ResearchPad - hpt-axis-and-thyroid-hormone-action https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells]]> https://www.researchpad.co/article/elastic_article_8796 Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hypothyroidism or resistance to TH (RTH), TH-TR binding is dominantly disrupted, leading to the various symptoms such as motor deficits. However, in such cases, all the cells that express TR get affected by the disrupted TR signaling; thus, the specific mechanism has not been cleared. It has been well known that proper motor coordination is deeply related to long term depression (LTD) of synaptic transmission from parallel fiber (PF) to Purkinje cell (PC) in the cerebellum (Ito, 1989). Therefore, we examined the involvement of TR in synaptic plasticity at PF-PC synapses by using transgenic mice (Mf-1 mice) which express dominant-negative TR specifically in PCs. Since Mf-1 display the impairment of motor coordination and motor learning, a decrease in TR signaling in PCs may alter synaptic plasticity and contribute to motor incoordination. A whole-cell patch clamp recording of Mf-1 PCs revealed the inhibition of LTD but instead the induction of long term potentiation (LTP) of the synaptic transmission at PF-PC synapses. This indicates that the intracellular calcium dynamics may be disrupted in Mf-1 PCs since LTD requires a higher elevation of the intracellular calcium concentration in PCs than LTP does. Indeed, single-PC qPCR showed that the mRNA levels of some important molecules for the intracellular calcium dynamics in PCs (SERCA2, IP3R, and P/Q-type calcium channel) are downregulated in Mf-1 PCs. This result suggests those genes as possible TH-target genes. Taken together, the present study suggested a novel possible role of TR in synaptic plasticity at PF-PC synapses by regulating the expression of some important genes for LTD occurrence in the cerebellum. This finding could give a new insight into the mechanism of motor deficits in thyroid diseases.

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<![CDATA[SAT-450 Essential Role of GATA2 in the Negative Regulation of the Prepro-Thyrotropin-Releasing Hormone Gene by Liganded T3 in the Rat Paraventricular Nucleus]]> https://www.researchpad.co/article/elastic_article_8676 T3 inhibits thyrotropin-releasing hormone (TRH) synthesis in hypothalamic paraventricular nucleus (PVN). Although T3 receptor (TR) β2 is known to mediate the negative regulation of prepro-TRH gene, its molecular mechanism remains unknown. Our previous studies on the T3-dependent negative regulation of the thyrotropin β subunit (TSHβ) gene indicate the tethering mechanism, where T3-bound TRβ2 interferes with the function of the transcription factor GATA2, which is essential for TSHβ expression. Interestingly, the transcription factor Sim1, a determinant of PVN differentiation in hypothalamus, is reported to induce the expressions of TRβ2 and GATA2. Indeed, our immunohistochemistry revealed the expression of GATA2 in the TRH neuron of the rat PVN. According to the experimental report with transgenic mice, the DNA sequence from nt. -547 to nt. +84 is sufficient for the expression of the prepro-TRH gene in PVN. Using the CAT reporter gene harboring this region, we found that this promoter is activated by GATA2 approximately 6-fold in CV1 cells. The deletion and mutation analyses identified a functional GATA-responsive element (GATA-RE) between nt. -357 and nt. -352. When TRβ2 was co-expressed, T3 reduced GATA2-dependent promoter activity to approximately 30%. T3-dependent repression was maintained after the mutation of the putative negative T3 responsive element (site4). Although the melanocortin 4 receptor signaling is known to stimulate the prepro-TRH promoter via protein kinase A pathway in the PVN, inhibition by T3 was dominant over the 8-bromo-cAMP-induced activation. We observed the in vivo recognition of GATA-RE by GATA2 using chromatin immunoprecipitation assay with CA77 cells, which express endogenous TRH. The electrophoretic mobility shift assay also demonstrated that GATA2 bound to oligonucleotide containing the GATA-RE. These results suggest that, as in the case of the TSHβ gene, GATA2 transactivates the prepro-TRH gene and that T3-bound TRβ2 interferes with its function, resulting in the negative regulation of this gene.

