Thyroid Hormone Action Research Articles

The effect of diet-induced weight-loss on subcutaneous adipose tissue expression of genes associated with thyroid hormone action

Background & AimsWe have recently demonstrated that subcutaneous adipose tissue (SAT) expression of genes associated with thyroid hormone (TH) action is altered in obesity and insulin resistance. The aim of the present study was to examine the effect of diet-induced weight-loss on SAT expression of genes associated with TH action. MethodsThe study group comprised 38 individuals with overweight/obesity, which completed 12-week dietary intervention program. Hyperinsulinemic-euglycemic clamp and SAT biopsy were performed before and after the program. Fifteen normal-weight individuals were examined at baseline only. ResultsOverweight/obese individuals had lower free thyroxine (fT4) and higher free triiodothyronine (fT3)/fT4 ratio, lower SAT TH receptor isoforms (TRα and TRβ, encoded by THRA and THRB, respectively) and peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A) mRNA expression and higher SAT type II and type III iodothyronine deiodinase (encoded by DIO2 and DIO3, respectively) and nuclear receptor corepressor (NCOR1) mRNA expression in comparison with normal-weight individuals. Diet-induced weight loss resulted in a decrease in fT3 and fT3/fT4 ratio and an increase in SAT THRA, THRB and PPARGC1A. SAT NCOR1 and forkhead box protein O1 (FOXO1) decreased only in individuals, who lost at least 10 kg (n=20). Higher increase in insulin sensitivity after weight loss was associated with a lower decrease in fT3/fT4 ratio. ConclusionsDiet-induced weight loss partly reverses alterations in SAT expression of genes associated with TH action. Responses of circulating TH and SAT expression of genes associated with TH action to diet-induced weight loss are related to body weight and insulin sensitivity.

Inclusive Exploration of Harmonizing and Alternative Treatments for Hypothyroidism

: A clinical syndrome known as hypothyroidism occurs due to a shortage of thyroid hormone as a result of decreased production, abnormal distribution, or no action of thyroid hormones. The most typical clinical symptoms included are dry skin, hair loss, weight gain, painful-prolonged periods, infertility, balance problems, slow speech, bradycardia, hypothermia, fatigue, anxiety & depression, joint pain, and indigestion. Basically, age, gender, the severity of the ailment, and a few other factors affect the various signs and symptoms of hypothyroidism. The limitations of allopathic modalities necessitate the investigation of alternative treatment options. Future healthcare initiatives for the poor world will increasingly depend on CAM approaches to these concerns because lifestyle, diet, obesity, lack of exercise, and stress are significant contributing factors to the development of hypothyroidism. This review's objective is to provide information on herbs as well as complementary and alternative medications which are grouped into five major domains: Biologically Based therapies, Manipulative body-based therapies, Mind body-based therapies, and the whole Medical system. These have traditionally been used to treat thyroid dysfunction. The distribution of diseases in emerging nations is altering as a result of globalization. Hence the existing and potential roles of CAM techniques in the general practice of medicine are illustrated in these approaches. Scientists are being compelled to consider traditional herbal medical treatments and CAM therapy in order to combat adverse medication occurrences, high treatment costs, and compliance problems thus described in this review paper.

In Silico, In Vitro, and In Vivo Studies Indicate the Endocrine-Disrupting Effects of Cyproconazole Stereoisomers.

The widespread use of chiral triazole fungicide cyproconazole (CPZ) in agricultural fields has led to frequent detection of CPZ in the environment. The restriction of CPZ in the EU raised wide concerns regarding its potential endocrine-disrupting effects (EDEs). The present study was conducted to evaluate EDEs of CPZ stereoisomers in vitro, in silico, and in vivo. The reporter gene assay indicated that all CPZ stereoisomers were agonists to the human estrogenic receptor α. (2S,3S)-(+)- and (2R,3S)-(-)-CPZ exhibited stronger binding capacities to ERα compared with (2R,3R)-(-)- and (2S,3R)-(+)-CPZ. Our computational studies showed consistent results with reporter gene assay, elucidating the stereoselective binding mode of CPZ to estrogen receptor. In zebrafish embryos, the 96h-lethality of CPZ stereoisomers ordered (2R,3R)-(-)- > (2R,3S)-(-)- > (2S,3S)-(+)- > Rac- > (2S,3R)-(+)-CPZ. Stereoselective developmental toxicity of CPZ was observed while (2R,3S)-(-)-CPZ is the most toxic isomer. The estrogenic hormones were significantly decreased in (2S,3R)-(+)- and (2R,3S)-(-)-CPZ groups and enhanced in (2S,3S)-(+)- and (2R,3R)-(-)-CPZ, along with the gene expression in hypothalamic-pituitary-gonad axis altered. CPZ shows no thyroid hormone activity. These data clarified that CPZ is a new-found endocrine disruptor threatening human health and each stereoisomer of CPZ showed stereoselective EDEs by regulating the nuclear receptor-mediated gene expression.

