measures, and thyroid function testing were conducted during early pregnancy. Deiodinase activity was evaluated using the free-triiodothyronine-to-free-thyroxine ratio (FT3:FT4). The standard 75-g oral glucose tolerance test was performed during 24 to 28 weeks of gestation to diagnose GDM. A mediation analysis was performed using PROCESS 3.5 to examine the mediating effects of thyroid parameters between prepregnancy BMI or maternal weight gain during early pregnancy on the subsequent risk of GDM.The FT3:FT4 ratio was a significant mediator between prepregnancy BMI or maternal weight gain and GDM, accounting for 16.5% and 18.6% of total effects, respectively. FT3 also mediated the association of prepregnancy BMI with GDM, accounting for 3.3% of the total effects. Thyroid-stimulating hormone suppressed the effects of prepregnancy BMI and maternal weight gain on GDM risk, and the proportion of their total effects was 2.4% and 6.4%, respectively.Deiodinase activity, as indicated by the FT3:FT4 ratio, was the strongest mediator among thyroid parameters between prepregnancy BMI or maternal early weight gain and GDM.

BACKGROUND: Multinodular goiter (MNG) is the most common disorder of the thyroid gland. Aging and genetic mutations that impair thyroid hormone (TH) production have been implicated in the development of MNG. XB130 is an adaptor/scaffold protein predominantly expressed in the thyroid gland. XB130 deficiency leads to transient postnatal growth retardation in mice due to congenital hypothyroidism. We studied the formation of MNG and possible mechanisms in elderly mice. METHODS: Thyroid glands of male and female Xb130-knockout (Xb130(−/−)), heterozygous (Xb130(+/−)), and wild-type (Xb130(+/+)) mice at the ages of 12–20 months were harvested for visual examination, histopathological, and immunohistological analyses. Blood and thyroid samples were collected after feeding elderly mice with a low iodine diet for (125)I uptake and perchlorate discharge assay. The activity of thyroperoxidase (Tpo) was examined by spectrophotometric evaluation of iodide oxidation. RESULTS: While moderate MNG was seen in Xb130(+/+) and Xb130(+/−) mice, severe MNG, characterized by multiple nodules intermixed with dilated colloid-rich macrofollicles, was found only in Xb130(−/−) mice at 18 months. Thyrocyte cytoskeletal structure and cell adhesion molecules were disorganized, and TH production was significantly reduced. Reduced iodide organification was seen in elderly Xb130(+/+) mice and further enhanced in Xb130(−/−) mice. In Xb130(+/+) mice, Tpo shows high affinity with hydrogen peroxide (H(2)O(2)) throughout aging, but reduced affinity with iodide in an age-dependent manner. By contrast, in elderly Xb130(−/−) mice, the affinity of Tpo for iodide remained high, but the affinity of Tpo for H(2)O(2) was reduced. CONCLUSIONS: The pathophysiological features in the thyroid glands of aged Xb130(−/−) mice closely resemble the features of MNG in humans. Moderate MNG in elderly mice was dramatically aggravated by XB130 deficiency. Reduced affinity of Tpo for H(2)O(2) may contribute to MNG development via oxidative stress. This could be specific to XB130 deficiency but also could be a common mechanism in MNG. Its clinical relevance should be further investigated.

Objective The absence of specific markers can make the diagnosis of neuroimmune disorders difficult, making other biomarkers such as thyroid peroxidase antibodies (TPO-Abs) more relevant. Laboratory tests are susceptible to interference, especially those tests performed using immunoassay techniques. The effect of treatment with human intravenous immunoglobulin (IVIG) on the results of TPO-Abs assays has not been previously characterized. Materials and Methods We analyzed TPO-Abs levels in 170 children monitored in the neuroimmune disease department of a tertiary hospital. We analyzed the characteristics of patients with increased TPO-Abs values and compared their progress with and without treatment. Results We found that 97% of patients with elevated TPO-Abs had received IVIG. After withdrawal from IVIG, a mean TPO-Abs decrease of 62.5% at 1 month was observed. The IVIG drug preparation was found to contain 1176 U/mL of TPO-Abs. An interferogram confirmed interference. Conclusion It is advisable to measure levels of TPO-Abs before starting immunotherapy and remain vigilant regarding possible interference in the event of unsubstantiated elevations of this analyte.

Iodothyronine deiodinases (DIO) are key enzymes that influence tissue-specific thyroid hormone levels during thyroid-mediated amphibian metamorphosis. Within the larger context of evaluating chemicals for thyroid system disrupting potential, chemical activity toward DIOs is being evaluated using high-throughput in vitro screening assays as part of U.S. EPA’s ToxCast program. However, existing data gaps preclude any inferences between in vitro chemical inhibition of DIOs and in vivo outcomes relevant to ecological risk assessment. This study aimed to generate targeted data in a laboratory model species (Xenopus laevis) using a model DIO inhibitor, iopanoic acid (IOP), to characterize linkages between in vitro potency, in vivo biochemical responses, and adverse organismal outcomes. In vitro potency of IOP toward DIOs was evaluated using previously developed in vitro screening assays, which showed concentration-dependent inhibition of human DIO1 (IC50: 97 µM) and DIO2 (IC50: 231 µM) but did not inhibit human or X. laevis DIO3 under the assay conditions. In vivo exposure of larval X. laevis to 0, 2.6, 5.3, and 10.5 µM IOP caused thyroid-related biochemical profiles in the thyroid gland and plasma consistent with hyperthyroxinemia but resulted in delayed metamorphosis and significantly reduced growth in the highest 2 exposure concentrations. Independent evaluations of dio gene expression ontogeny, together with existing literature, supported interpretation of IOP-mediated effects resulting in a proposed adverse outcome pathway for DIO2 inhibition leading to altered amphibian metamorphosis. This study highlights the types of mechanistic data needed to move toward predicting in vivo outcomes of regulatory concern from in vitro bioactivity data.

