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Thyroid hormone system disruption (THSD) negatively affects multiple developmental processes and organs. In fish, inhibition of deiodinases, which are enzymes crucial for (in)activating thyroid hormones (THs), leads to impaired swim bladder inflation. Until now, the underlying mechanism has remained largely unknown. Therefore, the objective of this study was to identify the process during swim bladder development that is impacted by deiodinase inhibition. Zebrafish embryos were exposed to 6 mg/L iopanoic acid (IOP), a model deiodinase inhibitor, during 8 different exposure windows (0-60, 60-120, 24-48, 48-72, 72-96, 96-120, 72-120 and 0-120 h post fertilization (hpf)). Exposure windows were chosen based on the three stages of swim bladder development: budding (24-48 hpf), pre-inflation, i.e., the formation of the swim bladder tissue layers (48-72 hpf), and inflation phase (72-120 hpf). Exposures prior to 72 hpf, during either the budding or pre-inflation phase (or both), impaired swim bladder inflation, while exposure during the inflation phase did not. Based on our results, we hypothesize that DIO inhibition before 72 hpf leads to a local decrease in T3 levels in the developing swim bladder. Gene transcript analysis showed that these TH level alterations disturb both Wnt and hedgehog signaling, known to be essential for swim bladder formation, eventually resulting in impaired development of the swim bladder tissue layers. Improper development of the swim bladder impairs swim bladder inflation, leading to reduced swimming performance. This study demonstrates that deiodinase inhibition impacts processes underlying the formation of the swim bladder and not the inflation process, suggesting that these processes primarily rely on maternal rather than endogenously synthetized THs since TH measurements showed that THs were not endogenously synthetized during the sensitive period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The available evidence on selenium supplementation in the treatment of autoimmune thyroiditis (AIT) was inconclusive. This research serves to assess the effects of selenium supplementation in the treatment of AIT., Methods: Online databases including PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to 10 June 2022. The AMSTAR-2 tool was used to assess the methodological quality of included studies. The information on the randomized controlled trials of the included studies was extracted and synthesized. The GRADE system was used to assess the certainty of evidence., Results: A total of 6 systematic reviews with 75 RCTs were included. Only one study was rated as high quality. The meta-analysis showed that in the levothyroxine (LT4)-treated population, thyroid peroxidase antibody (TPO-Ab) levels decreased significantly in the selenium group at 3 months (SMD = -0.53, 95% CI: [-0.89, -0.17], p < 0.05, very low certainty) and 6 months (SMD = -1.95, 95% CI: [-3.17, -0.74], p < 0.05, very low certainty) and that thyroglobulin antibody (Tg-Ab) levels were not decreased. In the non-LT4-treated population, TPO-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. Tg-Ab levels decreased significantly in the selenium group at 3 and 6 months and did not decrease at 12 months. The adverse effects reported in the selenium group were not significantly different from those in the control group, and the certainty of evidence was low., Conclusion: Although selenium supplementation might reduce TPO-Ab levels at 3 and 6 months and Tg-Ab levels at 3 and 6 months in the non-LT4-treated population, this was based on a low certainty of evidence.

The objective of this study was to investigate the expression of thyroid peroxidase (TPO) in papillary thyroid carcinoma (PTC) and to preliminarily investigate its value as a marker of lymph node metastasis and recurrence in patients with PTC. Clinical data of PTC patients and TPO expression were collected from The Cancer Genome Atlas (TCGA) database for analysis. We recruited 230 consecutive PTC patients from the Department of Thyroid Surgery of the First Affiliated Hospital of Kunming Medical University, collected their clinicopathological data, and also performed immunohistochemical analysis of TPO expression on their thyroid specimens to validate the results of bioinformatics analysis. In addition, the construction of protein-protein interaction networks was performed too. Functional enrichment analysis and immuno-infiltration analysis characterized the pathways in which TPO genes may be involved. Data mining based on the TCGA database showed that TPO expression in PTC tissues was significantly lower than in paired normal thyroid tissues. The expression level of TPO in PTC tissues correlated with tumor lymph node metastasis and recurrence. Follow-up data from our center also validated the difference in TPO expression and its relationship with lymph node metastasis in PTC patients. Functional enrichment analysis showed that TPO function was significantly associated with signaling pathways related to amino acid metabolism, gene expression regulation and tumorigenesis. TPO expression was also significantly associated with immune infiltration. Our study showed that reduced TPO expression was significantly associated with lymph node metastasis and recurrence in patients with PTC, and we validated this result in our central cohort. These data suggest that TPO may serve as a prognostic indicator for PTC., (© 2023. The Author(s).)

Objective: I explore objective data not supporting the addition of liothyronine (medication) (LT3) to levothyroxine (medication) (LT4) in patients with hypothyroidism. Accurate identification of patients with symptomatic (almost exclusively overt) hypothyroidism is important in evaluating clinical outcomes of therapies. Recent studies have documented that nearly a third of individuals who are offered thyroid hormone are euthyroid at the time of initiation. Additionally, others are clinically diagnosed without biochemical confirmation, so a sizable proportion of those started on LT4 are not hypothyroid. The assumption that nonhypothyroid symptoms will resolve with LT4 is problematic. The true underlying cause of these symptoms remains unidentified and untreated., Methods: In a narrative fashion I will review the positive predictive value of and correlation of symptoms consistent with hypothyroidism and confirmed hypothyroidism likely to favorably respond to thyroid hormone replacement., Results: Following a review of the reliability of thyroid-stimulating hormone (TSH) in predicting a euthyroid state, the correlation of circulating triiodothyronine (serum measurement) (T3) levels with symptoms and predictive value of T3 to forecast the outcome of adding LT3 to LT4 will be reviewed. The utility of striving for high, middle, or low TSH set points within the expected range to predict changes in clinical quality of life and the ability of blinded patients to sense subtle differences along this spectrum will be documented. In addition, the clinical impact of single nucleotide polymorphisms in the type 2 deiodinase gene will be reviewed. Finally, the overall satisfaction of selected patients with their thyroid hormone treatments will be outlined and preferences for T3-containing treatments from blinded studies will be summarized., Conclusion: Basing thyroid hormone treatment decisions on patient symptoms likely results in missed diagnoses We should encourage primary care physicians to assess a differential diagnosis, exclude other diagnoses, and not assume a thyroid etiology when TSH is normal. Modifying treatment to a particular TSH target or adjusting based on a low T3 level does not seem to enhance patient outcomes. Finally, pending further trials of "symptomatic" participants, using sustained release LT3 to mimic normal physiology, and including monocarboxylate 10 transporter and Type 2 deiodinase polymorphisms and objective outcomes, I will continue to depend on therapy with LT4 monotherapy and seek alternative explanations for my patients' nonspecific symptoms., Competing Interests: Disclosures The author has consulted on clinical trial design for: AbbVie, a LT4 manufacturer; Allergan, a desiccated thyroid extract manufacturer; and Spectrix, a LT4-LT3 product in development., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Pyriproxyfen is an agricultural chemical pesticide that has been detected in the aquatic environment. This study aimed to clarify the effects of pyriproxyfen on the growth as well as thyroid hormone- and growth-related gene expression of zebrafish (Danio rerio) during its early life stage. Pyriproxyfen exhibited a lethal effect in a concentration-dependent manner: the lowest and no effect concentrations were 250.7 and 111.7 μg/L, respectively. These concentrations were considerably higher than the residual environmental concentrations, indicating the low risk of this pesticide when present at such concentrations. In the zebrafish group treated with 56.6 μg/L pyriproxyfen, thyroid hormone receptor β gene expression levels remained unchanged, whereas thyroid-stimulating hormone β subunit, iodtyronin deiodinase 2, and thyroid hormone receptor α gene expression levels significantly decreased compared with the control group expression levels. In zebrafish treated with 111.7 or 250.7 μg/L pyriproxyfen, iodtyronin deiodinase 1 gene expression levels significantly increased. These results indicate that pyriproxyfen disrupts thyroid hormone activity in zebrafish. Furthermore, pyriproxyfen exposure inhibited zebrafish growth; consequently, we examined the expression of growth hormone (gh) and insulin-like growth factor-I (igf-1), which are important for growth. Pyriproxyfen exposure suppressed gh expression; however, the igf-1 expression levels remained unchanged. Therefore, growth inhibition due to pyriproxyfen exposure was attributed to the suppression of gh expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: The impact of mild subclinical hypothyroidism on pregnancy outcomes in TPOAb-negative women is poorly explored. The aim of the present study was the evaluation in a wide cohort of TPOAb-negative pregnant women the role of subclinical hypothyroidism (SCH) on several pregnancy outcomes., Methods: The study included women aged ≥ 18 years with a singleton pregnancy without known thyroid disease with serum TSH concentration between 0.4 and 10 mIU/L and TPOAb negative. Data about clinical and demographic features were collected. A blood sample was drown to test TSH, TPOAb, ANA and ENA concentration. The mean uterine artery pulsatility index was measured. Risk of adverse obstetric and fetal outcomes was collected., Results: The cohort included 2135 pregnant women. Pregnant women with TSH 4-10 mUI/L had a significantly higher frequency of family history of thyroid diseases, and personal history of celiac disease diseases, type 1 diabetes mellitus, rheumatic disease, antinuclear antibody (ANA) and anti-extractable nuclear antigen (ENA) positive tests. The risk for pre-eclampsia and small for gestational age (SGA) was significantly higher in pregnant women with first-trimester TSH 4-10 mIU/L. A first-trimester TSH serum level greater than 4 mIU/L was associated with a significant increase in the occurrence of abnormal uterine artery pulsatility index, with a more than threefold increase in the risk of developing pre-eclampsia and with the risk of SGA., Conclusions: In TPOAb-negative pregnant women, a first-trimester serum TSH level ranging from 4 to 10 mIU/L is significantly and independently linked to an increased uterine artery pulsatility index as well as to negative pregnancy outcomes such as pre-eclampsia, SGA and gestational diabetes., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