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<![CDATA[SAT-434 Phenotype and Genotype Analysis of Patients with Resistance to Thyroid Hormone β: A Single-Center Experience]]> https://www.researchpad.co/article/elastic_article_8551 Introduction Resistance to thyroid hormone β (RTHβ) is caused by mutations in THRB, the gene that encodes thyroid hormone receptor β. The clinical phenotype is variable and may include goiter, tachycardia, and learning disability with or without hyperactive behavior. The biochemical hallmark of RTHβ is elevated T4 and T3 with non-suppressed TSH concentrations. We here describe the phenotype and genotype of three Thai patients diagnosed with RTHβ in a pediatric referral center. Patients had previously been misdiagnosed and inappropriately treated with antithyroid drugs (ATDs). Methods Clinical features and thyroid function tests (TFTs) of three unrelated RTHβ patients were retrospectively reviewed. Genomic DNA of the RTHβ patients and affected family members was amplified for exon 7-10 of the THRB gene and sequenced to identify mutation by Sanger sequencing. The impact of the p.L341V novel mutation on the affinity for T3 and T3-induced transcriptional activity was previously determined in vitro. Results Three female patients were diagnosed with RTHβ. All of them had been misdiagnosed with hyperthyroidism and treated with ATDs prior to referral. The mean age at diagnosis was 8 years. The main presenting symptoms were diffuse goiter and tachycardia. The mean duration of ATD treatment was 3 years. During the treatment, patients had fluctuating thyroid hormone and increased TSH levels. An older sister and mother of one patient also had similar TFTs abnormalities, for which the mother had undergone a subtotal thyroidectomy. RTHβ was diagnosed based on the high FT3 and FT4 with normal (non-suppressed) TSH concentrations and confirmed by mutation analysis. Anti-thyroid peroxidase, anti-thyroglobulin, and TSH receptor antibody (TRAb) were negative, excluding autoimmune thyroid disease. Heterozygous missense mutations of the THRB gene were identified in all patients and affected family members. Two mutations had been previously reported (p.R243W and p.L456F), and one mutation was novel (p.L341V). In vitro studies confirmed an important role of Leu341 in T3 binding of the TRβ and functional impairment of the p.L341V novel mutation and were reported separately. According to available literature, only nine Thai RTHβ patients (in three families) carrying three different mutations (p.G251V, p.M313T, and p.A317T) had been previously reported. Goiter was the most common clinical finding, and almost all patients had a history of receiving unnecessary treatment with ATDs. Conclusion We report a series of RTHβ patients carrying THRB gene mutations, including one novel mutation (p.L341V). Clinicians should be alert that RTHβ can be found in patients with goiter and tachycardia. Elevated T4 and T3 with non-suppressed TSH concentration is the main diagnostic clue for this disease. Mutation analysis allows definitive diagnosis of RTHβ and may help to avoid potential misdiagnosis and improper treatment.

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<![CDATA[SAT-449 Factors Associated with Reduced Thyroid Hormones in Cushing Syndrome Patients Before and After Surgical Cure]]> https://www.researchpad.co/article/elastic_article_8546 Background: Hypercortisolemia adversely affects thyroid hormone secretion. We previously described the temporal pattern of thyroid function recovery in 23 patients (1). However, the factors leading to suppression and recovery of the hypothalamic-pituitary-thyroid (HPT) axis in Cushing’s syndrome (CS) are not fully understood. We performed two separate studies to investigate these factors. Methods: In study 1, we examined patients (pts, n=62) with CS who underwent curative surgery and recorded their serum morning and evening cortisol, ACTH, tumor volume and duration of symptoms and 24-hour urine free cortisol (UFC) at baseline and the morning serum free T4, TSH and T3 at six-month intervals after cure. Data were log-transformed and Pearson correlations were performed. Linear mixed models were used to study factors that predict recovery of thyroid function. In study 2, we examined the diurnal variation of TSH by performing hourly TSH measurement between 3—7 PM and 12—4 AM on a cohort of pts (n=45) before surgery. Wilcoxon Signed-Rank method was used for comparisons of mean TSH across time and Pearson correlations were performed on log-transformed data. P values <.05 were considered significant. Results: Study 1: In this larger cohort, we confirmed previous findings of suppressed or low normal fT4 and TSH values with active hypercortisolism, with normalization after cure that reflected changes in the T3:TSH, fT4:TSH and T3:fT4 ratios. There were inverse linear correlations between log10 UFC, serum AM and PM cortisol; and log10 TT3, fT4 and TSH before surgery. Independent negative prognosticators of circulating fT4 recovery included UFC greater than 1000mcg/day (nl: 3.5—45mcg/day), duration of symptoms of less than one year, and ACTH levels greater than 60pg/mL(nl: 5—45pg/mL) Study 2: The nocturnal (12 - 4AM) TSH surge was reduced, so that the difference in day and night TSH values was not statistically significant; this contrasts with the 30—50% nocturnal TSH increase above daytime values seen in healthy subjects. There was an inverse relationship between UFC and nocturnal TSH, daytime TSH and TBG values, but there was no direct relationship between UFC and percent changes in nocturnal TSH values. Conclusions: Our findings suggest that a deficit in TSH stimulation of the thyroid gland may explain the reduction in T3 and T4 levels. There is a dose-response relationship between various measures of hypercortisolemia and both thyroid hormones and the pattern of TSH secretion. Finally, the severity of hypercortisolism correlates with a longer time to recovery of the HPT axis in pts with CS after curative surgery. 1. Shekhar S et al. HPG and HPT Axes in Cushing Syndrome. J Endocr Soc, 3 S1, April May 2019