High levels of 3-mono- and 3,5-diiodotyrosine (MIT and DIT, respectively) in urine have been related to iodotyrosine dehalogenase 1 deficiency, a type of congenital hypothyroidism. However, the determination of MIT and DIT in urine is not included in newborn screening programs performed in clinical laboratories to detect inborn errors of metabolism. We report here on the development of an analytical method for the determination of MIT and DIT in newborn urine and dried urine spots (DUS) by Liquid Chromatography Isotope Dilution tandem Mass Spectrometry (LC-IDMSMS). The development included the synthesis of

Objective: Although some previous data have suggested a high iodine intake in Brazil, the prevalence of antithyroperoxidase antibodies (TPOAb) in the country is compatible with rates from countries with adequate iodine intake. This observation emphasizes the importance of knowing the incidence of TPOAb in Brazil. Materials and methods: This prospective analysis included euthyroid participants with negative TPOAb at baseline and a thyroid function assessment at a 4-year follow-up. TPOAb was measured by electrochemiluminescence and considered positive when titers were ≥34 IU/mL. TSH and free T4 (FT4) levels were determined by a third-generation immunoenzymatic assay. The incidence of TPOAb is expressed in percentage per year or as a cumulative incidence within the 4-year follow-up period. Results: Of 8,922 euthyroid participants (mean age 51.1 years; 50.9% women) with a negative TPOAb test at baseline, 130 presented incident TPOAb at the 4-year follow-up, yielding an annual incidence of TPOAb of 0.38%/year (95% confidence interval [95% CI], 0.37-0.39%/year) and a cumulative incidence over 4 years of 1.46% (95% CI, 1.21-1.71%). In men, the annual incidence was 0.32% (95% CI, 0.31-0.33%), and the cumulative incidence over 4 years was 1.23% (95% CI, 0.90-1.56%). In women, the annual incidence was 0.43%/year (95% CI, 0.42-0.44%/year) and the cumulative incidence over 4 years was 1.67% (95% CI, 1.30-2.04%). The only factor associated with incident TPOAb was the occurrence of thyroid diseases at follow-up. No differences in TPOAb incidence were detected across ELSA-Brasil research centers. Conclusion: Based on the results of this study, the incidence of TPOAb per year and at a 4-year follow-up period are compatible with those of a country with adequate iodine intake.

Thyroid hormone (TH) signaling is strictly regulated by iodothyronine deiodinase activity, which both preserves the circulating levels of the biologically active triiodothyronine (T3) and regulates TH homeostasis at the local level, in a cell- and time-dependent manner. Three deiodinases have been identified—namely iodothyronine deiodinase 1 (DIO1), DIO2, and DIO3—that differ in their catalytic properties and tissue distribution. The deiodinases represent a dynamic system that changes in the different stages of life according to their functions and roles in various cell types and tissues. Deiodinase activity at the tissue level permits cell-targeted fine regulation of TH homeostasis, mediating the activation (DIO1 and DIO2) and inactivation (DIO3) of THs. Deiodinase homeostasis is the driving force that leads T3-target cells towards customized TH signaling, which takes into account both the hormonal circulating levels and the tissue-specific response. This review analyzes the complex role of deiodinases in physiological and pathological contexts, exploring new challenges and opportunities deriving from a deeper knowledge of the dynamics underlying their roles and functions.

Maternal hyperthyroidism is associated with an increased incidence of congenital abnormalities at birth, but it is not clear which of these defects arise from a transient developmental excess of thyroid hormone and which depend on pregnancy stage, antithyroid drug choice, or unwanted subsequent fetal hypothyroidism. To address this issue, we studied a mouse model of comprehensive developmental thyrotoxicosis secondary to a lack of type 3 deiodinase (DIO3). Dio3-/- mice exhibited reduced neonatal viability on most genetic backgrounds and perinatal lethality on a C57BL/6 background. Dio3-/- mice exhibited severe growth retardation during the neonatal period and cartilage loss. Mice surviving after birth manifested brain and cranial dysmorphisms, severe hydrocephalus, choanal atresia, and cleft palate. These abnormalities were noticeable in C57BL/6J Dio3-/- mice at fetal stages, in addition to a thyrotoxic heart with septal defects and thin ventricular walls. Our findings stress the protecting role of DIO3 during development and support the hypothesis that human congenital abnormalities associated with hyperthyroidism during pregnancy are caused by transient thyrotoxicosis before clinical intervention. Our results also suggest thyroid hormone involvement in the etiology of idiopathic pathologies including cleft palate, choanal atresia, Chiari malformations, Kaschin-Beck disease, and Temple and other cranio-encephalic and heart syndromes.

Maternal hormones, such as thyroid hormones (THs) transferred to embryos and eggs, are key signaling pathways for mediating maternal effects. To be able to respond to maternal cues, embryos must express the key molecular "machinery" of hormone pathways, such as enzymes and receptors. While altricial birds begin TH production only at or after hatching, experimental evidence suggests that their phenotype can be influenced by maternal THs deposited into the egg. However, it is not understood how or when altricial birds express genes in the TH pathway. For the first time, we measured the expression of key TH-pathway genes in altricial embryos by using two common altricial ecological model species, pied flycatcher (

Studies on the association of thyroid autoimmunity with cardiometabolic risk and coronary artery disease (CAD) have produced conflicting results. This study aimed to investigate the relationship of thyroid autoimmune bodies (thyroid peroxidase antibody [TPOAb] and thyroglobulin antibody [TgAb]) with CAD in euthyroid subjects undergoing coronary angiography. A total of 307 subjects who underwent coronary angiography were included. The severity of coronary atherosclerosis was evaluated by using Gensini score. Serum TSH, total T3, total T4, TPOAb, TgAb, lipid levels et al were measured and compared between the groups with and without CAD. Logistic multivariate regression analysis were performed to assess the associations. Levels of thyroid hormones were comparable between the two groups. The positive percentage of anti-Tg antibodies was higher in non-CAD group (15.22% vs 7.91%, χ2 = 3.95, p = .047) while no significant difference was observed for anti-TPO antibodies (19.57% vs 17.21%, χ2 = 0.243, p = .622). The natural log-transformed Gensini score (ln (Gensini score)) was lower in the TgAb+ group (2.94 ± 1.11 vs 2.41 ± 1.18, P = .015). There was no significant difference for ln (Gensini score) between TPOAb- and TPOAb+ group (2.90 ± 1.14 vs 2.85 ± 1.09, P = .782). Logistical regression analysis revealed that positive TgAb was inversely associated with the presence of CAD (OR: 0.387, 95% CI: 0.157-0.952, p = .039) independent of other risk factors. The results showed that TgAb positivity might be an independent protective factor for CAD.