Actions of thyroid hormones and thyromimetics on the liver.

Thyroid hormones (triiodothyronine and thyroxine) are pivotal for metabolic balance in the liver and entire body. Dysregulation of the hypothalamus-pituitary-thyroid axis can contribute to hepatic metabolic disturbances, affecting lipid metabolism, glucose regulation and protein synthesis. In addition, reductions in circulating and intrahepatic thyroid hormone concentrations increase the risk of metabolic dysfunction-associated steatotic liver disease by inducing lipotoxicity, inflammation and fibrosis. Amelioration of hepatic metabolic disease by thyroid hormones in preclinical and clinical studies has spurred the development of thyromimetics that target THRB (the predominant thyroid hormone receptor isoform in the liver) and/or the liver itself to provide more selective activation of hepatic thyroid hormone-regulated metabolic pathways while reducing thyrotoxic side effects in tissues that predominantly express THRA such as the heart and bone. Resmetirom, a liver and THRB-selective thyromimetic, recently became the first FDA-approved drug for metabolic dysfunction-associated steatohepatitis (MASH). Thus, a better understanding of the metabolic actions of thyroid hormones and thyromimetics in the liver is timely and clinically relevant. Here, we describe the roles of thyroid hormones in normal liver function and pathogenesis of MASH, as well as some potential clinical issues that might arise when treating patients with MASH with thyroid hormone supplementation or thyromimetics.

A-9-Years-Old Female with Diabetes Mellitus Type 1 with Hyperthyroidism

Diabetes Mellitus Type 1 (DMT1) and thyroid disease can occur together, which is defined as a variant of autoimmune polyglandular syndrome type 3. It is known that the action of insulin and thyroid hormones affect cellular metabolism, thyroid hormones contribute to carbohydrate metabolism and pancreatic function. Since the thyroid gland plays a central role in the regulation of metabolism, abnormal thyroid function can have a major impact on the control of diabetes and poor glycemic control can cause alterations in thyroid hormone. A female, 9 years old, with decreased consciousness. Previous medical history, polyuria, increased appetite, and drastic weight loss. She also complained of sweating even in a cold room and was often emotional. On physical examination, there was fever, shortness of breath, tachycardia, and a soft and diffused slightly enlarged thyroid gland, with no bruit on auscultation. Laboratory tests showed blood glucose levels at 739 mg/dL, HbA1c 9.2%, C-peptide 0.2 ng/mL, TSH levels 0.01 µIU/mL, FT4 levels 2.77 ng/dL, the presence of metabolic acidosis, proteinuria, glucosuria, and ketonuria. Thyroid dysfunction will have a negative effect on DM control while poor glucose control will harm the work of thyroid hormones. Improvement in glycemic control and routine insulin injection with the right dose will reduce the risk of diabetic vascular and metabolic complications onset and progression.