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<![CDATA[SAT-453 Delayed TSH Elevation in Small for Gestational Age Infants: A Need for Second Screening?]]> https://www.researchpad.co/article/elastic_article_7187 The incidence of CH with a delayed TSH elevation was higher in ELBW and VLBW infants compared with infants weighing ≥1500 grams. Second screening should be considered in preterm neonates, low birth weight (LBW) and very low-birth weight (VLBW) neonates, ill and preterm newborns admitted to NICU, specimen collection within the first 24 hours of life, and multiple births (particularly same-sex twins). Purpose of this study was to determine incidence of delayed TSH elevation with or without congenital hypothyroidism in SGA infants and to Investigate necessity for second screening. Retrospective analysis was performed. 66 SGA newborns with 34-40 weeks’ gestation born at Keimyung University Dongsan Medical Center from 2015 to 2018 were enrolled. Primary screening was performed 48 hours - 7 days after birth. Second screening including venous TSH and venous free T4 at postnatal 8-40 days. Exclusion criteria were infants with congenital hypothyroidism at primary screening (NBS), descendants of mothers with immune thyroid disease, congenital malformations, renal, hepatic, and metabolic diseases, history of steroid or dopamine usage. Initial NBS were collected onto pre-printed filter at the age of 2-7 days by heel prick. (normal TSH < 10 mIU/L). Second sample was obtained at the age of 8-49 days by venous sampling (normal TSH < 5 mIU/L). TSH and free T4 were measured on venous samples with Cobas 8000 e801 (electrochemiluminescence, Roche, Diagnostics, Basel, Switzerland) using standard methods.

Incidence of delayed TSH elevation was 27% (18/66). Of them number of transient hyperthyrotropinemia was 13. Mean TSH at initial elevation was 7.56 mIU/L and median age at initial TSH elevation was 18.6 days. Median age at resolution of TSH elevation was 41.5 days. Number of hypothyroidism undergoing l-thyroxine medication was 5. Mean TSH at initial elevation was 22.1 mIU/L. Median age at initial TSH elevation was 14 days. Mean peak TSH was 23.4 mIU/L.

The presence of delayed TSH elevation was not related to very low birth weight. SGA infants might be at a risk of delayed TSH elevation. Considering 2nd screening test within 1 month. Further study with more SGA infants are needed. Limitation of this study was relative small number of patients and iodine status was not considered

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<![CDATA[SAT-439 Thyroid Ultrasound Reports and Thyroid Function Tests in Florida Firefighters: Data from the Firefighter Cancer Initiative]]> https://www.researchpad.co/article/elastic_article_7137 Background: Several epidemiological studies suggest firefighters are at risk for numerous site-specific malignancies, including thyroid cancer. However, it is not well known if chronic exposure to carcinogenic compounds or radio frequency radiation, increases the rate of thyroid nodules and/or affect the thyroid function in this high-risk occupational group. To gain a better understanding, we examine the rate of thyroid nodules and assess the presence of thyroid dysfunction in a sample of Florida firefighters. Methods: A cross sectional study design was conducted to evaluate 103 firefighters, with not known thyroid disease, who were assessed by a physician-performed, real time ultrasound protocol followed by a blood collection to evaluate TSH, Free T4, T4, T3, TPO and Tg antibodies. Additional data such as gender, age and race were also collected and analyzed. Results: Among the 103 firefighters who completed the study protocol, the sample mean age was 39.4+-7.6 years (range 26 to 60) 88.4% male, 87.6% Caucasian and 65% Hispanic. 8.7% of men and 33% of women were found to have thyroid nodules. Of the 20 participants with thyroid nodules only three nodules were above 1 cm, and only one was classified as high risk and met criteria for fine needle aspiration. 8.7 % of men and 33% of women were found to have +TPO antibodies. 18.6% of men and 25% of women were found to have isolated low T3. Conclusion: The prevalence of thyroid nodules, and of Hashimoto thyroiditis, among Florida firefighters, is comparable with the rate found in the general population based on previous epidemiological data. Surprisingly, we found that a significant number of subjects have isolated low T3. In this study, the level of Free T3 was not assessed, however since T4 was normal, we can conclude that the low T3 was not related to a low level of TBG. Low T3 is usually found in systemic illness and has been postulated as a prognostic factor in cardiovascular disease, chronic fatigue syndrome, survival after stroke, and Alzheimer’s disease. The clinical significance and the prevalence of Low T3 in a healthy population has not been well described. Further research is needed to fully understand the significance of this finding.