Larval metamorphosis in bivalves is a key event for the larva-to-juvenile transformation. Previously we have identified a thyroid hormone receptor (TR) gene that is crucial for larvae to acquire “competence” for the metamorphic transition in the mussel Mytilus courscus (Mc). The mechanisms of thyroid signaling in bivalves are still largely unknown. In the present study, we molecularly characterized the full-length of two iodothyronine deiodinase genes (McDx and McDy). Phylogenetic analysis revealed that deiodinases of molluscs (McDy, CgDx and CgDy) and vertebrates (D2 and D3) shared a node representing an immediate common ancestor, which resembled vertebrates D1 and might suggest that McDy acquired specialized function from vertebrates D1. Anti-thyroid compounds, methimazole (MMI) and propylthiouracil (PTU), were used to investigate their effects on larval metamorphosis and juvenile development in M. coruscus. Both MMI and PTU significantly reduced larval metamorphosis in response to the metamorphosis inducer epinephrine. MMI led to shell growth retardation in a concentration-dependent manner in juveniles of M. coruscus after 4 weeks of exposure, whereas PTU had no effect on juvenile growth. It is hypothesized that exposure to MMI and PTU reduced the ability of pediveliger larvae for the metamorphic transition to respond to the inducer. The effect of MMI and PTU on larval metamorphosis and development is most likely through a hormonal signal in the mussel M. coruscus, with the implications for exploring the origins and evolution of metamorphosis.

Background: Human chorionic gonadotropin (hCG) is a marker of placental function, which also stimulates the maternal thyroid gland. Maternal thyroid function can be associated with the pathophysiology of gestational diabetes mellitus (GDM). We aimed to study whether there is an association of hCG concentrations in early pregnancy with GDM and whether it is mediated through maternal thyroid hormones. Methods: This study included 18,683 pregnant women presenting at a tertiary hospital in Shanghai, China, between January 2015 and December 2016. GDM was diagnosed using a 2-hour, 75-g, oral glucose tolerance test (OGTT) according to the American Diabetes Association guidelines. Multivariable logistic or linear regression models were used to identify associations, adjusting for maternal age, education level, family history of diabetes, parity, fetal sex, thyroperoxidase antibody (TPOAb) status, and prepregnancy body-mass index. Results: Higher hCG concentrations were associated with a lower plasma glucose level during the OGTT, but not with fasting plasma glucose or hemoglobin A1c concentrations tested during early pregnancy. hCG in early pregnancy was negatively associated with GDM risk (p = 0.027). Mediation analysis identified that an estimated 21.4% of the association of hCG-associated GDM risk was mediated through changes in free thyroxine (fT4) concentrations (p < 0.05). In the sensitivity analysis restricted to TPOAb-positive women, hCG was not associated with GDM (p = 0.452). Conclusions: Higher hCG levels in early pregnancy are associated with a lower risk of GDM. Maternal fT4 may act as an important mediator in this association.

This study aims to investigate the beneficial effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on trabecular meshwork cells under oxidative stress and predict candidate genes associated with this process. Trabecular meshwork cells were pretreated with BMSC-derived exosomes for 24 h, and exposed to 0.1 mM H2O2 for 6 h. Survival rate of trabecular meshwork cells was measured with CCK-8 assay. Production of intracellular reactive oxygen species (iROS) was measured using a flow cytometer. RT-PCR and ELISA were used to detect mRNA and protein levels of inflammatory cytokines and matrix metalloproteinases (MMPs). Sequencing of RNA and miRNA for trabecular meshwork cells from Exo and control groups was performed on BGISEQ500 platform. Phenotypically, pretreatment of BMSC-derived exosomes improves survival rate of trabecular meshwork cells exposed to H2O2, reduces production of iROS, and inhibits expression of inflammatory cytokines, whereas increases expression of MMPs. There were 23 miRNAs, 307 lncRNAs, and 367 mRNAs differentially expressed between Exo and control groups. Exosomes derived from BMSCs may protect trabecular meshwork cells from oxidative stress. Candidate genes responsible for beneficial effects, such as DIO2 and HMOX1, were predicted.

The type 2 deiodinase (D2) in the neonatal liver accelerates local thyroid hormone triiodothyronine (T3) production and expression of T3-responsive genes. Here we show that this surge in T3 permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increases H3K9me3 levels during post-natal days 1–5 (P1–P5), and results in methylation of 1,508 DNA sites (H-sites) in the adult mouse liver. These sites are associated with 1,551 areas of reduced chromatin accessibility (RCA) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,363 genes. There is strong spatial correlation between density of H-sites and RCA sites. Chromosome conformation capture (Hi-C) data reveals a set of 81 repressed genes with a promoter RCA in contact with an intergenic RCA ~300 Kbp apart, within the same topologically associating domain (χ2 = 777; p, Whether thyroid hormones affect gene expression via DNA methylation is not well known. Here the authors show that type 2 deiodinase (D2) converts T4 to produce T3, which prevents DNA methylation of discrete areas in the neonatal liver. In the absence of D2, DNA methylation occurs and is associated with reduced chromatin accessibility in promoters and enhancers and affects gene expression.

The thyroid hormones (THs), thyroxine (T4) and triiodothyronine (T3), are of vital importance for fetal development. The concentration of THs in fetal circulation varies throughout gestation and differs from the concentration in the maternal serum, indicating the presence of maternal-fetal thyroid homeostasis regulatory mechanisms in the placenta. The passage of THs from maternal circulation to fetal circulation is modulated by plasma membrane transporters, enzymes, and carrier proteins. Monocarboxylate transporter 8, iodothyronine deiodinases (DIO2 and DIO3), and transthyretin are especially involved in this maternal-fetal thyroid modulation, shown by a greater expression in the placenta. THs also play a role in placental development and as expected, abnormal variations in TH levels are associated with pregnancy complications and can result in damage to the fetus. Although new evidence regarding TH regulation during pregnancy and its effects in the mother, placenta, and fetus has been published, many aspects of these interactions are still poorly understood. The objective of this review is to provide an evidence-based update, drawn from current data, on the metabolism and transport of THs in the placenta and their vital role in the maternal-fetal relationship.