We developed a histochemical method to demonstrate iodide peroxidase activity in various thyroid disorders and compared it with the biochemical and ultrastructural-cytochemical methods. All of the 26 adenomatous goiters and 43 follicular adenomas were peroxidase-positive. In the 74 cases of thyroid carcinomas examined, about half of the follicular carcinomas (17 of 33 patients), and a few papillary carcinomas (3 of 41 patients) were peroxidase-positive. Peroxidase-negative cases were seen in 70% (52 of 74 patients) of the follicular and papillary carcinomas. All the non-tumorous thyroid tissues adjacent to various disorders were peroxidase-positive. Since our histochemically demonstrated peroxidase activities almost parallel those determined biochemically and ultrastructural-cytochemically, we conclude that histochemical examination is a simple and useful method for the detection of peroxidase activity. As for the relationships between histochemically proved peroxidase activity and the histology of tumors, the histological differentiation of tumors was not consistent with their functional differentiation classified according to peroxidase activity.

Introduction: Therapy for hypothyroid obese patients is still under definition since the thyrotropin-stimulating hormone (TSH) level is a less reliable marker of euthyroidism than nonobese patients. Indeed, TSH levels positively correlate with body mass index (BMI), and this increase may be a compensatory mechanism aimed at increasing energy expenditure in obese people. In contrast, the correlation of BMI with thyroid hormone levels is not completely clear, and conflicting results have been obtained by several studies. The L-T4 replacement dose is more variable in obese hypothyroid patients than in nonobese patients, and a recent study indicated that the L-T4 replacement dose is related to lean body mass in obese thyroidectomized patients. We aimed to study the correlations of L-T4-administered dose, thyroid hormone levels and TSH secretion with basal metabolic rate (BMR) and total calculated deiodinase activity (GD) in obese and nonobese athyreotic patients. We also looked for individualized L-T4 replacement dose set points to be used in clinical practice., Methods: We studied retrospectively 160 athyreotic patients, 120 nonobese and 40 obese. GD was calculated by SPINA Thyr 4.2, the responsiveness of the hypothalamic/pituitary thyrotrope by Jostel's thyrotropin (TSH) index and BMR by the Mifflin-St. Jeor formula, the interplay of GD and BMR with L-T4, thyroid hormones and TSH index (TSHI) was also evaluated., Results: In our study, the L-T4 dose was an independent predictor of GD, and approximately 30% of athyreotic patients under L-T4 therapy had a reduced GD; FT4 levels were higher and negatively modulated by BMR in obese athyreotic patients respect to nonobese, in these patients a T4 to T3 shunt, in terms of TSHI suppression is observed suggesting a defective hypothalamic pituitary T4 to T3 conversion and a resistance to L-T4 replacement therapy., Conclusions: L-t4 dose is the most important predictor of GD, BMR modulates T4 levels in obese athyreotic patients that are resistant to L-T4 replacement therapy., (© 2023 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Introduction: We have reported that high total homocysteine and the coexistence of inadequate thyroid hormones in maternal serum increase the risk of fetal neural tube defects (NTDs). Placental iodothyronine deiodinases (DIOs: DIO1, DIO2, and DIO3) play a role in regulating the conversions between different forms of maternal thyroid hormones. This study hypothesized that single nucleotide polymorphisms (SNPs) in placental DIOs genes could be related to NTDs., Methods: We performed a case-control study from 2007 to 2009 that included pregnant women from Lüliang, Shanxi Province, China. Nine distinct SNPs in DIOs genes were analyzed, and placental samples were obtained from 83 pregnant women with NTD fetuses and 90 pregnant women with normal fetuses. The nine SNPs were analyzed using the Cochran-Armitage test and the Fisher's exact test., Results: There were no statistically significant differences between case and control in the nine SNPs of DIOs (p &gt; 0.05)., Conclusions: The results of this study suggested that SNPs of DIO genes in the placenta among pregnant women have no statistically significant difference between the two groups, suggesting that other factors might be involved in metabolism of maternal thyroid hormone provided to fetuses, such as epigenetic modification of methylation and homocysteinylation and genomic imprinting in the placenta. Further functional studies on placenta samples are necessary., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Thyroid hormones (THs) play important roles in vertebrates such as the control of the metabolism, development and seasonality. Given the pleiotropic effects of thyroid disorders (developmental delay, mood disorder, tachycardia, etc), THs signaling is highly investigated, specially using mammalian models. In addition, the critical role of TH in controlling frog metamorphosis has led to the use of Xenopus as another prominent model to study THs action. Nevertheless, animals regarded as non-model species can also improve our understanding of THs signaling. For instance, studies in amphioxus highlighted the role of Triac as a bona fide thyroid hormone receptor (TR) ligand. In this review, we discuss our current understanding of the THs signaling in the different taxa forming the metazoans (multicellular animals) group. We mainly focus on three actors of the THs signaling: the ligand, the receptor and the deiodinases, enzymes playing a critical role in THs metabolism. By doing so, we also pinpoint many key questions that remain unanswered. How can THs accelerate metamorphosis in tunicates and echinoderms while their TRs have not been yet demonstrated as functional THs receptors in these species? Do THs have a biological effect in insects and cnidarians even though they do not have any TR? What is the basic function of THs in invertebrate protostomia? These questions can appear disconnected from pharmacological issues and human applications, but the investigation of THs signaling at the metazoans scale can greatly improve our understanding of this major endocrinological pathway., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Thyroid hormones (THs) are important mediators of vertebrate central nervous system (CNS) development, thereby regulating the expression of a wide variety of genes by binding to nuclear TH receptors. TH transporters and deiodinases are both needed to ensure appropriate intracellular TH availability, but the precise function of each of these regulators and their coaction during brain development is only partially understood. Rodent knockout models already provided some crucial insights, but their in utero development severely hampers research regarding the role of TH regulators during early embryonic stages. The establishment of novel gain- and loss-of-function techniques has boosted the position of externally developing non-mammalian vertebrates as research models in developmental endocrinology. Here, we elaborate on the chicken as a model organism to elucidate the function of TH regulators during embryonic CNS development. The fast-developing, relatively big and accessible embryo allows easy experimental manipulation, especially at early stages of brain development. Recent data on the characterisation and spatiotemporal expression pattern of different TH regulators in embryonic chicken CNS have provided the necessary background to dissect the function of each of them in more detail. We highlight some recent advances and important strategies to investigate the role of TH transporters and deiodinases in various CNS structures like the brain barriers, the cerebellum, the retina and the hypothalamus. Exploiting the advantages of this non-classical model can greatly contribute to complete our understanding of the regulation of TH bioavailability throughout embryonic CNS development., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Tumor formation and maintenance depend on a small fraction of cancer stem cells (CSCs) that can self-renew and generate a wide variety of differentiated cells. CSCs are resistant to chemotherapy and radiation, and can represent a reservoir of cancer cells that often cause relapse after treatment. Evidence suggests that CSCs also give rise to metastases. Thyroid hormone (TH) controls a variety of biological processes including the development and functioning of most adult tissues. Recent years has seen the emergence of an intimate link between TH and multiple steps of tumorigenesis. Thyroid hormone controls the balance between the proliferation and differentiation of CSCs, and may thus be a druggable anti-cancer agent. Here, we review current understanding of the effects of TH on colorectal CSCs, including the cross regulatory loops between TH and regulators of CSC stemness. Targeting TH in the tumor microenvironment may improve treatment strategies., (Copyright © 2017. Published by Elsevier B.V.)