7885 Thyroid Hormone Stimulates Heaptic Lipid Metabolism in the Resolution of Liver Fibrosis

Abstract Disclosure: A. Mendoza: None. C. Wang: None. A. Lugo: None. V. Rodrigues: None. S. Houghton: None. D. Redmond: None. A. Hollenberg: None. Metabolic dysfunction-associated steatotic liver disease (MASLD) progression to steatohepatitis and fibrosis is a global health burden, leading to liver failure and death. While the pathogenesis is complex, dysregulated lipid metabolism plays a crucial role. Thyroid hormones (THs) are key metabolic regulators in the liver, promoting lipogenesis and fatty acid oxidation. Previously, we demonstrated that the carbohydrate-responsive element binding protein (ChREBP) is a critical mediator of both these processes in hepatocytes, acting downstream of the thyroid hormone receptor beta1 (TRβ1). Interestingly, while ChREBP ablation abolished TH-induced lipogenesis through downregulation of lipogenic gene expression, its role in TH-mediated fatty acid oxidation remained unclear, suggesting a multifaceted role for ChREBP in TH-regulated hepatic metabolism. Given the critical role of lipid metabolism in the progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, we aim to delineate the mechanisms by which TH promotes the regression of fibrosis. Here, we used a carbon tetrachloride (CCL4) model of liver fibrosis in TRβ1KO and ChREBPKO mice (0.4 ul/g biweekly, 9 injections). All mice in the experiments were also on a PTU-Low Iodine diet to induce hypothyroidism. In the last week of the protocol, all mice were sorted into two groups which received either water or T3 (1ug/ml). 24 hours after the last CCL4 injection all mice were sacrificed and the livers were harvested and prepared for analysis. Herein we show that T3 promotes the resolution of liver fibrosis in wild-type mice. Importantly, this resolution was abolished in both TRβ1 and ChREBP KO mice demonstrating this pathways essential role in TH-induced resolution of fibrosis. RNA-Seq analysis of TRβ1KO mice demonstrated a dual mechanism of TH action: 1. TH upregulates gene expression in multiple metabolic pathways, suggesting a rescue of hepatic metabolism towards normal liver function and 2., TH has antifibrotic action via downregulation of pathways controlling extracellular matrix synthesis and inflammation, key drivers of fibrosis. Strikingly, ChREBP was dispensable for the antifibrotic action of TH suggesting that the ChREBP-dependent regulation of hepatic metabolism is critical for the resolution of fibrosis mediated by TH. To identify novel metabolic pathways regulated by TH via ChREBP, we intersected liver mRNA-seq from TRβ1KO mice with liver-specific ChREBP Chip-Seq and identifed multiple targets regulating autophagy that require ChREBP for their activation after TH treatment. These data suggest that the ability of ChREBP to regulate TH-induced fatty-acid oxidation is mediated by the upregulation of autophagy. This supports the notion that the ability of T3 to promote the resolution of liver fibrosis is primarily dependent of it’s ability to stimulate hepatic fatty acid metabolism. Presentation: 6/1/2024

8398 Non-genomic Effects of Thyroid Hormones on the Breast Cancer Microenvironment

Abstract Disclosure: L. Drago: None. S. Shahrivari: None. N. Schwenk: None. P. Nelson: None. H. Hosseini: None. C. Spitzweg: None. Objective: Mesenchymal stem cells (MSCs) are central players in the genesis of the breast cancer tumor microenvironment and play a role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment. There is increasing evidence for an association between thyroid function and breast cancer risk. Thyroid hormone effects mediated through the αvβ3 integrin, a thyroid hormone receptor, are proposed as a pathophysiologic link to this observation. Methods: To evaluate the migratory behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed. MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different breast cancer cell lines representative of different breast cancer subtypes including T47D as Luminal B, MCF7 as Luminal A, BT-474 and MDA-MB-453 as HER2, and MDA-MB-231 as Triple negative subtype. Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed directed chemotaxis towards tumor-CM with a significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. The cellular migration towards tumor-CM of MDA-MB-453, BT-474, and T47D was more effective upon MSC treatment with T3, but less so with T4. MSCs treated with T4 showed a better migratory performance towards the CM of MCF7 and MDA-MB-231. Except for T47D-CM, additional treatment with tetrac inhibited the enhanced effects of T3 and T4 on MSC migration demonstrating that this effect is mediated through αvβ3 integrin. Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and the thyroid hormone metabolite tetrac on MSC migration shows a distinct behaviour of MSCs in the presence of either T3 or T4 depending on the breast cancer cell subtype, suggesting a role of non-genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation. Presentation: 6/3/2024