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<![CDATA[SAT-441 Transcriptome Analysis Under Differential Thyroid Hormone Treatment During Mouse Cerebellar Development]]> https://www.researchpad.co/article/elastic_article_7027 Background: Thyroid hormone (TH) plays essential roles in the development of the cerebellum by regulating transcription of target genes. TH binds to TH receptor (TR) located in the cell nucleus and stimulates transcription through TH response element (TRE). The expression of many genes is temporary and spatially regulated by TH during cerebellar development. However, the mode of transcription by TR may vary among target genes. In the liver, different duration of TH exposure resulted in distinct gene expression profiles. To examine the mechanisms of transcriptional regulation by TH in cerebellar development, gene expression profile induced by various TH exposure duration was studied. Methods: Anti-thyroid drug propylthiouracil (250 ppm in drinking water) was administered to C57BL/6J mice from the gestational day 14 to postnatal day (P) 7 to generate perinatal hypothyroid mice. To study the effect of continuous TH exposure, TH was subcutaneously administered to hypothyroid pups from P2 to P7 (6 days group). To study the effect of single TH administration, TH was injected on P7 and mice were sacrificed either 6 (6 hours group) or 24 hours (24 hours group) after injection. Cerebellar samples were collected to extract RNA and subject to microarray analysis. Microarray results were confirmed by RT-qPCR. Results: In microarray result, compared with mRNA levels of hypothyroid mice, 6 days group induced upregulation in 1007 genes and downregulation in 1009 genes, 6 hours group induced upregulation in 355 genes and downregulation in 977 genes, and 24 hours group induced upregulation in 365 genes and downregulation in 1121 genes. Only 7.6% of the genes were overlapped in three groups among positively regulated genes. In contrast, 57.2% of the genes were common in the negatively regulated genes. In RT-qPCR result, among genes known to harbor TRE, Hairless, Pcp2, and Nrgn, showed differential upregulation patterns. Hairless was upregulated in all groups, whereas Pcp2 was upregulated only in 5 days group and Nrgn was not upregulated in all groups. These results suggest that different mode of transcriptional regulation occurred in an exposure time-dependent manner of TH. Conclusion: We identified gene groups whose expression were modified by TH during cerebellar development. TH distinctively regulates transcription of target genes depending on the exposure schedule in mouse developing cerebellum.

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<![CDATA[SAT-442 The Impact of Chronic Excess Iodine Intake in Adult Mice Behavior]]> https://www.researchpad.co/article/elastic_article_6838 Iodine is one of the essential micronutrient which is required for the synthesis of thyroid hormones. Thus, iodine deficiency may result in the hypothyroidism. Iodine deficiency is one of the most common causes of preventable mental retardation and brain damage in the world. On the other hand, Japanese iodine intake exceeds that of most other countries, due to the significant seaweed consumption such as kelp. The Japanese Ministry of Health, Labour and Welfare estimates average iodine consumption at 1.2mg/day in Japan. In contrast, the recommended tolerable upper intake levels for adult is 1.1 mg / day in the United States. Generally, Japanese takes twenty times higher amount of iodine than Americans. Iodine tolerance among individual humans varies greatly, and the excess iodine can cause both hyper- and hypo- thyroidism. Furthermore, the effect of thyroid dysfunction due to iodine excess on brain function has not been clarified. In this study, we generated a mouse models for chronic iodine excess and evaluated its effect on brain development. C57BL/6 dams and their pups mice were treated with KIO3 37.4mg/l through drinking water. Behavioral experiments (novel object recognition test, novel object in location test, visual discrimination test, and three-room social behavior test) were conducted at 10-weeks-old. After the behavioral analysis, mice were sacrificed to collect trunk blood and tissues. Excess iodine intake caused hypertrophy of thyroid follicles regardless of the administered dose. However, there were no differences in thyroid hormone status among groups. Thyroid hormone responsive genes in the hippocampus were also not affected in experiment group. In the behavioral analysis, female mice showed an increase in learning ability. In summary, although the chronic overdose of iodine does not affect thyroid hormone levels, it may affect cognitive learning function. The gender difference in the consequence was also observed. These results indicate that the chronic iodine excess may cause various changes, although the body is tolerable with excess iodine.