Thyroid hormone (TH) regulates such crucial biological functions as normal growth, development and metabolism of nearly all vertebrate tissues. In skeletal muscle, TH plays a critical role in regulating the function of satellite cells, the bona fide skeletal muscle stem cells. Deiodinases (D2 and D3) have been found to modulate the expression of various TH target genes in satellite cells. Regulation of the expression and activity of the deiodinases constitutes a cell-autonomous, pre-receptor mechanism that controls crucial steps during the various phases of myogenesis. Here, we review the roles of deiodinases in skeletal muscle stem cells, particularly in muscle homeostasis and upon regeneration. We focus on the role of T3 in stem cell functions and in commitment towards lineage progression. We also discuss how deiodinases might be therapeutically exploited to improve satellite-cell-mediated muscle repair in skeletal muscle disorders or injury., (Copyright © 2017. Published by Elsevier B.V.)

In seasonal rodents, reproduction is activated by a long photoperiod. Furthermore, maintaining an inhibitory short photoperiod for over 20 weeks triggers a spontaneous reactivation of the gonadotropic axis called photorefractoriness. Photoactivation is proposed to involve melatonin, hypothalamic thyroid hormones (TH) and (Arg) (Phe)-amide peptides. The mechanisms involved in photorefractoriness are so far unknown. We analyzed the dynamic changes in long photoperiod- and photorefractory-induced activation of reproduction in both Syrian and Djungarian hamsters to validate the current model of photoactivation and to uncover the mechanisms involved in photorefractoriness. We detected a conserved early inhibition of expression of the TH catabolizing enzyme deiodinase 3 (Dio3) in tanycytes, associated with a late decrease of the TH transporter MCT8. This suggests that an early peak of hypothalamic TH may be involved in both photoinduced and photorefractory reactivation. In photoactivation, Dio3 downregulation is followed by an upregulation of Dio2, which is not observed in photorefraction. The upregulation of (Arg) (Phe)-amides occurs several weeks after the initial Dio3 inhibition. In conclusion, we uncovered a so far unreported early inhibition of Dio3. This early downregulation of Dio3 is reinforced by an upregulation of Dio2 in photoactivated hamsters. In photorefractoriness, the Dio3 downregulation might be sufficient to reactivate the gonadotropic axis.

Thyroid hormones (THs) play key roles in modulating the overall metabolism of the body, protein synthesis, fat metabolism, neuronal and bone growth, and cardiovascular as well as renal functions. In this review, we discuss on the thyroid hormone synthesis and activation, thyroid hormone receptors (TRs) and mechanism of action, applications of thyroid hormone analogues, particularly the compounds that are selective ligands for TRβ receptors, or enzyme inhibitors for the treatment of thyroidal disorders with a specific focus on thyroid peroxidase and iodothyronine deiodinases. We also discuss on the development of small-molecule deiodinase mimetics and their mechanism of deiodination, as these compounds have the potential to regulate the thyroid hormone levels., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The appropriate age-related reference intervals for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) are important in interpreting the results of thyroid function tests in children and adolescents. However, these reference intervals are scanty. This study aimed to establish the reference intervals for FT4, TSH, and thyroid peroxidase antibody (TPO Ab), and identify the epidemiological prevalence of thyroid dysfunction in a Korean pediatric population., Methods: The data from a sample of 2042 children and adolescents aged 10-18years who underwent a nationwide Korean representative sampling and cross-sectional survey with blood collection for a thyroid function test using an electrochemiluminescence immunoassay were evaluated., Results: Based on the National Academy of Clinical Biochemistry (NACB) criteria, the median and range (2.5th - 97.5th percentile) for FT4 and TSH in total were 16.47pmol/L (12.61-21.49pmol/L) and 2.48mIU/L (0.63-7.03mIU/L), respectively. Positive TPO Ab (3.1%) by NACB was >19.16kIU/L (boys) and >29.30kIU/L (girls) for adolescents aged 10-18years. FT4 and TSH were associated with increasing and decreasing age, respectively. Boys' FT4 and girls' TPO Ab levels were greater than for the other sex, respectively. Using the new reference interval, overt hypothyroidism, subclinical hypothyroidism, subclinical hyperthyroidism, and overt hyperthyroidism were found in 0.5%, 2.1%, 1.3%, and 1.2%, respectively, of Korean children and adolescents., Conclusions: This study provides evidence-based age- and sex-specific reference intervals for thyroid hormones and autoantibodies, and identifies the current prevalence of thyroid dysfunction in a Korean pediatric group., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Adequate levels of thyroid hormone (TH) are needed for proper brain development, deficiencies may lead to adverse neurologic outcomes in humans and animal models. Environmental chemicals have been linked to TH disruption, yet the relationship between developmental exposures and decline in serum TH resulting in neurodevelopmental impairment is poorly understood. The present study developed a quantitative adverse outcome pathway where serum thyroxin (T4) reduction following inhibition of thyroperoxidase in the thyroid gland are described and related to deficits in fetal brain TH and the development of a brain malformation, cortical heterotopia. Pregnant rats were exposed to 6-propylthiouracil (PTU 0, 0.1, 0.5, 1, 2, or 3 parts per million [ppm]) from gestational days 6-20, sequentially increasing PTU concentrations in maternal thyroid gland and serum as well as in fetal serum. Dams exposed to 0.5 ppm PTU and higher exhibited dose-dependent decreases in thyroidal T4. Serum T4 levels in the dam were significantly decreased with exposure to 2 and 3 ppm PTU. In the fetus, T4 decrements were first observed at a lower dose of 0.5 ppm PTU. Based on these data, fetal brain T4 levels were estimated from published literature sources, and quantitatively linked to increases in the size of the heterotopia present in the brains of offspring. These data show the potential of in vivo assessments and computational descriptions of biologic responses to predict the development of this structural brain malformation and use of quantitative adverse outcome pathway approach to evaluate brain deficits that may result from exposure to other TH disruptors., (Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the public domain in the US.)

Background: Thyroid autoimmunity is more common in patients with rheumatic diseases than in healthy populations. The degree of association seems subject to influence from patients' geographical location. Here, we aimed to ascertain the prevalence of thyroid autoantibodies in a cohort of patients with systemic rheumatic disease and the degree of association between its presence and inflammatory activity., Design and Setting: Cross-sectional observational study in a rheumatology unit., Methods: 301 patients with systemic lupus erythematosus (SLE), 210 with rheumatoid arthritis (RA), 58 with scleroderma (SSc) and 80 with spondyloarthritis (SpA) were studied regarding thyroid function (TSH and T4), anti-thyroglobulin (TgAb) and anti-thyroperoxidase (TPOab) and compared with 141 healthy controls. Disease activity in patients with rheumatic disease was assessed through appropriate indexes., Results: There were more antithyroid antibodies in SLE patients with hypothyroidism (P = 0.01; odds ratio, OR 2.7; 95% confidence interval, CI: 1.20-6.26) and in those without hypothyroidism (P = 0.06; OR 2.4; 95% CI: 1.28-4.55) than in controls. SSc patients also showed: P = 0.03 both with antithyroid antibodies and hypothyroidism (OR 3.4; 95% CI: 1.06-10.80) and without hypothyroidism (OR 3.1; 95% CI: 1.11-0.13). RA and SpA patients had the same prevalence as controls (P not significant). Presence of autoantibodies with and without hypothyroidism was not associated with the activity or functional indexes evaluated., Conclusion: SLE and SSc were associated with higher prevalence of thyroid autoantibodies in patients with and without hypothyroidism, unlike SpA and RA. There was no link between thyroid autoantibody presence and disease activity or functional impairment.