Background: It is unclear whether levels of hypothyroid symptoms in pregnant women with (sub)clinical thyroid dysfunction differ from euthyroid controls and whether free thyroxine (fT4)/thyrotropin (TSH) changes throughout pregnancy affect hypothyroid symptom levels. The objective was twofold: (1) To compare hypothyroid symptom levels between thyroid dysfunction subgroups and a carefully defined reference group; (2) to assess the association between fT4/TSH changes throughout pregnancy and hypothyroid symptom levels adjusted for depressive symptoms. Methods: The current study was a longitudinal prospective cohort study in 1800 healthy pregnant women. At each trimester of pregnancy, hypothyroid symptoms were assessed with a 12-item symptom hypothyroidism checklist and depressive symptoms with the Edinburgh Depression Scale. Thyroid dysfunction was defined using the 2.5-97.5th fT4/TSH percentile of thyroid peroxidase antibodies-negative women. Euthyroid controls consisted of women with appropriate fT4 levels within the 10-90th percentile and with a normal TSH level. Hypothyroid symptom mean scores were compared between controls and several thyroid dysfunction subgroups. Growth mixture modeling was performed to evaluate possible longitudinal trajectories of hypothyroid and depressive symptoms. The association between hypothyroid symptom trajectories (adjusted for depression) and fT4/TSH changes was assessed with multivariate logistic regression analysis. Results: Women with overt hypothyroidism (fT4 97.5th) and hypothyroxinemia (fT4 97.5th), because 82% of these SCH women had fT4 levels in the euthyroid range. Two groups of hypothyroid and depressive symptoms were defined: a persistently low and persistently high symptom group. fT4 decreased in 98% of the women from the first to third trimester and per unit pmol/L fT4 decrease (not TSH increase), the likelihood to present persistently high hypothyroid symptoms increased with 46%, adjusted for depression. Conclusions: A properly defined euthyroid control group distinguishes women with hypothyroid symptoms. An fT4 decrease toward end term is associated with persistently high hypothyroid symptom levels. Clinicians should be aware of the importance of fT4 stratification in SCH women.

BackgroundUnexplained recurrent spontaneous abortion is a serious reproductive problem of unknown etiology. Thyroid peroxidase antibodies (TPO-Ab) may be associated with pregnancy outcomes in unexplained recurrent spontaneous abortion with normal thyroid function.ObjectiveThis study aimed to investigate the relationship between TPO-Ab and the first trimester miscarriage rate/live birth rate in women of unexplained recurrent spontaneous abortion with normal thyroid function.MethodsWe retrospectively analyzed the clinical data of 297 women who met our strict inclusion criteria, comparing the first trimester miscarriage rate/live birth rate between the TPO-Ab positive and TPO-Ab negative groups. For the same purpose, we also performed subgroup analysis.ResultsOf the included women, 76 (25.6%) were TPO-Ab positive, and 221 (74.4%) were negative. First trimester miscarriage rate differed between the two groups (36.8% vs 24.0%, RR = 1.54, 95% CI: 1.05–2.24, P = 0.030). In the younger subgroup (P = 0.030; 36.5% vs 21.7%, RR = 1.69, 95% CI: 1.10–2.58, P = 0.020). While the live birth rate was lower in women with TPO-Ab positive, the difference did not reach statistical significance, even in the subgroup analysis.ConclusionOur results suggest that TPO-Ab is associated with first trimester miscarriage rate in euthyroid women with unexplained recurrent spontaneous abortion.

biBackground:/i/bEpidemiological and experimental studies suggest that thyroid peroxidase antibody (TPOAb)- and thyroglobulin antibody (TGAb)-positive exposure during gestation may contribute to offspring's adverse neural development. However, limited knowledge is available on the association between joint exposure on TPOAb and TGAb and children's emotional and behavioral development. Furthermore, the sex-specific effect on the developmental process of preschoolers' emotions and behaviors is unknown. The present research intends to examine the sex-specific effect of TPOAb- and TGAb-positive exposure in gestation on the developmental process of preschoolers' emotions and behaviors.biMethods:/i/bA total of 2455 mother-child pairs were included from the Ma'anshan Birth Cohort study. The serum TPOAb and TGAb of pregnant women was measured retrospectively by electrochemical immunoassay during the follow-up period. Preschoolers' emotional and behavioral development was assessed by a child behavior checklist 1.5-5. Growth mixture modeling was adopted to fit thyroid antibody (TAb) trajectories. Poisson regression models were used, stratifying by sex, to examine the association between TAb trajectories, as well as four categories of maternal TAb exposure and preschoolers' emotional and behavioral problems.biResults:/i/bBoys born to mothers with TPOAb positivity in the first, second, and third trimesters of pregnancy had an increased risk of autism spectrum problems after adjusting for confounders, with relative risk (RR) [confidence interval, CI] of 2.01 [1.24-3.27], 2.15 [1.08-4.26], and 2.13 [1.20-3.79], respectively. Maternal TGAb positivity and TPOAb negativity in the first trimester were associated with a high risk of attention-deficit/hyperactivity problems in boys (RR = 1.74 [CI 1.01-2.99]). The prevalence of depressive problems in girls was 33.3% after exposure to TPOAb alone in the third trimester of pregnancy. Exposure to TPOAb alone in the third trimester of pregnancy was associated with an increased risk of depressive problems in girls (RR = 1.78 [CI 1.09-2.90]).biConclusions:/i/bMaternal TPOAb positivity in all three trimesters was associated with the risk of autism spectrum problems in boys. Isolated maternal TGAb positivity in the first trimester was associated with attention-deficit/hyperactivity problems in boys, whereas isolated maternal TPOAb positivity in the third trimester was associated with depressive problems in girls.

BackgroundThe preoperative risk stratification for patients with papillary thyroid carcinoma (PTC) plays a crucial role in guiding individualized treatment. We aim to construct a predictive model that aids in distinguishing between patients with low-risk and high-risk PTC based on preoperative clinical and ultrasound characteristics.Materials and methodsPatients who underwent open surgery and were diagnosed with PTC via a postoperative pathological report between January 2020 and December 2020 were retrospectively reviewed. Data including basic information, preoperative ultrasound characteristics, thyroid function, and postoperative pathology characteristics were obtained. Univariate logistic regression analysis and least absolute shrinkage and selection operator regression analysis were performed to screen candidate variables. Finally, the preoperative predictive model for PTC was established based on the results of the multivariate logistic regression analysis.ResultsA total of 1,875 patients with PTC were enrolled. Eight variables (sex, age, number of foci, maximum tumor diameter on ultrasound, calcification, capsule, lymph node status on ultrasound, and thyroid peroxidase (TPO) antibody level) significantly associated with risk stratification were included in the predictive model. A nomogram was constructed for clinical utility. The model showed good discrimination, and the area under the curve was 0.777 [95% confidence interval (CI): 0.752–0.803] and 0.769 (95% CI: 0.729–0.809) in the training set and validation set, respectively. The calibration curve exhibited a rather good consistency with the perfect prediction. Furthermore, decision curve analysis and clinical impact curve showed that the model had good efficacy in predicting the prognostic risk of PTC.ConclusionsThe nomogram model based on preoperative indicators for predicting the prognostic stratification of PTC showed a good predictive value. This could aid surgeons in deciding on individualized precision treatments.