8398 Non-genomic Effects Of Thyroid Hormones On The Breast Cancer Microenvironment

Abstract Disclosure: L. Drago: None. S. Shahrivari: None. N. Schwenk: None. P. Nelson: None. H. Hosseini: None. C. Spitzweg: None. Objective: Mesenchymal stem cells (MSCs) are central players in the genesis of the breast cancer tumor microenvironment and play a role in tumor initiation, progression, invasion, metastasis, angiogenesis as well as resistance to treatment. There is increasing evidence for an association between thyroid function and breast cancer risk. Thyroid hormone effects mediated through the αvβ3 integrin, a thyroid hormone receptor, are proposed as a pathophysiologic link to this observation. Methods: To evaluate the migratory behavior of MSCs in the presence or absence of thyroid hormone treatment in response to tumor-derived signals, a 3D migration assay was performed. MSCs pretreated with T3 (1nM) or T4 (1μM) with or without tetrac (100nM) (T4 analog, specific inhibitor of αvβ3 integrin-mediated thyroid hormone action) for 24 h were subjected to a gradient between serum-free medium and serum-free conditioned medium (CM) from five different breast cancer cell lines representative of different breast cancer subtypes including T47D as Luminal B, MCF7 as Luminal A, BT-474 and MDA-MB-453 as HER2, and MDA-MB-231 as Triple negative subtype. Results: MSCs subjected to a gradient between CM derived from each breast cancer cell line and serum-free medium showed directed chemotaxis towards tumor-CM with a significantly increased forward migration index (FMI) and center of mass (CoM). This migratory behavior was significantly enhanced upon treatment with T3 or T4. The cellular migration towards tumor-CM of MDA-MB-453, BT-474, and T47D was more effective upon MSC treatment with T3, but less so with T4. MSCs treated with T4 showed a better migratory performance towards the CM of MCF7 and MDA-MB-231. Except for T47D-CM, additional treatment with tetrac inhibited the enhanced effects of T3 and T4 on MSC migration demonstrating that this effect is mediated through αvβ3 integrin. Conclusion: Our preliminary in vitro data on the effects of thyroid hormones T3 and T4, and the thyroid hormone metabolite tetrac on MSC migration shows a distinct behaviour of MSCs in the presence of either T3 or T4 depending on the breast cancer cell subtype, suggesting a role of non-genomic, integrin αvβ3-mediated thyroid hormone action on MSC biology within the breast tumor microenvironment that warrants further investigation. Presentation: 6/3/2024

7494 Glycerol Phenylbutyrate Treatment of Two Patients with Monocarboxylate Transporter 8 Deficiency

Abstract Disclosure: A. Zung: None. N. Sonntag: None. U. Schweizer: None. E. Banne: None. D. Braun: None. Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease that leads to severe global developmental delay. MCT8 facilitates thyroid hormone (TH) transport across the cell membrane, and the serum TH profile is characterized by high T3 and low T4 levels. Currently, the two thyromimetic agents 3,5-diiodothyropropionic acid (DITPA) and triiodothyroacetic acid (TRIAC) have been evaluated in the treatment of these patients, as they both partially restore intracellular TH action independent of MCT8. Recent studies have shown that the chemical chaperone sodium phenylbutyrate (NaPB) restored mutant MCT8 function and increased TH content in patient-derived induced pluripotent stem cells, making it a potential treatment for MCT8 deficiency. Objective: We aimed to assess the efficacy and safety of glycerol phenylbutyrate (GPB) in MCT8 deficiency. Methods: We treated two monozygotic twins aged 14.5 years with MCT8 deficiency due to P321L mutation with escalating doses of GPB over 13 months. We recorded TH, serum markers of peripheral hyperthyroidism, vital signs, anthropometric measurements and neurocognitive functions by several neurodevelopment validated tests. Resting metabolic rate (RMR) was measured by indirect calorimetry. Serum metabolites of GPB were monitored as a safety measure. In-vitro effects of NaPB were evaluated in MDCK1 cells stably expressing the MCT8P32[1]L mutation. Results: NaPB restored mutant MCT8 expression in MDCK1 cells and increased T3 transport into cells carrying the P321L mutation. GPB treatment yielded a dose-dependent decrease in FT3 and an increase in FT4 serum levels. The patients showed an elevation in cholesterol levels in parallel with GPB dose, but sex-hormone binding protein (SHBG), another marker of peripheral hyperthyroidism was not affected. The patients showed a significant weight gain simultaneously with a reduction in RMR. Only minor neuro-cognitive improvement was observed, mainly in hyperreflexia score, slight improvement in gross motor functions and a mild progression in cognitive functions. Serum metabolites of GPB did not exceed the toxic range but elevated liver transaminases restricted the dose intensification of GPB. Conclusions: In the first report of GPB treatment in MCT8 deficiency patients we found an improvement in TH profile and body-mass index (BMI). The reduction in T3 levels could contribute to the remarkable increase in BMI-SDS, since various aspects of peripheral hyperthyroidism in MCT8 deficiency, including poor weight gain, were attributed to elevated T3. The limited effects of GPB treatment on cognitive and motor functions can derive from the advanced age of the patients at the time of the intervention. Presentation: 6/2/2024

8596 Brain Type 3 Deiodinase Is Induced in Two Disease Models That Lead to Cognitive Impairment: Liver Dysfunction and Alzheimer Disease