A euthyroid state in the brain is crucial for its adequate development and function. Impairments in thyroid hormones (THs; T3 or 3,5,3'-triiodothyronine and T4 or thyroxine) levels and availability in brain can lead to neurological alterations and to psychiatric disorders, particularly mood disorders. The thyroid gland synthetizes mainly T4, which is secreted to circulating blood, however, most actions of THs are mediated by T3, the transcriptionally active form. In the brain, intracellular concentrations of T3 are modulated by the activity of type 2 (D2) and type 3 (D3) deiodinases. In the present work, we evaluated learning and memory capabilities and anxiety-like behavior at adult stages in mice lacking D2 (D2KO) and we analyzed the impact of D2-deficiency on TH content and on the expression of T3-dependent genes in the amygdala and the hippocampus. We found that D2KO mice do not present impairments in spatial learning and memory, but they display emotional alterations with increased anxiety-like behavior as well as enhanced auditory-cued fear memory and spontaneous recovery of fear memory following extinction. D2KO mice also presented reduced T3 content in the hippocampus and decreased expression of the T3-dependent gene Dio3 in the amygdala suggesting a hypothyroid status in this structure. We propose that the emotional dysfunctions found in D2KO mice can arise from the reduced T3 content in their brain, which consequently leads to alterations in gene expression with functional consequences. We found a downregulation in the gene encoding for the calcium-binding protein calretinin (Calb2) in the amygdala of D2KO mice that could affect the GABAergic transmission. The current findings in D2KO mice can provide insight into emotional disorders present in humans with DIO2 polymorphisms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The iodothyronine deiodinases are selenoenzymes that regulate the activity of thyroid hormone via specific inner- or outer-ring deiodination. In humans, type 1 deiodinase (D1) is highly expressed in the liver, but the mechanism by which its gene expression is regulated remains to be elucidated. Liver X receptor α (LXRα), a transcription factor of the nuclear receptor superfamily, is highly expressed in the liver, where it functions as a sensor for excess intracellular oxysterols. LXRα interacts with other nuclear receptors on promoters of genes that contain a binding core sequence for nuclear receptors. In addition, it is reported that the promoter of the gene encoding human D1 (hDIO1) contains the core sequence for one of nuclear receptors, thyroid hormone receptor (TR). We investigated the involvement of LXRα in the regulation of hDIO1, in the liver. We performed hDIO1 promoter-reporter assays using a synthetic LXR agonist, T0901317, and compared promoter activity between a human liver carcinoma cell line, HepG2, and a clone of human embryonic kidney cells, TSA201. We defined the region between nucleotides -131 and -114, especially nucleotides -126 and -125, of the hDIO1 promoter as critical for basal and LXRα-mediated specific transcriptional activation in HepG2 cells. An increase in hDIO1 expression was observed in LXRα-stimulated cells, but absent in cycloheximide-treated cells, indicating that new protein synthesis is required for LXRα-mediated regulation of hDIO1. On the other hand, electrophoretic mobility shift assays revealed that LXRα and RXRα bound to the hDIO1 promoter. We also demonstrated that LXRα and TRβ compete with each other on this specific region of the promoter. In conclusion, our results indicated that LXRα plays a specific and important role in activation of TH by regulating D1, and that LXRα binds to and regulates the hDIO1 promoter, competing with TRβ on specific sequences within the promoter.

Background: Thyroid peroxidase (TPO) is essential for physiological function of the thyroid gland. The high prevalence of thyroid peroxidase antibodies (TPOAbs) in patients with breast cancer and their protective role had previously been demonstrated, indicating a link between breast cancer and thyroid autoimmunity. Recently, TPO was shown to be present in breast cancer tissue samples but its antigenicity has not been analyzed., Methods: In this study, we investigated TPO expression levels in a series of fifty-six breast cancer samples paired with normal (peri-tumoral) tissue and its antigenic activity using a panel of well-characterized murine anti-human TPOAbs., Results: We have shown that TPO transcripts were present in both normal and cancer tissue samples, although the amounts in the latter were reduced. Additionally, we observed that TPO levels are lower in more advanced cancers. TPO protein expression was confirmed in all tissue samples, both normal and cancerous. We also found that the antigenicity of the immunodominant regions (IDRs) in breast TPO resembles that of thyroid TPO, which is crucial for effective interactions with human TPOAbs., Conclusions: Expression of TPO in breast cancer together with its antigenic activity may have beneficial effects in TPOAb-positive breast cancer patients. However, further studies are needed to confirm the beneficial role of TPOAbs and to better understand the underlying mechanism.

Context: A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions., Objectives: To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis., Design: We compared the presurgical hormonal status of thyroidectomized LT4-treated patients who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients. We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models., Subjects and Methods: A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohistochemistry and immunoblotting were performed for D2 protein., Results: The DIO2 genotyping revealed an association between low FT3 values and Thr92Ala. Specifically, the mean postsurgery FT3 levels were significantly lower in patients carrying the mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to presurgery levels. The -258 G/A variation was not associated with hormonal alteration. We found that endogenous wild-type D2 and Thr92Ala share the same subcellular localization but differ in protein stability. Importantly, Thr92Ala reduced D2-mediated thyroxine to T3 conversion., Conclusions: Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular and serum T3 concentrations that are not adequately compensated for by LT4, thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients., (Copyright © 2017 by the Endocrine Society)

Iodide Handling Disorders lead to defects of the biosynthesis of thyroid hormones (thyroid dyshormonogenesis, TD) and thereafter congenital hypothyroidism (CH), the most common endocrine disease characterized by low levels of circulating thyroid hormones. The prevalence of CH is 1 in 2000-3000 live births. Prevention of CH is based on prenatal diagnosis, carrier identification, and genetic counseling. In neonates a complete diagnosis of TD should include clinical examination, biochemical thyroid tests, thyroid ultrasound, radioiodine or technetium scintigraphy and perchlorate discharge test (PDT). Biosynthesis of thyroid hormones requires the presence of iodide, thyroid peroxidase (TPO), a supply of hydrogen peroxide (DUOX system), an iodine acceptor protein, thyroglobulin (TG), and the rescue and recycling of iodide by the action of iodotyrosine deiodinase or iodotyrosine dehalogenase 1 (IYD or DEHAL1). The iodide transport is a two-step process involving transporters located either in the basolateral or apical membranes, sodium iodide symporter (NIS) and pendrin (PDS), respectively. TD has been linked to mutations in the solute carrier family 5, member 5 transporter (SLC5A5, encoding NIS), solute carrier family 26, member 4 transporter (SLC26A4, encoding PDS), TPO, DUOX2, DUOXA2, TG and IYD genes. These mutations produce a heterogeneous spectrum of CH, with an autosomal recessive inheritance. Thereafter, the patients are usually homozygous or compound heterozygous for the gene mutations and the parents, carriers of one mutation. In the last two decades, considerable progress has been made in identifying the genetic and molecular causes of TD. Recent advances in DNA sequencing technology allow the massive screening and facilitate the studies of phenotype variability. In this article we included the most recent data related to disorders caused by mutations in NIS, TPO, TG and IYD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The role of TPO gene polymorphism in the susceptibility to Graves' disease (GD) remains unclear. However, single-nucleotide polymorphisms (SNPs) near TPO have been recently associated with serum levels of thyroid peroxidase (TPO) antibody in two independent genome-wide association studies. Moreover, we have observed a strong association between the rs11675434 SNP located near TPO and the presence of clinically evident Graves' ophthalmopathy (GO). The aim of the current study was to reevaluate and dissect this association in an extended group of 1231 well-characterized patients with GD (1043 adults and 188 children) and 1130 healthy controls from the Polish Caucasian population, considering possible gender-dependent and age-of-onset-specific effects of the studied SNP. We found that the T allele of rs11675434 was significantly more frequent in GD patients with than without GO (odds ratio (OR)=1.26, 95% confidence interval (CI)=1.05-1.51, P=0.012), which was consistent with our previous findings. Further analyses performed in subgroups of patients showed that the association with GO was significant in adult patients with age of GD onset ⩾45 years (OR=1.34, 95% CI=1.03-1.75, P=0.031), but not in children and adolescents or adult patients with earlier onset of the disease (OR=1.72, 95% CI=0.77-3.84, P=0.18 and OR=1.05, 95% CI=0.79-1.40, P=0.75, respectively). Moreover, a strong association with GO was present in males (OR=2.06, 95% CI=1.40-3.02, P=0.0002), whereas it was absent in females (OR=1.10, 95% CI=0.90-1.35, P=0.35). The results of our study further suggest that rs11675434 SNP located near TPO is associated with the development of GO, especially in males and patients with later age of GD onset.