Risk factors associated with antidepressant treatment-emergent mania(ATEM) are poorly characterized in child and adolescent populations. To identify better biomarkers, we aimed to explore whether thyroid autoimmunity is associated with ATEM in pediatric mood disorders. We enrolled two groups of pediatric mood disorders, those with ATEM+ (n = 29) and those with ATEM- controls (n = 31). All diagnoses were made according to structured interviews by the clinicians. Autoimmune thyroiditis (anti-thyroid peroxidase antibodies [TPO-abs] and thyroid function (thyroid-stimulating hormone [TSH] and free thyroxin [FT4]) were assessed. Logistic regression was used to explore the relationship between TPO-abs seroprevalence and ATEM+ while controlling for covariates. Group comparisons showed that the patient with ATEM+ had significantly higher seroprevalence and titer of TPO-abs compared to ATEM- controls. In logistic regression analysis adjusting for age, gender, Tanner stage, body mass index, antipsychotic treatments, smoking status and family history of thyroid disorder, the seroprevalence of TPO-abs (>60 U/mL) was significantly associated with ATEM+ (OR = 3.67, 95% confidence interval [CI] = 1.2-11.1, p = 0.022). Our findings demonstrated that seroprevalence and titer of TPO-abs in pediatric mood disorders are associated with ATEM+ status. TPO-abs could potentially serve as a biomarker when assessing the risk of ATEM in the child and adolescent population.

Funder: Sherman Foundation, Funder: NIHR Cambridge Biomedical Centre, Development and differentiation of the thyroid gland is directed by expression of specific transcription factors in the thyroid follicular cell which mediates hormone biosynthesis. Membrane transporters are rate-limiting for cellular entry of thyroid hormones (TH) (T4 and T3) into some tissues, with selenocysteine-containing, deiodinase enzymes (DIO1 and DIO2) converting T4 to the biologically active hormone T3. TH regulate expression of target genes via hormone-inducible nuclear receptors (TRα and TRβ) to exert their physiological effects. Primary congenital hypothyroidism (CH) due to thyroid dysgenesis may be mediated by defects in thyroid transcription factors or impaired thyroid stimulating hormone receptor function. Dyshormonogenic CH is usually due to mutations in genes mediating thyroidal iodide transport, organification or iodotyrosine synthesis and recycling. Disorders of TH signalling encompass conditions due to defects in membrane TH transporters, impaired hormone metabolism due to deficiency of deiodinases and syndromes of Resistance to thyroid hormone due to pathogenic variants in either TRα or TRβ. Here, we review the genetic basis, pathogenesis and clinical features of congenital, dysgenetic or dyshormonogenic hypothyroidism and disorders of TH transport, metabolism and action.

Background The objectives of this study are to assess the prevalence of clinical and subclinical hypo- and hyperthyroidism and their associated factors among Jordanian adults. Methods In a cross-sectional population-based survey, a representative sample that included 3753 Jordanian adults was selected from the 12 governorates that represent the three regions of the country, in the year 2017. Sociodemographic and clinical data were obtained and blood samples were collected from all participants. Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4), thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) were measured to evaluate the thyroid function. Results The overall prevalence of thyroid dysfunction was 11.9%. Around 76% of patients with thyroid dysfunction were previously undiagnosed. The prevalence of hypothyroidism and subclinical hypothyroidism was 3.1 and 5.3%, respectively. The prevalence of hyperthyroidism and subclinical hyperthyroidism was 1.0 and 2.5%, respectively. Female preponderance which was mainly related to hypothyroid disorders was evident. The prevalence of positive TPOAb and TgAb in the study population was 14.9 and 15.3%, respectively. The prevalence of detectable TPOAb and TgAb in the euthyroid participants was10.3 and 11.9%, respectively. Logistic regression analysis revealed that female sex, age ≥ 50 years and the presence of TgAb and TPOAb were strongly associated with hypothyroidism. Hyperthyroidism was significantly associated with the presence of TPOAb and age ≥ 50 years. Conclusion The prevalence of unrecognized thyroid dysfunction is high among Jordanians. A public health policy of screening high risk groups particularly those ≥50 years of age is recommended.

Objective Iodothyronine deiodinases (DIOs) are important selenoproteins that play a key role in the bone and joint diseases. Osteoarthritis (OA) is the most prevalent joint disease especially in elders. This bioinformatic analysis was performed to explore the role of DIOs in OA pathogenesis. Methods The biological functions of selenoprotein DIOs were analyzed by bioinformatic techniques, including GenCLip 3.0, Database for Annotation, Visualization and Integrated Discovery (DAVID), STRING, Cytoscape, and Network Analyst. The expression of DIOs in the healthy individuals and OA patients was determined by mining OA-related microarray data in the gene expression omnibus (GEO) database of National Center for Biotechnology Information and performing a Meta-analysis of the data with Review Manager 5.3. Results Cluster analysis revealed that the function of the DIOs was associated with thyroid hormone receptor and iodothyronine; GO analysis showed that DIOs were mainly involved in biological processes, such as ethanol metabolism and phenol-containing compound metabolism and primarily involved in the cytochrome P450 metabolism of exogenous organisms and thyroid hormone signaling; SULT1A1 was the core node of the PPI network; miRNAs and thyroid hormones had some iterations with

Context There are well-established interactions between the thyroid and the kidney. Thyroid hypofunction is associated with reduced renal plasma flow (RPF), and hypothyroidism is highly prevalent in chronic kidney disease; however, less is known about the thyroid-kidney axis in the euthyroid state. Objective This work aimed to study the association of thyroid function with renovascular parameters in a well-phenotyped cohort of euthyroid normotensive and hypertensive individuals. Methods This cross-sectional, multicenter study of the HyperPATH Consortium took place in 5 US and European academic institutions. A total of 789 individuals, aged 18 to 65 years, with serum thyrotropin (TSH) 0.4 to 5.5 mIU/L, participated; individuals with uncontrolled or secondary hypertension or on medication affecting the hypothalamus-pituitary-thyroid axis were excluded. Hemodynamic parameters including RPF, thyroid function testing, and the Thr92Ala deiodinase 2 (D2) polymorphism were assessed in the setting of a liberal and restricted salt diet. We searched for associations between thyroid function and renovascular parameters and accounted for confounding factors, such as older age, hypertension, and diabetes. Results Serum TSH was inversely associated with RPF assessed in the setting both of liberal and restricted salt diets. This association remained significant and independent when accounting for confounding factors, whereas free thyroxine index (fTI) and the Thr92Ala polymorphism, associated with lower D2 catalytic activity and disrupted thyroid hormone tissue availability, were not independently associated with RPF. Serum TSH remained an independent predictor of RPF on a liberal salt diet when the analysis was restricted to healthy young individuals. Conclusion Serum TSH levels, but not fTI nor the Thr92Ala D2 polymorphism, were independently inversely associated with RPF in individuals of the HyperPATH Consortium. These findings suggest a direct interconnection between TSH and renovascular dynamics even with TSH within reference range, warranting further investigation.