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<![CDATA[SAT-451 Chronic Stress During Adolescence of Rats Shows Sex Dimorphism in the Thyroid Axis Response to Voluntary Exercise in Adulthood]]> https://www.researchpad.co/article/elastic_article_6780 Exposure to chronic stress during adolescence causes long-term effects on the response of Hypothalamus-Pituitary-Adrenal (HPA) axis, affecting behavior and energy homeostasis. Voluntary exercise activates the HP-Thyroid (HPT) axis allowing efficient fluxes of substrates to active target organs. Chronic stress in adult rats blunts HPT axis response to voluntary exercise in a sex-dependent manner (Front Endocrinol 10(418):1-13, 2019). As adolescents show sex-dependent responses to stress, we sought to evaluate the effect of chronic stress at this period in the response of HPT axis to voluntary exercise in adulthood. Wistar male and female rats were divided in an undisturbed group (Control, C) and one group exposed to chronic variable stress (CVS) where the rats were daily subjected to different stressors during postnatal day (PND) 30 to 60 for females and PND 30 to 70 for males. At adulthood (PND 74 for females and PND 84 for males) rats were exposed to running wheel following published protocol (Endocrinology 155:2020-2030, 2014). As females are more susceptible to stress during adolescence than males, additional independent experiments were performed with female rats kept in group or individual housing, since PND 30 (2 per cage or isolated (Iso)). At PND 64, Iso rats were housed in pairs and exposed to CVS every 3 days until PND 80; later, rats were exercised 26 days. Hormones were quantified by ELISA or RIA; mRNA expression was determined by RT-PCR. Voluntary exercise reduced fat mass in C groups, dependent on the amount of exercise performed; stressed rats exercised did not lose fat, indicating that adolescent stress avoids an appropriate energy distribution during exercise. The expression of Crh and Avp in hypothalamic paraventricular nucleus (PVN) decreased in stressed groups mainly in females, as reported. Exercise decreased corticosterone levels only in C rats, suggesting that CVS during adolescence modifies the HPA axis response to exercise. CVS inhibited Pomc expression induced by exercise and increased Npy expression in arcuate nucleus, decreased Trh expression in PVN for both sexes and in dorsomedial hypothalamus in males. Thyroid hormones were not altered in CVS males and Iso females; however, T3 and T4 levels were high in CVS females, so different stress exposures may modify the HPT axis state in females. The response to exercise of the target organs of thyroid hormones reveals with more accuracy the activity of HPT axis, exercise stimulated the expression of Adrb3 and Dio2 in brown adipose tissue of C females, and the expression of Dio2 and Pgc1a in skeletal muscle (gastrocnemius) of both sexes, changes attenuated by CVS. These results indicate that chronic stress during adolescence blunts the response of HPT axis to voluntary exercise, strongly in females than males.