The role of thyroid hormones (THs) in the central regulation of energy balance is increasingly appreciated. Mice lacking the type 3 deiodinase (DIO3), which inactivates TH, have decreased circulating TH levels relative to control mice as a result of defects in the hypothalamic-pituitary-thyroid axis. However, we have shown that the TH status of the adult Dio3-/- brain is opposite that of the serum, exhibiting enhanced levels of TH action. Because the brain, particularly the hypothalamus, harbors important circuitries that regulate metabolism, we aimed to examine the energy balance phenotype of Dio3-/- mice and determine whether it is associated with hypothalamic abnormalities. Here we show that Dio3-/- mice of both sexes exhibit decreased adiposity, reduced brown and white adipocyte size, and enhanced fat loss in response to triiodothyronine (T3) treatment. They also exhibit increased TH action in the hypothalamus, with abnormal expression and T3 sensitivity of genes integral to the leptin-melanocortin system, including Agrp, Npy, Pomc, and Mc4r. The normal to elevated serum levels of leptin, and elevated and repressed expression of Agrp and Pomc, respectively, suggest a profile of leptin resistance. Interestingly, Dio3-/- mice also display elevated locomotor activity and increased energy expenditure. This occurs in association with expanded nighttime activity periods, suggesting a disrupted circadian rhythm. We conclude that DIO3-mediated regulation of TH action in the central nervous system influences multiple critical determinants of energy balance. Those influences may partially compensate each other, with the result likely contributing to the decreased adiposity observed in Dio3-/- mice., (Copyright © 2017 by the Endocrine Society.)

The impact of thyroid hormone (TH) disorders on male reproductive biology has been a controversial issue for many years. Recently, we reported that hypothyroid male rats have a disruption of the seminiferous epithelium, which may compromise spermatogenesis. To improve the understanding of the reproductive pathogenesis of hypothyroidism and hyperthyroidism, male Wistar rats that developed these dysfunctions in adulthood were used as an experimental model. We evaluated the sperm production, reserves, transit time, morphology, and functionality (acrosome integrity, plasma membrane integrity, and mitochondrial activity), and the testicular expression of the TH receptors (Thra1 and Thra2, Thrb1, and Thrb2), deiodinases (Dio2 and Dio3), and the Mct8 transporter (Slc16a2) were assessed by reverse transcription followed by real-time quantitative PCR (RT-qPCR). The results were evaluated statistically by ANOVA and Tukey HSD test (P < 0.05). Hypothyroidism decreased the total and daily sperm productions and increased the sperm transit time through the epididymis, while the sperm functionality was reduced in both thyroid dysfunctions. Regarding the modulation of gene expression in the testis, hypothyroidism increased the expression of Thra1 and decreased the expression of Dio3, and hyperthyroidism increased the expression of Slc16a2. The observed alterations in spermatic production and function and in the expression of the TH receptor, deiodinase, and the TH transporter are suggestive of TH participation in spermatogenesis in adulthood.

This study considered a possible relationship between the severity of oral lichen planus (OLP), serum anti-TPO autoantibodies (TPOAb) titer and thyroid disease in OLP patients. Forty-six OLP patients with positive TPOAb results (> 35 IU/ml) who had also been diagnosed with thyroid disease were included in the study group. The control group consisted of 46OLP patients with no thyroid disease. The study and control groups (92) were divided to two subgroups of erosive OLP (EOLP) and non-erosive OLP (NEOLP). Serum TPOAb levels and IL-8 (to measure OLP severity) were evaluated using the independent t-test, chi-square and conditional logistic regression analysis (α = 0.05). A significant positive correlation was found between serum IL-8 and TPOAb levels in the study group (r = 0.783; p = 0.001). The positive blood levels of TPOAb were significantly associated with an increased risk of EOLP (OR = 4.02 at 95%CI; 1.21-13.4; p = 0.023). It is possible to used positive serum TPOAb levels in patients with OLP as in indicator of possible undetected thyroid disorders in those patients. Because erosive OLP has been associated with TPOAb in thyroid patients, it may be useful to determine TPOAb levels of such patients to diagnose a possible undetected thyroid disorders and follow-up for malignancy.

A depressive disorder is a disease characterized by a heterogenous background. The important processes observed and diagnosed in depressed patients indicate that the etiology of depression may include disturbances in thyroid hormone (TH) levels and the occurrence of immune-inflammatory activation. Type 1 (DIO1) and type 3 (DIO3) iodothyronine deiodinases are the enzymes which determine the peripheral and tissue levels of TH, but also interfere with immunological cells and inflammatory processes. We aimed to investigate the levels of DIO1 and DIO3 in the patients suffering from recurrent depressive disorders (rDD). Data collected from 91 rDD patients and 105 healthy controls were analyzed. The diagnoses were made based on the ICD-10 criteria (F33.0-F33.8). The expression levels of DIO1 and DIO3 were estimated using the polymerase chain reaction method and the enzyme-linked immunosorbent assay (ELISA). The expression of DIO1 on mRNA/protein levels in the rDD patients was reduced in comparison to the control subjects, while the expression of DIO3 was higher in the patients suffering from depression. No significant relationship was found between the investigated DIOs and other clinical parameters. Our results indicate and suggest a role of DIO1 and DIO3-related pathways in the pathophysiology of depression. The results represent a promising way to investigate the biological markers of depression.

Objective: Subclinical hypothyroidism (SCH) is defined as high levels of TSH in the presence of normal levels of serum FT4. Since thyroid peroxidase (TPO) plays a key role in thyroid hormone synthesis, variations in the TPO gene can change the enzyme structure and result in the production of anti-TPO antibodies. The aim of this study was to examine the relationship between the Asn698Thr (A2095C) and Thr725Pro (A2173C) polymorphisms of the TPO gene and anti-TPO levels in patients with SCH., Design: In this study, 150 individuals (75 cases and 75 controls), aged 19-75 years, were selected randomly by a clinician. The thyroid function tests included were FT3, FT4, TSH and anti-TPO antibodies using ELISA. The TPO gene polymorphisms were examined by PCR-RFLP., Results: Anti-TPO levels in the experimental group was significantly increased (P=0.020). The A2095C genotype frequency in the experimental and control groups were 37.3% vs 34.7% for the AA healthy genotype, 20% vs 46.7% for AC and 42.7% vs 18.6% for CC, respectively (P=0.001). The A2173C genotype frequency in the experimental and control groups were 22.6% vs 68% for healthy AA, 40% vs 25.3% for AC and 37.4% vs 6.7% for CC, respectively (P <0.001). The increased anti-TPO antibodies were significantly associated with the A2173C polymorphism (P=0.035). The findings showed that the chance (odds ratio) of developing subclinical hypothyroidism in individuals who had C alleles was 1.5 and 5.6-fold higher than in individuals without these alleles in the A2095C and A2173C regions, respectively., Conclusions: Determination of anti-TPO antibody levels and exon 12 TPO gene polymorphisms in patients with SCH can be helpful for prediction of overt hypothyroidism.

Background: Autoimmune thyroid disease is a prevalent condition affecting women of reproductive age, leading to thyroid dysfunction and impacting pregnancy outcomes. While the critical role of thyroid hormone in pregnancy outcomes is well-established, the potential association between positive antithyroid peroxidase antibodies (TPOAb) and adverse pregnancy outcomes in pregnant women with normal thyroid function remains unclear. Objective: This study aims to investigate the relationship between maternal TPOAb positivity and adverse pregnancy outcomes with normal thyroid function. Methods: We collected baseline information from pregnant women who visited our hospital between February 2009 and June 2012. Blood samples were taken to measure thyroid stimulating hormone (TSH), free thyroxine (FT4), TPOAb, and anti-thyroglobulin antibodies (TGAb). The incidence of adverse pregnancy outcomes was compared between TPOAb-positive and TPOAb-negative groups among participants with normal thyroid function. Results: A total of 7,046 pregnant women with normal thyroid function were included, comprising 6,700 with negative TPOAb and 346 with positive TPOAb. The TPOAb-positive group exhibited a higher age (26.0 vs. 27.0 years, p = 0.02) and greater serum TSH levels (1.72 vs. 1.94 mIU/L, p = 0.029), while the gestational week of blood collection was lower (31.9 vs. 26.5 weeks, p = 0.001). Univariate analysis revealed a higher incidence of low birth weight (LBW) in offspring of TPOAb-positive women compared to the TPOAb-negative group (3.5% vs. 1.9%, p = 0.035). After adjusting for confounding factors such as age, gestational week of blood collection, menstrual history, education level, gestational diabetes, gestational hypertension, TGAb, TSH, and FT4, TPOAb positivity emerged as an independent risk factor for LBW infants (OR: 2.317, 95% CI: 1.057-5.076, p = 0.036), while other adverse pregnancy outcomes did not show a significant correlation with TPOAb positivity. Conclusion: Our findings suggest that TPOAb-positive pregnant women with normal thyroid function are more likely to deliver LBW infants. Regular monitoring of TPOAb-positive pregnancies and timely interventions throughout all stages of pregnancy are crucial. [ABSTRACT FROM AUTHOR]