Abstract Disclosure: S. Wajner: None. T. Oliveira: None. M. Dreher: None. R. Ribeiro: None. C. Gonçalves: None. M.R. Alveres-da-Silva: None. Thyroid hormone is the leading regulator of cell energy production in most tissues, mainly the brain. While the activation process of T4 into T3 depends on D1 and D2 deiodinases, type 3 is the main enzyme that inactivates T3. Several mechanisms, among them oxidative stress, led by disease, imbalances and induces D3, diminishing T3 levels. The response of D3 in the brain in the context of different disease models has yet to be studied. Here we evaluated D3 induction in the brain in two animal disease models, one systemic and the other local. Methodology: To the metabolic dysfunction-associated steatosis liver disease model Male/adult Sprague Dawley rats (n=20) were assigned to control group (standard diet-2.93kcal/g) or high-fat-diet group (CDHF-4.3kcal/g). In the streptozotocin-induced (STZ) Alzheimer's model Adult Wistar rats (n=16) were allocated to the control group (5uL of citrate) or 5uL of streptozotocin. Sham animals were used as controls. D3 expression, oxidative stress parameters, endoplasmic stress and mitochondrial amount measured in the brain. Levels of D3 increased in the brain (∼30% in each group, P<0.0001) in both MASLD and STZ groups. Cerebral tissue from both groups had augmented carbonyl levels (P<0.001) and reduced sulfhydryl (P<0.001). Glutathione was diminished. Antioxidant defenses endoplasmic reticulum function and mitochondrial concentration were altered (P=0.001). The augmented T3 inactivation by D3 dysfunction in brain due to oxidative stress disrupts ER-mitochondrial contact interaction, changing the function of organelles in both brain disease models, shedding light to new mechanisms of action of thyroid hormone in severe brain disease. Presentation: 6/3/2024

7308 A Case of Thyroid Hormone Resistance Associated With a Novel Mutation in the THRA Gene

Abstract Disclosure: J.A. Siddiqui: None. M. Barbosa: None. V. Fettig: None. C.J. Romero: None. Introduction: Thyroid hormone resistance (THR) is a syndrome leading to decreased response of target organs to thyroid hormone. Normal thyroid hormone action is mediated by thyroid hormone nuclear receptors and is essential for normal development and metabolism. Two isoforms are encoded by the thyroid hormone receptor α and β genes (THRA and THRB). Mutations in THRB are commonly reported with limited cases of THRA mutations. We report a 15-month-old and her mother with a pathogenic variant in the THRα receptor leading to thyroid hormone resistance. CASE: A 15-month-old ex-39-week gestation female was born small for gestational age (birth weight: 2450 grams,3rd %ile and birth length: 17 inches,1st %ile). The newborn screen was normal. She presented with macroglossia, low tone and global developmental delay. She had severe constipation complicated by rectal prolapse that required surgical correction. There are multiple relatives (mother, maternal half-brother and maternal grandparents) with neurodevelopmental issues. The mother’s previous genetic evaluation was non-diagnostic. Mother reports a thyroid condition but without treatment. The patient was initially referred to genetics and whole exome sequencing revealed a heterozygous c.1205 T>C p. (L402P) variant in the THRα gene, which was maternally inherited and reported as a variant of uncertain significance. On physical exam, Heart rate was 112 bpm; height <1%ile (Z-score -3.22 SD), weight 3%ile (Z-score -1.89 SD). Patient has a wide anterior fontanelle (4x3 cm), macroglossia and delayed teeth eruption. Other exam findings: non-palpable thyroid and postaxial polydactyly on the 5th digit of the right toe. Thyroid hormone testing: normal TSH 1.829 uIU/mL, low total T4 4.4 mcg/dL, low Free T4 of 0.58 ng/dL and high free T3 of 4.24 pg/mL. Levothyroxine treatment was initiated(25 mcg daily). After 1 month treatment, TSH level was 0.23 uIU/mL, total T4 was 6.1 mcg/dL and low reverse T3 of 5.8 ng/dL. DISCUSSION: Thyroid hormone resistance due to THRα mutations are rare and under-recognized. The main clinical phenotype includes growth retardation, delayed development, decreased muscle tone, delayed tooth eruption and constipation. Unlike patients with THRβ mutations, the hypothalamus-pituitary-thyroid axis in patients with THRα mutations is minimally affected with a normal TSH level. Total T3 levels are elevated with slightly low total T4 and free T4:T3 ratio is low. Treatment with levothyroxine leads to suppressions of TSH levels, therefore confirming intact central T3 feedback loop. Reports, however, show minor clinical improvements with treatment; therefore further research is needed in these patients to explore more effective therapeutic options. We present a case of a novel congenital THRA mutation leading to a clinical phenotype consistent with THR. She continues care in our clinic with hopes to further study her mutation. Presentation: 6/2/2024