Aims/Introduction Type 2 diabetes mellitus is a group of metabolism abnormalities in carbohydrates and energy. Our aim was to investigate resting energy expenditure (REE) and blood glucose changes after biliary diversion in mice with diabetes. Materials and Methods Male mice with diabetes were randomly divided into biliary diversion and sham groups. REE was detected by indirect calorimetry, the levels of fasting blood glucose, total bile acids and triiodothyronine were analyzed. After mice were killed, the weight amount of brown adipose tissue (BAT) and gastrocnemius was measured, and the expression level of G protein‐coupled bile acid receptor and type 2 iodothyronine deiodinase in BAT and gastrocnemius were examined. Results The two groups of mice were pair‐fed, the bodyweights (P, Biliary diversion increased resting energy expenditure in mice with diabetes. Total bile acids increased after biliary diversion. G protein‐coupled bile acid receptor highly expressed in adipose tissue and gastrocnemius after surgery.

Objective Serum lipids have been shown to regulate inflammatory and immune processes, but little is known about their association with thyroid autoimmunity. This study aimed to investigate the association of serum lipids with thyroid autoantibody positivity in the general population with normal thyroid-stimulating hormone (TSH) levels. Methods Data regarding the 7,688 subjects’ baseline characteristics were retrospectively collected. All subjects were categorized into four groups according to thyroid autoantibodies against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) positivity and serum lipid levels were compared. Binary logistic regression models were used to evaluate the risk of TgAb or TPOAb positivity with increasing serum lipid levels. Results In 6,456 included subjects, after adjusting for confounders, the risk of TgAb positivity was positively associated with increasing low-density lipoprotein cholesterol (LDL-C) levels (OR 1.10, 95%CI 1.02–1.19, P = 0.014) and negatively correlated with the increasing high-density lipoprotein cholesterol (HDL-C) levels (OR 0.80, 95%CI 0.67–0.96, P = 0.014). In female subjects, the association between increasing LDL-C (OR 1.15, 95%CI 1.05–1.26, P = 0.004) or HDL-C levels (OR 0.74, 95%CI 0.60–0.91, P = 0.005) and TgAb positivity become more pronounced. Moreover, there was a positive correlation between LDL-C levels and TPOAb positivity (OR 1.14, 95%CI 1.02–1.26, P = 0.016). Conclusion We have shown the associations of HDL-C and LDL-C with thyroid autoantibody positivity in the general population with normal TSH levels in a gender-dependent manner. This study highlights that serum lipids may be new predictors of thyroid autoimmunity even when TSH is within the reference range.

Objective: To compare the thyroid autoantibody status of patients with papillary thyroid cancer (PTC) and benign nodular goiter as well as possible associations between thyroid autoantibodies and clinicopathologic features of PTC. Methods: A total of 3934 participants who underwent thyroidectomy were enrolled in this retrospective study. Patients were divided into PTC and benign nodule groups according to pathological diagnosis. Based on the preoperative serum antibody results, PTC patients were divided into thyroid peroxidase antibody (TPOAb)-positive, thyroglobulin antibody (TgAb)-positive, dual TPOAb- and TgAb-positive, or antibody-negative groups. Results: Of the 3934 enrolled patients, 2926 (74.4%) were diagnosed with PTC. Multivariate regression analyses suggested that high thyroid-stimulating hormone levels (adjusted odds ratio [OR] = 1.732, 95% CI [1.485-2.021], P < .001), positive TgAb (adjusted OR = 1.768, 95% CI [1.436-2.178], P < .001), and positive TPOAb (adjusted OR = 1.452, 95% CI [1.148-1.836], P = .002) were independent risk factors for predicting malignancy of thyroid nodules. Multinomial multiple logistic regression analyses indicated that positive TPOAb alone was an independent predictor of less central lymph node metastasis in PTC patients (adjusted OR = 0.643, 95% CI [0.448-0.923], P = .017), whereas positive TgAb alone was significantly associated with less extrathyroidal extension (adjusted OR = 0.778, 95% CI [0.622-0.974], P = .028). PTC patients with dual-positive TPOAb and TgAb displayed a decreased incidence of extrathyroidal extension (adjusted OR = 0.767, 95% CI [0.623-0.944], P = .012) and central lymph node metastasis (adjusted OR = 0.784, 95% CI [0.624-0.986], P = .037). Conclusion: Although preoperative positive TPOAb and TgAb are independent predictive markers for PTC, they are also associated with better clinicopathologic features of PTC. Refereed/Peer-reviewed

Background: Thyroid peroxidase (TPO) gene mutation leads to a change in enzyme built structure resulting in the anti-TPO autoantibodies production that may cause thyroid destruction. Aim: To evaluate the association of three single nucleotide polymorphisms (SNPs) of the TPO gene and anti-TPO levels in Egyptian patients with autoimmune hypothyroidism and correlate them with the disease severity. Methods: Two hundred patients with newly discovered autoimmune hypothyroidism were included in the study (100 with subclinical hypothyroidism and 100 of them with overt hypothyroidism) and 100 healthy individuals as a control group were genotyped by PCR-REFLP. Results: The TT genotype of rs2071400 C/T and the T allele were significantly more frequent in patients with subclinical hypothyroidism and overt hypothyroidism than in the control group. But there were no significant differences in the TT genotype and T allele between subclinical and overt hypothyroidism patients. As regards TPO rs732609 A/C polymorphism, the CC genotype of rs732609 A/C and the C allele were significantly increased in patients with subclinical hypothyroidism and overt hypothyroidism than in controls. There was a significant difference in the CC genotype and C allele between subclinical and overt hypothyroidism patients. Concerning TPO rs1126797 C/T polymorphism, there were no significant differences of genotype or allele frequencies between patients groups and control group. Conclusion: We found an association of rs2071400 C/T and rs732609A/C polymorphisms with autoimmune hypothyroidism and correlated anti-TPO levels with different genotypes in hypothyroid patients. Also, we found an association of rs732609A/C polymorphism with the disease severity.