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<![CDATA[SAT-440 Phthalates Expose and Thyroid Parameters in Euthyroid Patient with Type 2 Diabetes: Sex Specific Associations]]> https://www.researchpad.co/article/elastic_article_6607 Phthalates are ubiquitous in different environmental exposure media around the world. Recent years, issues on the relationships of phthalates and endocrine disorders raise attention. Evidence of thyroid disruption as a result of phthalates expose among euthyroid participants with diabetes is very limited. We aimed to evaluate the association between phthalate and thyroid function, and to explore whether thyroid autoimmunity mediated this association. Concurrent urine and blood samples were collected from 538 participant in METAL study. We measured urinary concentrations of ten phthalate metabolites (urinary creatinine adjusted), along with serum levels of thyroid-stimulating hormone (TSH), free thyroxin (FT4), free triiodothyronine (FT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb). Euthyroidism was defined as TSH within normal range. After adjusting for age, sex (only with the entire sample), BMI and smoking status, linear regression analyses showed exactly opposite directional results among men and women. TSH levels were negatively associated with mono-2-ethyl-5-carboxypentylphthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexylphthalate (MEOHP), mono-2-carboxymethyl-hexyl phthalate (MCMHP) and sum of di (2-ethylhexyl) phthalate metabolites (ΣDEHPm) in men, but positively associated with monoisobutylphthalate (MiBP) and mono-n-butylphthalate (MnBP) in women. Meanwhile, FT4 was positively associated with mono-2-ethylhexylphthalate percentage (%MEHP) in men, but negatively associated with MnBP, MEOHP and MCMHP in women. Further, in women, TPOAb was increasing along with the increased level of MEHP and %MEHP. In the mediation analysis, TPOAb demonstrated a mediating effect whereby MEHP or %MEHP had a positive effect on TSH and a negative effect on FT4 only in women (all P<0.05). We got a conclusion that among euthyroid participants with diabetes, urinary phthalate metabolites maybe associated with altered TSH, FT4 and TPOAb levels in different direction in men and women. Further, our present study maybe the first to suggest that TPOAb might be a potential mediator of the association between phthalate metabolites and thyroid function in women.

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<![CDATA[SAT-435 A Direct Comparison of Thyroid Hormone Receptor (THR) Protein Levels in Mice Provides Unexpected Insights into TH Action]]> https://www.researchpad.co/article/elastic_article_6514 Thyroid Hormone (TH) action is mediated by three major THR isoforms α1, β1 and β2 (THRA1, THRB1 and THRB2), encoded by two genes Thra and Thrb. A fourth non-T3 binding isoform is termed THRA2. Previous characterization and comparison of THR isoform expression using QPCR of mRNA levels does not assess translational or post-translational control of THR protein levels. Moreover, reliable antibodies against all THR isoforms are not currently available. To address these concerns, we generated knock-in mouse models expressing endogenously and identically 2X HA tagged THRs (THRA1/2, THRB1 and THRB2), which could then be detected by commercially available anti-HA antibodies. We characterized THR expression in 16 mouse organs. We found that in all peripheral tissues tested except the liver, the dominant THR isoform is THRA1, and THRB1 and THRA2 are expressed at significantly lower levels or are undetectable. Surprising THRB1 levels were very low in metabolically active organs such fat and muscle. In some organs, mRNA transcript levels predicted THR protein amounts, while in others the prediction was inaccurate. For instance, adipose depots have similar levels of Thrb1 and Thra1 transcripts, however THRA1 protein levels are up to 10-fold higher than THRB1. In contrast to peripheral organs, brain tissues express low levels of both THRB1 and THRA1, but have very high levels of THRA2. As expected and confirmed in this study, THRB2 has limited expression and was only detected in pituitary of the organs tested. Interestingly, THRB2 expression in female was much higher than male mice (the only sex-difference in THR expression found); and expression of the THRB2 target gene, Tshb, was lower in female mice. For the first time, these HA-THR mouse lines can be used to accurately compare isoform-specific actions of THRs in organs. The predominant expression of THRA1 in most peripheral organs, for example, suggests that many peripheral actions of THRB1 could be indirectly mediated.