Background: Many studies have reported the link between gut microbiota and thyroid dysfunction. However, the causal effect of gut microbiota on thyroid dysfunction and the changes in gut microbiota after the onset of thyroid dysfunction are not clear. Methods: A two-sample Mendelian randomization (MR) study was used to explore the complex relationship between gut microbiota and thyroid dysfunction. Data on 211 bacterial taxa were obtained from the MiBioGen consortium, and data on thyroid dysfunction, including hypothyroidism, thyroid-stimulating hormone alteration, thyroxine deficiency, and thyroid peroxidase antibodies positivity, were derived from several databases. Inverse variance weighting (IVW), weighted median, MR-Egger, weighted mode, and simple mode were applied to assess the causal effects of gut microbiota on thyroid dysfunction. Comprehensive sensitivity analyses were followed to validate the robustness of the results. Finally, a reverse MR study was conducted to explore the alteration of gut microbiota after hypothyroidism onset. Results: Our bidirectional two-sample MR study revealed that the genera Intestinimonas, Eubacterium brachy group, Ruminiclostridium5, and Ruminococcaceae UCG004 were the risk factors for decreased thyroid function, whereas the genera Bifidobacterium and Lachnospiraceae UCG008 and phyla Actinobacteria and Verrucomicrobia were protective. The abundance of eight bacterial taxa varied after the onset of hypothyroidism. Sensitivity analysis showed that no heterogeneity or pleiotropy existed in the results of this study. Conclusion: This novel MR study systematically demonstrated the complex relationship between gut microbiota and thyroid dysfunction, which supports the selection of more targeted probiotics to maintain thyroid--gut axis homeostasis and thus to prevent, control, and reverse the development of thyroid dysfunction. [ABSTRACT FROM AUTHOR]

To maintain normal level of thyroid hormone, especially for free thyroxine (FT4), individuals with latent thyroid gland damage might have required higher thyroid stimulating hormone (TSH) than those without latent thyroid gland damage. Anti-thyroid peroxidase antibody (TPO-Ab) is a main cause of auto-immune thyroiditis, and therefore euthyroid individuals positive for TPO-Ab might have latent damage to the thyroid gland. Therefore, the association between TSH values and TPO-Ab positivity may be useful to determine the influence of latent thyroid gland damage on requirement of TSH. Furthermore, because latent damage of thyroid might elevate TSH level but not FT4 level, those associations should be observed independent from FT4. This cross-sectional study analyzed 1431 Japanese with normal ranges of free triiodothyronine (FT3) and FT4. Since TPO-Ab is associated with atherosclerosis in euthyroid individuals, cardiovascular risk factors might underlie the association between TPO-Ab and TSH values. After adjusting for FT4 and known cardiovascular risk factors, the adjusted odds ratio (95% confidence interval) of TPO-Ab positivity for logarithmic value of TSH was 1.53 (1.20, 1.95). Essentially the same association was observed when the analysis was restricted to individuals without subclinical hypothyroidism (1.54 [1.15, 2.13]). Euthyroid individuals with latent thyroid gland damage might have increased the requirement of TSH. [ABSTRACT FROM AUTHOR]

Background and Objectives: Thyroid disease has been associated with autoimmune disorders. As systemic lupus erythematosus (SLE) is a systemic autoimmune disease with diverse manifestations spanning across all organ systems, the relationship of SLE with thyroid disorders needs investigation. In particular, the relationship of SLE with autoimmune thyroid disease has attracted the interest of the research community. The aim was to evaluate the relationship of SLE with autoimmune thyroid disease. Materials and Methods: A cohort of 45 consecutive patients with a mean age of 47.97 years (range 21–79 years) and 45 age- and sex-matched controls were prospectively studied over a period of 12 months for the presence of thyroid disease and the prevalence of antithyroid antibodies. Results: Four patients (8.9%) were found to suffer from primary hypothyroidism, five (11.11%) from subclinical hypothyroidism and one (2.22%) from hyperthyroidism, whereas one (2.22%) of the controls had primary hypothyroidism and one (2.22%) had hyperthyroidism. Five patients (11.11%) had a thyroid hormone profile that was compatible with the presence of euthyroid sick syndrome. Thyroid peroxidase (TPOab) and thyroglobulin (Tgab) antibodies were detected in 20/45 and 15/45 of the SLE population and in 7/45 and 5/45 of the controls, respectively (p < 0.05, chi-square test). Conclusions: In conclusion, the incidence of clinical thyroid disease is greater amongst SLE patients than in a control population, and in a significant number of these patients, antithyroid antibodies are detectable. Thus, a subset of lupus patients appears to be predisposed to the development of thyroid disease, and this should be considered when evaluating patients with SLE. [ABSTRACT FROM AUTHOR]

Background: Thyroid autoimmunity (TAI) has been associated with the risk of recurrent pregnancy loss (RPL). This systematic review and meta-analysis was conducted to evaluate the influence of TAI on subsequent pregnancy outcome of women with RPL. Methods: A systematic search of Medline, Web of Science, and Embase was conducted to identify studies evaluating the influence of TAI on subsequent risk of pregnancy loss (PL) in women with RPL. Study quality was evaluated via the Newcastle–Ottawa Scale. A random-effects model was utilized to pool the results, accounting for heterogeneity. Results: Ten observational studies were included. Compared to women without thyroid autoantibodies, RPL women with TAI had a higher risk of PL in their subsequent pregnancy (risk ratio [RR]: 1.46. 95% confidence interval [CI]: 1.20 to 1.78, p < 0.001; I2 = 35%). Sensitivity analyses showed consistent results in studies with thyroid peroxidase antibody positivity (RR: 1.50, 95% CI: 1.23 to 1.82) and in studies with TAI assessed before pregnancy (RR: 1.28, 95% CI: 1.07 to 1.53). Subgroup analyses showed that the results were not significantly different in prospective and retrospective studies, in RPL defined as at least two or three PL, in euthyroid women and women with euthyroidism or subclinical hypothyroidism, in women with and without levothyroxine treatment, in studies reporting first-trimester or overall PL, and in studies with different quality scores (p for subgroup difference all > 0.05). Conclusions: In women with RPL, positive for TAI may be related to a higher risk of PL in subsequent pregnancy. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of Ophiocordyceps sinensis (OS) preparations for the treatment of Hashimoto's thyroiditis (HT). Methods: We searched eight databases to collect randomized controlled trials (RCTs) of OS combined with a low-iodine diet or levothyroxine for HT. The search period was from inception to June 2023. Meta-analysis was performed using Revman 5.3 software after two evaluators independently screened the literature, extracted data, and evaluated the risk of bias of the included studies. The GRADE system was used to assess the certainty of evidence. Results: A total of 14 RCTs involving 1,014 patients with HT were included. Meta-analysis showed that OS preparations combined with a low-iodine diet were more effective in reducing thyroid peroxidase antibody (TPOAb) [SMD = -3.81, 95% CI (-5.07, -2.54), p < 0.00001] and thyroglobulin antibody (TgAb) [SMD = -4.73, 95% CI (-6.86, -2.61), p < 0.00001] compared to a low-iodine diet. Compared with levothyroxine treatment alone, OS preparations combined with levothyroxine further reduced TPOAb [SMD = -2.04, 95% CI (-2.82, -1.26), p < 0.00001], TgAb [SMD = -2.01, 95% CI (-2.68, -1.33), p < 0.00001], tumor necrosis factor alpha (TNF-a) [SMD = -3.40, 95% CI (-5.66, -1.14), p = 0.003], interleukin-2 (IL-2) [SMD = -2.31, 95% CI (-3.98, -0.65), p = 0.006], and interleukin-6 (IL-6) [MD = -4.16, 95% CI (-6.17, -2.15), p < 0.0001], and elevated free thyroxine (FT4) [SMD = 1.34, 95% CI (0.59, 2.08), p = 0.0004], but no significant effect on free triiodothyronine (FT3) [SMD = 0.83, 95% CI (-0.12, 1.78), p = 0.09] and thyroid stimulating hormone (TSH) [SMD = -0.80, 95% CI (-1.71, 0.11), p = 0.08]. In terms of safety, three studies reported adverse reactions in 10 patients in each of the experimental and control groups. Conclusion: OS preparations in combination with other treatments (low-iodine diet or levothyroxine) may decrease thyroid autoantibodies and inflammatory responses in patients with HT. In HT patients with hypothyroidism, the combination of the OS preparations with levothyroxine also improved FT4. However, the quality of the included studies was generally low. Moreover, the safety of OS preparations remains unclear. Therefore, more high-quality, multicenter, large-sample RCTs are needed in the future to validate the efficacy and safety of OS preparations. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that thyroid peroxidase antibody (TPOAb) positivity exposure during pregnancy may contribute to changes in placental morphology and pathophysiology. However, little is known about the association of maternal TPOAb during pregnancy with placental morphology and cytokines. This study focuses on the effect of repeated measurements of maternal TPOAb during pregnancy on the placental morphology and cytokines. Methods: Based on Ma'anshan Birth Cohort (MABC) in China, maternal TPOAb levels were retrospectively detected in the first, second and third trimesters. Placental tissues were collected 30 minutes after childbirth, placental morphological indicators were obtained by immediate measurement and formula calculation, and cytokine mRNA expression was detected by real-time quantitative polymerase chain reaction (RT-qPCR) afterward. Generalized linear models and linear mixed models were analyzed for the relationships of maternal TPOAb in the first, second and third trimesters with placental indicators. Results: Totally 2274 maternal-fetal pairs were included in the analysis of maternal TPOAb levels and placental morphology, and 2122 pairs were included in that of maternal TPOAb levels and placental cytokines. Maternal TPOAb levels in early pregnancy were negatively associated with placental length, thickness, volume, weight and disc eccentricity, while positively correlated with placental IL-6, TNF-a, CRP, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78. In mid-pregnancy, maternal TPOAb levels were negatively correlated with placental length, width and area. In late pregnancy, maternal TPOAb levels were negatively correlated with placental length, area, volume and weight. Repeated measures analysis showed that maternal TPOAb positivity tended to increase placental TNF-a, CD68 and MCP-1 while decreasing placental length, width and area than TPOAb negativity. Repeated measures analysis showed that maternal TPOAb levels were positively correlated with placental IL-6, TNF-α, CD68, MCP-1, IL-10, HO-1, HIF-1α and GRP78, while negatively correlated with placental length, area, volume, weight, and disc eccentricity. Conclusion: There may be trimester-specific associations between maternal TPOAb levels and placental morphology and inflammatory and oxidative stress responses. The effect of maternal TPOAb levels on placental morphology is present throughout pregnancy. Early pregnancy may be the critical period for the association between maternal TPOAb levels and placental inflammatory and oxidative stress responses. [ABSTRACT FROM AUTHOR]