7684 Resistance to Thyroid Hormone Beta Mistaken as Primary Hypothyroidism: Variable Phenotypes and Diagnostic Dilemmas

Abstract Disclosure: H.F. Belal: None. A.N. Mukhtar: None. J.M. Chehade: None. Background: The differential diagnosis of hyperthyroxinemia and nonsupressed TSH includes assay interference, resistance to thyroid hormone beta (RTHb) and TSHoma. Correlation of laboratory findings with clinical presentation is crucial to avoid misdiagnosis. Clinical Case: A 50 year old female presented with palpitations, tremors, headaches, diarrhea, heat intolerance, chronic attention difficulty, pre-syncope and fatigue over several years. She had regular menses with no birth control use. There was no amiodarone, lithium or biotin use. Exam: vitals stable, no thyromegaly, no hand tremors, no exophthalmos. At 26 years old she was started on Levothyroxine (LEVO) 50 mcg for elevated TSH; FT4 was not measured. Over the past 10 years her labs demonstrated elevated FT4, elevated FT3, elevated FT4 by direct dialysis, normal TBG and inappropriately normal/elevated TSH while on LEVO 75 - 175 mcg. On LEVO 75 mcg: elevated TSH 5.94 uIU/mL (0.27-4.2), elevated FT4 2.2 ng/dL (0.8-1.7), elevated FT3 6.0 pg/mL (2.0-4.4), elevated FT4 direct dialysis 2.9 ng/dL (0.8-1.7), normal pituitary panel (including alpha subunit), low alpha subunit/TSH molar ratio (0.71). During an ED visit for chest pain, EKG revealed poor R wave progression, non-specific T wave abnormality. She was also found to have hepatic steatosis. RTHb was diagnosed and her LEVO was gradually tapered. Conclusion: TSH receptor beta is expressed in hypothalamus, pituitary, cochlea, retina, liver and kidney. TSH receptor alpha is expressed in skeletal muscle, heart, brain and bone. RTHb occurs at a frequency of 1 in 19,000 to 40,000 leading to resistance to thyroid hormone action at the HPA axis and liver. This produces higher FT4 and FT3 that act on normal TSH alpha receptors. Clinical phenotypes vary from euthyroid to hyperthyroid. Mistreating RTHb as hypothyroidism can worsen the thyrotoxic state. Testing for RTHb genetic mutation is available, yet 15% of RTHb patients do not have an identifiable pathogenic variant[1]. Treatment of RTHb ranges from observation, beta blockade, antithyroid drugs or TRIAC, a thyroid hormone analog which act at the HPA axis to inhibit TSH secretion.[1] Life threatening cases may require total thyroidectomy or radioiodine ablation; often avoided due to difficulty managing thyroid hormone replacement afterwards. Cases of goiter and ADHD in RTHb have been successfully treated with supraphysiologic every-other-day liothyronine.2 Management should be patient tailored and symptom specific.

Cortical actions of thyroid hormone: An exploration and metabolism crossroad

Classically, the central actions of thyroid hormones (THs) on metabolism occur within the hypothalamus. A recent article published in Cell by Sabatini and colleagues demonstrates that TH modulates cerebral cortical circuits of male mice, which might integrate exploratory behavior and whole-body metabolism.

Disturbed function of TBL1X has a differential effect on T3-regulated gene expression in two human liver cell models.

Mutations in TBL1X, part of the NCOR1/SMRT corepressor complex, were identified in patients with hereditary X-linked central congenital hypothyroidism and associated hearing loss. The role of TBL1X in thyroid hormone (TH) action, however, is incompletely understood. The aim of the present study was to investigate the role of TBL1X on T3-regulated gene expression in two human liver cell models. A human hepatoma cell line (HepG2) wherein TBL1X was downregulated using siRNAs, and human-induced pluripotent stem cell-derived hepatocytes (iHeps) generated from individuals with a TBL1X N365Y mutation. Both cell types were treated with increasing concentrations of T3. The expression of T3-regulated genes was measured by qPCR. KLF9, CPT1A, and PCK1 mRNA expression were higher upon T3 stimulation in the HepG2 cells with decreased TBL1X expression compared to controls, while DIO1 mRNA expression was lower. Hemizygous TBL1X N365Y iHeps exhibited decreased expression of CPT1A, G6PC1, PCK1, FBP1, and ELOVL2 compared to cells with the heterozygous TBL1X N365Y allele, but KLF9 and HMGCS2 expression was unaltered. Downregulation of TBL1X in HepG2 cells and the TBL1X N365Y variant in iHeps have differential effects on T3-regulated gene expression. This suggests that TBL1X may play a gene context role in TH action.