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<![CDATA[SAT-455 Mouse Thyroid Responds to Iodine Overload by Transcriptionally Enhancing the Keap1/Nrf2 Antioxidant Response and by Upregulating Nrf2-Dependent and Independent Inflammatory and Fibrosis Pathways]]> https://www.researchpad.co/article/elastic_article_6511 Nrf2 (Nfe2l2) is a transcription factor that regulates a series of cytoprotective and antioxidant enzymes. Its cytoplasmic inhibitor Keap1 senses the presence of oxidative or electrophilic stress though the interaction of sulfhydryl groups of its cysteines with reactive species and ceases to bind Nrf2. Thus, Nrf2 can transfer to the nucleus and induce its target genes. Follicular thyroid cells have physiologically high levels of reactive oxygen species as oxidation of iodine is essential for iodination of thyroglobulin and thyroid hormones synthesis. We have shown previously that Nrf2 pathway is active in thyroid and regulates the transcription of thyroglobulin. We thus hypothesized that the response of thyroid to iodine excess should comprise Nrf2-dependent and -independent pathways. To this end, 3 months-old male C57Bl6J WT or Nrf2 knockout (KO) mice were exposed to 0.05% sodium iodide in their water for 7 days. Thyroids were excised and used for RNA extraction; RNA-seq was performed by Exiqon, with a fold-change cutoff set at 2. Selected representative genes of the enriched pathways were quantified by real-time qPCR to validate RNA-seq results. Pathway analysis of the differentially expressed genes was performed using the Ingenuity Pathway Analysis (IPA) software. Pathways that were enriched with a p-value<0.05 were considered significant. 828 genes were differentially expressed in response to iodine exposure; 66% were upregulated, as were most of the highly enriched pathways (related to inflammatory-immune response, antioxidant response, xenobiotic metabolism, platelet activation and calcium signaling). About 300 genes were differentially expressed between WT and KO mice; highly enriched pathways were related to glutathione and xenobiotic metabolism, Ahr signaling and Nrf2 signaling and were all downregulated in KO mice. Analysis of the potential upstream regulators of these highly enriched pathways revealed that Nrf2 and NfkB are major regulators of the antioxidant and inflammatory response induction upon iodine exposure and that Tgfβ-Smad cascade regulates the induction of fibrosis signaling. Last, we performed an analysis limited to already known thyroid pathways. A few genes were enriched following this method; upregulation of Duoxa1 (hydrogen peroxide generator) and downregulation of Nis (sodium iodide symporter) upon iodine exposure, which are expected responses, and the downregulation of thyroglobulin and upregulation of Duoxa1 in KO mice that confirm our previous findings. In conclusion, Nrf2-driven cytoprotective response is upregulated after iodine overload along with induction of inflammatory pathways. Nrf2 regulates transcriptomic responses in the thyroid, including a small but significant part of the response to iodine challenge. Hence, Nrf2 can be considered a novel player in the frontiers of thyroid antioxidant response and thyroid economy.

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<![CDATA[SAT-457 The Association Between Thyroid Stimulating Hormone and Severe Depression: A Historical Cohort Study]]> https://www.researchpad.co/article/elastic_article_6440 Introduction: Hypothyroidism is implicated in the pathophysiology and clinical course of mood disorders. This study aimed to investigate the association between TSH and severe depression.

Methods: The historical cohort included all consecutive adult patients (≥ 18 years) who had a TSH and PHQ-9 questionnaire data within 6 months of index visit, between October 2016 and July 2019, at the University of Utah Health. Data on demographics, hypothyroidism, TSH, PHQ-9, thyroid hormone replacement (THR), and antidepressant medications were extracted electronically. T-test and chi-square were used to compare continuous and categorical variables respectively. Logistic regression and one-way ANOVA were used to evaluate the association between TSH and depression severity. A sub-group analysis was performed among mood disorder patients without a diagnosis of overt hypothyroidism, comparing euthyroid patients (TSH 0.3-4) and patients with sub-clinical hypothyroidism based on TSH 4-10.

Results: The cohort included 26,722 patients, mean age 46.3 years, 79.5% Caucasian, 68% females, and mean BMI 30. Mean PHQ-9 score was 8.2, 10% patients had severe depression (PHQ-9 ≥20), and 51% were on antidepressants and 26% on mood stabilizers. Mean TSH was 2.85, 19% patients had a diagnosis of hypothyroidism, and 20% patients were on THR. Patients with severe depression were more likely to have a higher mean TSH (p=0.06), be on antidepressants (p= <0.0001), and have a higher BMI (p=0.0003). There was a positive correlation between TSH and PHQ-9 score (p= 0.04). TSH was associated with severe depression, odds ratio 1.006 (1.003-1.009), after adjusting for potential co-variates. Hypothyroid patients who were on THR had a lower mean PHQ-9 score (p= <0.0001) as compared to hypothyroid patients not on THR. Patients with TSH from 7-10 had a higher PHQ-9 score as compared to those who had a TSH from 4-7 (p= <0.003).

Conclusion: Severe depression was associated with higher TSH. Subclinical hypothyroidism with TSH above 50th percentile was associated with higher PHQ-9 scores. Future RCTs should evaluate the effect of THR in (a) patients with severe depression and (b) patients with mood disorders who have subclinical hypothyroidism.