The deiodinases activate or inactivate the thyroid hormones (TH) in virtually all tissues in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2, and DIO3, have different catalytic functions and regulate TH tissue distribution. The aim of the present study was to evaluate the modulation of gene expression of the deiodinases and TH transporters and protein levels of DIO1 in parietal and frontal areas of cerebral cortex of spontaneously hypertensive rats (SHRs), after two successive mandibular extensions (ME). ME was performed on anesthetized rats by a dilatator appropriately designed and real-time PCR and western blotting techniques were employed for gene expression and protein level study. Mean blood pressure (MBP) significantly decreased in 2ME-treated rats when compared to sham-operated rats (p

Background: Thyroxine (T4) is generally considered to be a prohormone that requires conversion to triiodothyronine (T3) to exert biological activity. Although evidence suggests that T4 has intrinsic activity, it is questionable if this activity has any physiological relevance. Methods: To answer this question, triple knockout (KO) mice (Triples) that cannot express the types 1 (D1) and 2 (D2) deiodinase and the Pax8 genes were generated. Thus, they lack a thyroid and cannot convert T4 to T3. Triples were injected on alternate days with either vehicle or physiological doses of T4, T3, or T3+T4 from postnatal days 2–14. They were euthanized at P15, and RNA-seq was employed to profile gene expression in the liver. In another experiment, Pax8KO mice were injected with T3, T4, or T4+T3, and growth rate and survival to P84 were determined. Results: The growth retardation of Triples was not improved by either T3 or T4 alone but was significantly improved by T4+T3. In the liver, T4 significantly regulated the expression of genes that were also regulated by T3, but the proportion of genes that were negatively regulated was higher in mice treated with T4 than in mice treated with T3. Treatment with T4+T3 identified genes that were regulated synergistically by T3 and T4, and genes that were regulated only by T4+T3. Analysis of these genes revealed enrichment in mechanisms related to cell proliferation and cholesterol physiology, suggesting a unique contribution of T4 to these biological functions. Pax8KO mice all survived to P84 when injected with T4 or T4+T3. However, survival rate with T3 was only 50% and 10% at 3.5 and 12 weeks of life, respectively. Conclusions: T4 has intrinsic activity in vivo and is critical for survival and growth. At a physiological level, T4 per se can upregulate or downregulate many T3 target genes in the neonatal liver. While most of these genes are also regulated by T3, subsets respond exclusively to T4 or demonstrate enhanced or normalized expression only in the presence of both hormones. These studies demonstrate for the first time a complex dependency on both T4 and T3 for normal mammalian growth and development.

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy with a need for better understanding the disease pathogenesis. The biologically active thyroid hormone, T3, is considered a tumor suppressor by promoting cell differentiation and mitochondrial respiration. Tumors evolved a strategy to avoid these anticancer actions by expressing the T3 catabolizing enzyme, Deiodinase type 3 (DIO3). This stimulates cancer proliferation and aerobic glycolysis (Warburg effect). We identified DIO3 expression in HGSOC cell lines, tumor tissues from mice and human patients, fallopian tube (FT) premalignant lesion and secretory cells of normal FT, considered the disease site-of-origin. Stable DIO3 knockdown (DIO3-KD) in HGSOC cells led to increased T3 bioavailability and demonstrated induced apoptosis and attenuated proliferation, migration, colony formation, oncogenic signaling, Warburg effect and tumor growth in mice. Proteomics analysis further indicated alterations in an array of cancer-relevant proteins, the majority of which are involved in tumor suppression and metabolism. Collectively this study establishes the functional role of DIO3 in facilitating tumorigenesis and metabolic reprogramming, and proposes this enzyme as a promising target for inhibition in HGSOC.

Objective. Thyroid hormones play an important role in the development and maturation of the central nervous symptom and their failure in the prenatal period leading to an irreversible brain damage. Their effect on the brain of adult, however, has not been fully studied. With the discovery of neurogenesis in the adult brain, many recent studies have been focused on the understanding the basic mechanisms controlling this process. Many neurogenesis regulatory genes are not only transcribed but also translated into the blood cells. The goal of our study was to analyze the transcriptional activity of neurogenesis regulatory genes in peripheral blood cells in patients with thyroid pathology. Methods. The pathway-specific PCR array (Neurotrophins and Receptors RT2 Profiler PCR Array, QIAGEN, Germany) was used to identify and validate the neurogenesis regulatory genes expression in patients with thyroid pathology and control group. Results. The results showed that GFRA3, NGFR, NRG1, NTF3, NTRK1, and NTRK2 significantly decreased their expression in patients with autoimmune thyroiditis with rising serum of autoantibodies. The patients with primary hypothyroidism, as a result of autoimmune thyroiditis and postoperative hypothyroidism, had significantly lower expression of FGF2, NGFR, NRG1, and NTF3. The mRNA level of CNTFR was markedly decreased in the group of patients with postoperative hypothyroidism. No change in the ARTN, PSPN, TFG, MT3, and NELL1 expression was observed in any group of patients. Conclusion. The finding indicates that a decrease in thyroid hormones and a high level of autoantibodies, such as anti-thyroglobulin antibody and anti-thyroid peroxidase antibody, affect the expression of mRNA neurogenesis-regulated genes in patients with thyroid pathology.