Thyroid under Attack: The Adverse Impact of Plasticizers, Pesticides, and PFASs on Thyroid Function

Endocrine-disrupting chemicals (EDCs) are synthetic or natural compounds that interfere with the endocrine system, inducing harmful effects on organisms depending on the dose and period of exposure. Numerous studies have identified concerning amounts of EDCs in environmental and human samples. The thyroid gland is essential for thyroid hormone production and controls several body functions. Several EDCs have been classified as thyroid disruptors, impairing thyroid hormone production, synthesis, metabolism, transport, and/or actions. Notably, thyroid disorders are the second most prevalent endocrine disease worldwide, with incidence increasing significantly in recent years. Some studies have correlated this rise in thyroid dysfunctions and cancers with increased exposure to EDCs. Although many EDCs are linked to thyroid dysfunction, this review focuses on the deleterious effects of plasticizers, organochlorine pesticides, and per- and poly-fluoroalkyl substances on thyroid function. These contaminants are commonly found in food, water, and everyday products. Although the impact of human exposure to these EDCs is controversial, numerous epidemiological, in vivo, and in vitro studies have indicated their harmful effects on thyroid function. Given the critical role of thyroid function and hormone production in growth, metabolism, and development, this review summarizes the consequences of exposure to thyroid disruptors for human health.

Thyroid Hormone Clearance in the Paraventricular Nucleus of Male Mice Regulates Lean Mass and Physical Activity.

The actions of thyroid hormones (THs) in the central nervous system are relevant to food intake and energy expenditure. TH receptors exhibit high expression in brain areas modulating energy balance, including the arcuate, paraventricular (PVN), supraoptic, and ventromedial (VMH) hypothalamic nuclei. To examine the role of THs in the regulation of energy balance via action in specific hypothalamic nuclei of the adult mouse, we performed experiments of conditional inactivation of DIO3, the enzyme responsible for the clearance of THs, in the lateral hypothalamus (LH), and VMH and PVN hypothalamic nuclei. We accomplished DIO3 genetic inactivation via stereotaxic injection of the AAV-cre vector into adult mice homozygous for a "floxed" Dio3 allele. Dio3 inactivation in the LH and VMH of males or females did not result in significant changes in body weight 8 weeks after injection. However, inactivation of Dio3 in the PVN resulted in increased body weight (both fat mass and lean mass) and locomotor activity, and decreased hypothalamic Mc4r expression in male, but not female mice. However, PNV-specific Dio3 KO did not cause hyperphagia. These results suggest local TH action influences MC4R signaling and possibly other PVN-associated circuitries, with consequences for body composition and energy balance endpoints, but not for orexigenic pathways. They also support a regulatory role for PVN Dio3 in the central regulation of energy homeostasis in adult life.

Thyroid Hormone Regulates Postnatal Development of the Rete Testis in Mice.

Thyroid hormone regulates the rate of testis maturation in mammals. Manipulations of thyroid hormone levels in neonatal animals affect various aspects of testis biology. However, there were no studies examining the effects of thyroid hormone on the rete testis (RT). Here, we used animal models of neonatal hyperthyroidism (injections of triiodothyronine, or T3) and hypothyroidism (goitrogen PTU treatment) and found that higher levels of thyroid hormone accelerate RT development, while lower levels of thyroid hormone delay it. T3 and PTU treatments influence RT size, proliferation of RT cells, and expression of DMRT1 and androgen receptor in the RT. T3 supplementation accelerates RT development in an organ testicular culture, which indicates the local action of thyroid hormone. Additionally, it was found that follicle stimulated hormone could be involved in the regulation of both RT proliferation and RT size. The fact that RT cells in a cell culture do not respond to T3 suggests indirect action of thyroid hormone on the RT in vivo or the loss of the responsiveness to the hormone in vitro.

Temperature dependent cholinergic synapse induced by triphenyl phosphate and tris(1.3-dichloroisopropyl) phosphate via thyroid hormone synthesis in Cyprinus carpio