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<![CDATA[SAT-LB77 Thyroid Radiofrequency Ablation: A New Office Based Procedure for Endocrinologists]]> https://www.researchpad.co/article/elastic_article_6248 Recent FDA approval of thyroid RF has made it possible for endocrinologists in the USA to finally treat their own patients after obtaining training. I have 5 years experience working with these systems and have trained many endocrinologists in my practice. In 2019 I began a preliminary study of 12 patients with negative biopsies to see the feasibility of doing thyroid RF in my ultrasound room in my office without going to imaging centers or the hospital. The fee for office based RF is 3-6 times less expensive. RF system by RF Medical Korea was used in all cases. The results are promising. Skin and thyroid capsule local injection was all that was needed for pain control. Vital signs were monitored by my roving nurse. The maximal watts used was 20-40. There were no major complications and only one bruise in the neck area. No vocal symptoms. All 12 tolerated the procedure and after 30 minutes observation left with only a small band aid over the injection site. Two flew out of state that night.Conclusion: A preliminary assessment of in office thyroid RF without general of conscience sedation by trained endocrinologists suggests larger study with 80-100 cases is the next step.

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<![CDATA[SAT-437 Influence of Smoking on Thyroid Function in Japanese Subjects: Longitudinal Study for One Year of On-Off Smoking]]> https://www.researchpad.co/article/elastic_article_5981 Recent studies showed that various factors, including age, gender, race, iodine intake, obesity, the thyroid peroxidase antibody (TPO-Ab), and/or smoking, influence the thyroid status. In the present study, we analyzed and investigated the effects of these factors, particularly smoking and the thyroid peroxidase antibody (TPO-Ab) in Japanese euthyroxinemia individuals with serum free T4 level within normal range. A total of 12,289 subjects who underwent health check-ups were analyzed in a cross-sectional and longitudinal study. The mean age of subjects was 50 ± 10 years (age range: 21–88 years). Serum TSH levels and the prevalence of positivity for TPO-Ab increased with age in Japanese euthyroxinemia subjects. Mean and median serum TSH levels increased with age in smokers and non-smokers, but were significantly lower in smokers than in non-smokers among men and women in most age groups; the median 97.5th percentiles of TSH levels were 1.2 mU/liter and 2.9 mU/liter in smokers, and 1.4 mU/liter and 3.9 mU/liter in non-smokers in 31- to 40-year-old men, p<0.01, and 1.4mU/liter and 4.3 mU/liter, and 1.8mU/liter and 6.2 mU/liter in 61- to 70-year-old men, p<0.01. However, smoking had a negligible effect on serum TSH levels in women older than 50 years; 1.3 mU/liter in smokers and 1.6 mU/liter in non-smokers in 31- to 40-year-old women, p<0.01, and 1.5 mU/liter and 1.8 mU/liter in 51- to 60-year-old women, p=0.3. Furthermore, the present study confirmed that serum free T4 levels in men progressively decreased with age, whereas no significant change was observed in women. Smoking did not affect the relationship between age and serum free T4 levels in men or women, except for men in their 20s. Serum TSH levels were significantly higher in subjects with positivity for TPO-Ab than in those with negativity at all ages and in both genders; however, smoking did not affect free T4 levels or the positivity for TPO-Ab. The rate of smokers in men was significantly higher in patients with subclinical hyperthyroidism (25%) than in those with subclinical hypothyroidism (10%, p<0.05). Furthermore, the results of the longitudinal study revealed a significant decrease in serum TSH levels one year after the start of smoking in men (p<0.05). Since smoking appears to lower serum TSH levels in Japanese euthyroxinemia subjects careful consideration of the smoking status is needed when evaluating subclinical thyroid function.

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<![CDATA[SAT-456 Reduced Cholesterol Absorption and Synthesis Markers in Patients with Hyperthyroidism Due to Graves’ Disease]]> https://www.researchpad.co/article/N8c736aa0-8c67-49b1-9280-b9d31567f57b <![CDATA[SAT-446 Transcriptome Comparison of a Natural T3 Regulated Process and a Treatment with T3]]> https://www.researchpad.co/article/N569716c9-bdb3-4008-9167-1d4dc8df4477 <![CDATA[SAT-443 Impact of Fasting on Plasma Thyrotropin in Hypothyroid Patients Taking Levothyroxine During Ramadan (IFT-R Study)]]> https://www.researchpad.co/article/Nc3cf4998-f77b-4091-a4be-e8591895945b <![CDATA[SAT-436 Long-Term Analysis of Weight Change Following Thyroidectomy]]> https://www.researchpad.co/article/N1385e55d-5607-4034-9225-d97716468871 <![CDATA[SAT-LB79 Biotin Depleting Procedure Does Not Impact the Reliability of TSH, LH and FSH Immunoassays]]> https://www.researchpad.co/article/N4322b8c6-1c17-4d60-84a6-d8c8a5d77a00