This study explored whether thyroglobulin and thyroid disease prevalence rates were higher in pregnant Chinese women with a median urinary iodine concentration of 100–149 μg/L, compared with those with a median urinary iodine concentration of 150–249 μg/L maintained through sustainable universal salt iodization. This was a cross-sectional study in which 812 healthy pregnant women were enrolled to collect samples of their household edible salt, urine, and blood during their routine antenatal care in the 18 counties in Fujian Province, China. The levels of salt iodine concentration, urinary iodine concentration (UIC), free triiodothyronine (FT3), free thyroid hormone (FT4), thyroid-stimulating hormone (TSH), thyroglobulin (Tg), thyroid peroxidase antibody and thyroglobulin antibody were assessed during the routine antenatal care visits. The median UIC (mUIC) in pregnant women was 130.8 μg/L (interquartile range = 91.5–198.1 μg/L) in the counties with an mUIC of 100–149 μg/L (Group I), and 172.0 μg/L (interquartile range = 123.5–244.4 μg/L) in the counties with an mUIC of 150–249 μg/L (Group II). Goiter prevalence and thyroid nodule detection rates showed no difference between Group I and Group II (P > 0.05). Except for FT4 values, the TSH, FT4, FT3, Tg and Tg values > 40 (μg/L) and the thyroid diseases prevalence rate (TDR) showed no significant differences between Group I and Group II (P > 0.05), whether or not iodine supplementation measures were taken. Compared with an mUIC of 150–249 μg/L, not only there was no difference in thyroid morphology, but also the Tg value, rate of Tg values > 40 μg/L, and TDR were not higher in pregnant women in the counties with an mUIC of 100–149 μg/L achieved through sustainable universal salt iodization in Fujian Province, China. [ABSTRACT FROM AUTHOR]

Objective of this study was to investigate the association between serum thyroid measurements and homocysteine (HCy) in euthyroid participants.Methods: This retrospective study was based on Hospital Information Systems. After excluding participants with thyroid dysfunction and those who had recently taken medications that affected serum HCy, 775 participants were enrolled. We compared the serum thyroid function measurements of patients with or without hyperhomocysteinemia (HHCy) and analyzed the effect of thyroid indicators on HHCy prevalence and HCy levels. Multivariate regression analysis was utilized to analyze the association of thyroid-stimulating hormone (TSH) and thyroid peroxidase (TPOAb) with HCy.Results: The serum TSH level (2.10 ± 1.06 mIU/L) of HHCy patients (n = 98) was significantly higher than controls (n = 677) (1.65 ± 0.90 mIU/L) (p < 0.05), as was the positive rate of TPOAb (19.4% vs 10.0%, p < 0.05). The serum HCy levels in subjects with TSH within the highest quartile were significantly higher than those in the lowest quartile (13.49 ± 7.78 vs 9.81 ± 3.59 μmol/L, p < 0.05). HCy was also significantly higher in TPOAb-positive patients than in negative subjects (14.06 ± 8.89 vs 11.48 ± 5.47 μmol/L, p < 0.05). Among the TSH quartiles, the prevalence of HHCy showed a similar significant upward trend to that described above. The prevalence of HHCy was also significantly higher in TPOAb-positive patients. The results of multivariate regression analysis suggested that both TSH elevation and TPOAb positivity were independent risk factors for HCy elevation and HHCy prevalence. However, we found no definitive association between linear increases in TPOAb titers and HCy concentrations or HHCy prevalence.Conclusion: Patients with HHCy had significantly higher TSH levels and positive rates of TPOAb. Elevated TSH and positive TPOAb levels were independent risk factors for elevated HCy concentrations and HHCy risk. [ABSTRACT FROM AUTHOR]

Cold-induced thermogenesis in endotherms demands adaptive thermogenesis fueled by mitochondrial respiration and Ucp1-mediated uncoupling in multilocular brown adipocytes (BAs). However, dietary regulation of thermogenesis in BAs isn't fully understood. Here, we describe that the deficiency of Leucine-rich pentatricopeptide repeat containing-protein (Lrpprc) in BAs reduces mtDNA-encoded ETC gene expression, causes ETC proteome imbalance, and abolishes the mitochondria-fueled thermogenesis. BA-specific Lrpprc knockout mice are cold resistant in a 4°C cold-tolerance test in the presence of food, which is accompanied by the activation of transcription factor 4 (ATF4) and proteome turnover in BAs. ATF4 activation genetically by BA-specific ATF4 overexpression or physiologically by a low-protein diet feeding can improve cold tolerance in wild-type and Ucp1 knockout mice. Furthermore, ATF4 activation in BAs improves systemic metabolism in obesogenic environment regardless of Ucp1's action. Therefore, our study reveals a diet-dependent but Ucp1-independent thermogenic mechanism in BAs that is relevant to systemic thermoregulation and energy homeostasis.

The mechanisms underlying subclinical hypothyroidism (SCH) remain unclear, making timely and accurate differentiation between hypothyroidism and SCH, as well as severity assessment, challenging. This study aimed to investigate the role of NFE2 like bZIP transcription factor 2 (Nrf2), gp91phox, and interleukin-17 (IL-17) in the pathogenesis of SCH. In this prospective comparative study, 105 SCH patients, 105 hypothyroidism patients, and 105 healthy individuals were enrolled from January 2022 to August 2023. SCH patients were categorized into mild-moderate and severe groups based on thyroid-stimulating hormone (TSH) levels. Levels of TSH, free T4 (FT4), free T3 (FT3), thyroglobulin antibodies (TG-Ab), thyroid peroxidase antibodies (TPO-Ab), cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-ch), and low-density lipoprotein-cholesterol (LDL-ch) were measured. Nrf2, IL-1β, IL-6, IL-17, and gp91phox levels were tested using ELISA. Nrf2, IL-17 and gp91phox were significantly higher in SCH and hypothyroidism patients compared to the healthy controls, with hypothyroidism patients showing the highest levels. Nrf2 levels were negatively correlated with TSH, TG-Ab and IL-17, but not gp91phox. Nrf2, IL-17 and gp91phox could be used for diagnosis of SCH and severe SCH. Only TG-Ab, IL-17 and gp91phox were independent risk factors for severe SCH. This study demonstrates a negative correlation between serum Nrf2 levels and SCH severity. TG-Ab, IL-17, and gp91phox are independent risk factors, and their associations with SCH pathology suggest their potential roles in the disease mechanism. These findings provide insights into SCH pathogenesis and highlight the need for further research to elucidate their diagnostic or prognostic significance. [ABSTRACT FROM AUTHOR]