Triphenyl phosphate (TPHP) and tris(1.3-dichloroisopropyl) phosphate (TDCIPP) are emerging contaminants that pervade diverse ecosystems and impair the thyroid and neural signaling pathways. The intricate interactions between thyroid and neurodevelopmental effects mediated by TPHP and TDCIPP remain elusive. This study integrates in vivo, in vitro, and in silico approaches to elucidate these mechanisms in Cyprinus carpio at varying temperatures. It showed that TPHP and TDCIPP hindered fish growth, particularly at low temperatures, by interfering with thyroid hormone synthesis and transport processes. Both compounds have been identified as environmental hormones that mimic thyroid hormone activity and potentially inhibit acetylcholinesterase, leading to neurodevelopmental disorders characterized by brain tissue damage and disrupted cholinergic synapses, such as axon guidance and regeneration. Notably, the bioaccumulation of TPHP was 881.54 % higher than that of TDCIPP, exhibiting temperature-dependent variations with higher levels of TDCIPP at low temperatures (20.50 % and 250.84 % above optimum and high temperatures, respectively), suggesting that temperature could exacerbate the toxicity effects of OPEs. This study sheds new light on the mechanisms underlying thyroid endocrine disruption and neurodevelopmental toxicity in C. carpio. More importantly, these findings indicate that temperature affects the environmental fate and effects of TPHP and TDCIPP, which could provide an important basis for ecological environmental zoning control of emerging contaminants in the future.

Hormonal Balance and Cardiovascular Health: Exploring the Interconnection between Menopause, Body Composition, and Thyroid Function in a Cohort of Hypertensive Women

Background. The rise in global obesity has worsened the prevalence of metabolic syndrome and related cardiovascular complications, particularly among post-menopausal women. Dysfunctions in thyroid hormone activity, critical for metabolic regulation, are often implicated in obesity and its associated conditions. This study evaluated the interactions between thyroid function, body composition, and cardiovascular health in post-menopausal women. Material and Methods. We conducted an observational, prospective, open-label clinical study, involving post-menopausal women, stratified into two groups based on weight changes after menopause: the Menopausal Weight Gain Group (MWGG) and the Menopausal Weight Maintenance Group (MWMG). We included 12 cases (MWGG) and 8 control (MWMG) women. Participants underwent cardio-metabolic assessments, including evaluations of thyroid function, blood pressure, arterial stiffness, body composition, and cardiovascular risk profiles. The statistical analysis employed t-tests and Pearson correlations. Results. The MWGG showed significant increases in both the Augmentation Index (AI@75) and adiposity markers (BMI, total fat mass, in percentage and kg, and lean–to–fat mass ratio) compared to the MWMG. A notable decrease in FT3 and the FT3/FT4 ratio was observed in the MWGG. Moreover, discrepancies in Cholesterol levels and insulinemia were reported between groups. Moreover, differences in cholesterol levels and insulinemia were reported between groups. We analyzed the correlation between blood pressure, cardiovascular stiffness, and body composition parameters; notably, there was a strong correlation between AI@75 and weight, BMI, and total fat mass, and a strong negative correlation with the lean–to–fat mass ratio. Conclusions. The MWGG presented a higher BMI, greater total fat mass (kg) and a higher percentage of total fat mass compared to the MWMG. Interestingly, we reported a significant difference in intramuscular adipose tissue between the groups. These results highlight the importance of further research to elucidate the mechanisms involved and to develop targeted interventions for managing menopause-related cardio-metabolic risks.

Role of selenium in the pathophysiology of cardiorenal anaemia syndrome.

Chronic kidney disease (CKD) and cardiovascular disease (CVD) have multiple bidirectional mechanisms, and anaemia is one of the critical factors that are associated with the progression of the two disorders [referred to as cardiorenal anaemia syndrome (CRAS)]. Several lines of evidence indicate that CRAS confers a worse prognosis, suggesting the need to clarify the underlying pathophysiology. Among the micronutrients (trace elements) that are essential to humans, inadequate iron status has previously been implicated in the pathogenesis of CRAS; however, the roles of other trace elements remain unclear. Selenium critically regulates the function of selenoproteins, in which selenocysteine is present at the active centres. The human genome encodes 25 selenoproteins, and accumulating data indicate that they regulate diverse physiological processes, including cellular redox homeostasis, calcium flux, thyroid hormone activity and haematopoiesis, all of which directly or indirectly influence cardiac function. The essential role of selenium in human health is underscored by the fact that its deficiency results in multiple disorders, among which are cardiomyopathy and abnormal erythrocyte morphology. Studies have shown that selenium deficiency is not uncommon in CKD patients with poor nutritional status, suggesting that it may be an under-recognized cause of anaemia and cardiovascular disorders in these patients. In this review, we discuss the role of selenium in the pathophysiology of CKD, particularly in the context of the interconnection among CKD, cardiac dysfunction and anaemia. Given that selenium deficiency is associated with treatment-resistant anaemia and an increased risk of CVD, its role as a key modulator of CRAS merits future investigation.