Background: The type 2 deiodinase (DIO2) converts thyroxine to 3,3′,5-triiodothyronine (T3), modulating intracellular T3. An increase in DIO2 within muscle stem cells during skeletal muscle regeneration leads to T3-dependent potentiation of differentiation. The muscle stem cell niche comprises numerous cell types, which coordinate the regeneration process. For example, muscle stem cells provide secretory signals stimulating endothelial cell-mediated vascular repair, and, in turn, endothelial cells promote muscle stem differentiation. We hypothesized that Dio2 loss in muscle stem cells directly impairs muscle stem cell-endothelial cell communication, leading to downstream disruption of endothelial cell function. Methods: We assessed the production of proangiogenic factors in differentiated C2C12 cells and in a C2C12 cell line without Dio2 (D2KO C2C12) by real-time quantitative-polymerase chain reaction and enzyme-linked immunosorbent assay. Conditioned medium (CM) was collected daily in parallel to evaluate its effects on human umbilical vein endothelial cell (HUVEC) proliferation, migration and chemotaxis, and vascular network formation. The effects of T3-treatment on vascular endothelial growth factor (Vegfa) mRNA expression in C2C12 cells and mouse muscle were assessed. Chromatin immunoprecipitation (ChIP) identified thyroid hormone receptor (TR) binding to the Vegfa gene. Using mice with a targeted disruption of Dio2 (D2KO mice), we determined endothelial cell number by immunohistochemistry/flow cytometry and evaluated related gene expression in both uninjured and injured skeletal muscle. Results: In differentiated D2KO C2C12 cells, Vegfa expression was 46% of wildtype (WT) C2C12 cells, while secreted VEGF was 45%. D2KO C2C12 CM exhibited significantly less proangiogenic effects on HUVECs. In vitro and in vivo T3 treatment of C2C12 cells and WT mice, and ChIP using antibodies against TRα, indicated that Vegfa is a direct genomic T3 target. In uninjured D2KO soleus muscle, Vegfa expression was decreased by 28% compared with WT mice, while endothelial cell numbers were decreased by 48%. Seven days after skeletal muscle injury, D2KO mice had 36% fewer endothelial cells, coinciding with an 83% decrease in Vegfa expression in fluorescence-activated cell sorting purified muscle stem cells. Conclusion: Dio2 loss in the muscle stem cell impairs muscle stem cell-endothelial cell crosstalk via changes in the T3-responsive gene Vegfa, leading to downstream impairment of endothelial cell function both in vitro and in vivo.

Free triiodothyronine/free thyroxine (FT3/FT4) ratio is considered as an index of the activities of iodothyronine deiodinase types 1 and 2 (DIO1 and DIO2, respectively) and is reportedly associated with insulin resistance in euthyroid adults. Euthyroid women with polycystic ovary syndrome accompanied with insulin resistance have lesser deiodinase activities. Correspondingly, the serum insulin level in a fasted condition positively correlates with the FT3/FT4 ratio, and insulin depletion decreases the DIO2 activity in mice. Selected genetic variants in DIO1 are also associated with insulin resistance measures. Therefore, if insulin positively regulates DIO1 and DIO2, the FT3/FT4 ratio should decrease under impaired insulin action, and the casual insulin level and FT3/FT4 ratio should be negatively correlated. To evaluate this hypothesis, we conducted a single-center retrospective study between 2018 and 2021. All participants visited the selected hospitals monthly for type 2 diabetes mellitus treatment and casual plasma glucose and HbA1c level measurements. Furthermore, their casual serum insulin levels were measured annually. Meanwhile, we excluded patients treated with insulin injection. Ultimately, we evaluated 71 patients, which all exhibited euthyroid conditions. The FT3/FT4 ratio was independently associated with thyroid-stimulating hormone, casual plasma glucose, and casual insulin levels. In terms of the regression coefficients of the univariate linear regression analysis, the FT3/FT4 ratio negatively correlated with the casual serum insulin levels. Therefore, the risk of FT3/FT4 ratio underestimation should be considered when diagnosing Graves' disease, which is often accompanied with insulin resistance.

OBJECTIVE: To examine the expression of serum thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb) in children with immune thrombocytopenia (ITP). METHODS: A total of 120 children with ITP who were admitted from October 2019 to October 2021 were enrolled as the ITP group. A total of 60 children without ITP were enrolled as the non-ITP group. According to the clinical classification of ITP, the children in the ITP group were further divided into a newly diagnosed ITP group, a persistent ITP group, and a chronic ITP group. The clinical data were compared between the ITP group and the non-ITP group and between the children with different clinical classifications of ITP. The expression levels of serum TGAb and TPOAb in children with ITP were measured and their association with the clinical classification of ITP was analyzed. RESULTS: Compared with the non-ITP group, the ITP group had significantly lower levels of CD3(+), CD4(+), and platelet count (PLT) and significantly higher levels of CD8(+), TGAb, and TPOAb (P0 in evaluating the clinical classification of ITP in children. CONCLUSIONS: TGAb and TPOAb are abnormally expressed in children with ITP and are associated with the clinical classification of ITP in children.

Iodotyrosine deiodinase (IYD) is a type of deiodinase enzyme that scavenges iodide from the thyroid gland. Previously, we showed that H3 Ab acts as an agonist on IYD to induce migration of cells to the heart and differentiate human stem cells into brown adipocyte-like cells. To continue this study, we investigated the dual function of IYD in hypothyroidism by blocking IYD and in thermogenesis by looking at the induction of brown adipocyte-like cells by treatment with H3 Ab in a mouse model. Surprisingly, our results suggest H3 Ab acts on IYD as both an antagonist and agonist to reduce T4 and increase core body temperature in the mouse model. Taken together, the data suggest IYD has a dual function that can regulate physiological metabolism and enhance thermogenesis.

PURPOSE The development of the selective RET inhibitors selpercatinib and pralsetinib has revolutionized the treatment of metastatic progressive RET-mutant medullary thyroid carcinoma (MTC) and other RET-driven cancers, given their more favorable side-effect profile. The aim of this study is to investigate the mechanisms of selpercatinib-induced thyroid dysfunction in athyreotic patients with RET-mutant MTC and in patients with RET-mutant non–small-cell lung cancer (NSCLC) who had a functional thyroid. MATERIALS AND METHODS Thyroid hormone levels were evaluated in an observational cohort of five athyreotic patients with MTC and 30 patients with NSCLC before and after initiation of selpercatinib. In vitro experiments to identify the mechanism of selpercatinib-induced thyroid dysfunction were conducted in cells expressing endogenous D1, D2, and D3 iodothyronine deiodinases. RESULTS Upon initiating treatment with selpercatinib, athyreotic patients developed clinical hypothyroidism with approximately 60% lower T3 levels despite adequate levothyroxine supplementation, whereas in patients with NSCLC, who retain a normal thyroid, selpercatinib resulted in a more attenuated reduction in serum T3, which was dose-dependent. We conducted studies in cells endogenously expressing either D1, D2, or D3, the three iodothyronine deiodinases. Selpercatinib inhibited D2-mediated T3 production in MSTO-211 cells by 50%. A modest repression of D2 mRNA was present in human thyroid cancer TT cells that express RET, but not in the MSTO-211 cells that do not. No effect of the drug was observed on D1 (activating deiodinase) or D3 (inactivating deiodinase). Thus, a nontranscriptional effect of selpercatinib on D2 activity is the most plausible explanation for the low T3 levels. CONCLUSION An off-target effect of selpercatinib on D2-mediated T3 production leads to clinical hypothyroidism, primarily in levothyroxine-treated athyreotic patients. Liothyronine supplementation was needed to achieve normal T3 levels and restore clinical euthyroidism.