Background: Exposure to particles with an aerodynamic diameter of ≤2.5 μm (PM2.5) is associated with the occurrence of thyroid dysfunction among pregnant women and neonates, but it is not known if this association occurs in the general population. We aimed to determine the association of prolonged exposure to PM2.5 with the prevalence of thyroid disorders among adults in China. Methods: A nationally representative cross-sectional study of thyroid disorders, iodine status, and diabetes status was carried out in all 31 provinces across China from 2015 to 2017. In total, 73,900 adults aged 18 years and older were included. Serum concentrations of thyroid hormones, thyrotropin, and thyroid antibodies and the urine iodine concentration were measured. The environmental concentration of PM2.5 for each participant's residential address at a spatial resolution of 1 × 1 km was estimated. Results: The average long-term exposure to PM2.5 at residential addresses was 66.41 μg/m3, ranging from 17.58 μg/m3 to 120.40 μg/m3. Compared with that of individuals with lower exposure levels, the prevalence of thyroid diseases such as autoimmune thyroiditis and subclinical hypothyroidism was greater in those with PM2.5 concentrations within the third quartile range (60.18 to 73.78 μg/m3). Compared with those in the first quartile (17.58 to 46.38 μg/m3), participants in the highest PM2.5 quartile (73.78 to 120.40 μg/m3) presented an increased risk of overt hypothyroidism (OR 1.23 [CI 0.94–1.61]), subclinical hypothyroidism (1.10 [1.01–1.21]), autoimmune thyroiditis (1.09 [1.00–1.18]), and thyroglobulin antibody positivity (1.17 [1.07–1.29]). However, there was no association between PM2.5 exposure and overt hyperthyroidism, subclinical hyperthyroidism, Graves' disease, or thyroid peroxidase antibody positivity (p > 0.05). Each 10 μg/m³ increase in the PM2.5 concentration was associated with an increased risk of overt hypothyroidism (OR 1.05 [1.00–1.11]), subclinical hypothyroidism (1.02 [1.00–1.03]), and thyroglobulin antibody positivity (1.02 [1.00–1.04]). Furthermore, a nearly linear exposure–response relationship was observed between long-term PM2.5 exposure and thyroglobulin antibody positivity. Conclusions: PM2.5 exposure was associated with thyroid disorders among Chinese adults. A dose–response relationship between PM2.5 exposure and autoimmune thyroiditis, as well as thyroglobulin antibody positivity, was also observed. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) has been considered a T cell-mediated autoimmune demyelinating disorder. Nuclear factor κB (NF-κB) is one of the master transcription factors that regulate the activity of inflammatory cells the present study aimed to investigate the NFKB/P65 mRNA levels in patients with MS and to assess its role in the prediction of Hashimoto' thyroiditis (HT). Methods: 50 patients with clinically definite relapsing-remitting multiple sclerosis (according to the McDonald criteria 2017) compared to 50 healthy age and sex-matched controls. Thyroid serum antibodies, IgG index (IgG), and oligoclonal band (OCB) were assessed. The relative expression of NFKB/P65 mRNA was measured using real-time quantitative PCR. Results: there were significantly higher values of NFKB/P65 mRNA levels in patients with HT (2.4±0.54) compared to other patients without HT (1.3±1.45) and control group (0.8±0.17), p <0 .001. Significant associations were confirmed between NFKB/P65 mRNA correlated to thyroid autoimmunity and MS manifestations, p <0. 001. Linear regression revealed that only FT4 and TSH were independent variables correlated with NFKB/P65 mRNA, p < 0.001. Regarding prediction of MS, ROC curve revealed that the sensitivity of NFKB/P65 mRNA was 96 %, and specificity was 88% at cutoff 0.98 with (95% CI = 0.909-0.999). Concerning HT prediction, the cutoff 1.42 with (95% CI = 0.843-1.000)with a sensitivity of 93.8 % and, a specificity of 87.4%. Conclusions: NFKB/P65 mRNA increased in patients with MS more specifically in HT. Thus, NFKB/P65 mRNA could be used as noninvasive prediction markers of MS and HT. [ABSTRACT FROM AUTHOR]

The flavoprotein iodotyrosine deiodinase (IYD) was first discovered in mammals through its ability to salvage iodide from mono- and diiodotyrosine, the by-products of thyroid hormone synthesis. Genomic information indicates that invertebrates contain homologous enzymes although their iodide requirements are unknown. The catalytic domain of IYD from Drosophila melanogaster has now been cloned, expressed and characterized to determine the scope of its potential catalytic function as a model for organisms that are not associated with thyroid hormone production. Little discrimination between iodo-, bromo-, and chlorotyrosine was detected. Their affinity for IYD ranges from 0.46 to 0.62 μM (K d ) and their efficiency of dehalogenation ranges from 2.4 - 9 x 10 3 M -1 s -1 (k cat /K m ). These values fall within the variations described for IYDs from other organisms for which a physiological function has been confirmed. The relative contribution of three active site residues that coordinate to the amino acid substrates was subsequently determined by mutagenesis of IYD from Drosophila to refine future annotations of genomic and meta-genomic data for dehalogenation of halotyrosines. Substitution of the active site glutamate to glutamine was most detrimental to catalysis. Alternative substitution of an active site lysine to glutamine affected substrate affinity to the greatest extent but only moderately affected catalytic turnover. Substitution of phenylalanine for an active site tyrosine was least perturbing for binding and catalysis., (© 2016 The Protein Society.)

Deca-brominated diphenyl ether (deca-BDE), composed mainly of BDE-209, is subject to usage restrictions in North America and Europe, although global action on its continued use has yet to be undertaken. Relatively large concentrations of polybrominated diphenyl ethers (PBDEs), especially BDE-209 and its higher brominated degradation products, have been reported in tissues of ring-billed gulls (Larus delawarensis) breeding near the densely populated city of Montreal (QC, Canada). There is limited knowledge of BDE-209 biotransformation and toxicokinetics in birds. Deiodinases, a class of enzymes catalyzing thyroid hormone conversion, have been suggested to be involved in BDE-209 debromination in birds. The objective of the present study was to investigate the relationships between PBDE concentrations and type 1 deiodinase (D1) transcription and in vitro activity (microsomes) in livers of Montreal-breeding ring-billed gulls. The ring-billed gulls exhibiting the highest D1 activity in liver microsomes accumulated the greatest liver concentrations of hepta-BDEs and octa-BDEs. Activity of D1 was inversely related to concentration ratios of BDE-209 to octa-BDEs and ∑hepta-BDE. An even stronger inverse relation was found between D1 activity and BDE-209 to ∑nona + octa + hepta-BDE concentration ratios. The messenger ribonucleic acid (mRNA) levels of D1 in gull livers were inversely associated with liver concentrations of ∑octa-BDE. The present study's findings suggest that D1 is potentially involved in BDE-209 biotransformation and accumulation of higher brominated PBDEs in livers of ring-billed gulls. Environ Toxicol Chem 2016;35:2215-2222. © 2016 SETAC., (© 2016 SETAC.)

Objective: Plasma levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) are reduced in individuals with defective insulin signaling. Initial studies using liver-specific insulin receptor (InsR) knockout mice identified reduced expression of type 1 deiodinase (Dio1) as a potentially novel link between defective hepatic insulin signaling and reduced expression of the ApoA-I gene. Our objective was to examine the regulation of ApoA-I expression by Dio1., Approach and Results: Acute inactivation of InsR by adenoviral delivery of Cre recombinase to InsR floxed mice reduced HDL-C and expression of both ApoA-I and Dio1. Overexpression of Dio1 in InsR knockout mice restored HDL-C and ApoA-I levels and increased the expression of ApoA-I. Dio1 knockout mice had low expression of ApoA-I and reduced serum levels of HDL-C and ApoA-I. Treatment of C57BL/6J mice with antisense to Dio1 reduced ApoA-I mRNA, HDL-C, and serum ApoA-I. Hepatic 3,5,3'-triiodothyronine content was normal or elevated in InsR knockout mice or Dio1 knockout mice. Knockdown of either InsR or Dio1 by siRNA in HepG2 cells decreased the expression of ApoA-I and ApoA-I synthesis and secretion. siRNA knockdown of InsR or Dio1 decreased activity of a region of the ApoA-I promoter lacking thyroid hormone response elements (region B). Electrophoretic mobility shift assay demonstrated that reduced Dio1 expression decreased the binding of nuclear proteins to region B., Conclusions: Reductions in Dio1 expression reduce the expression of ApoA-I in a 3,5,3'-triiodothyronine-/thyroid hormone response element-independent manner., (© 2016 American Heart Association, Inc.)