Genetic background strongly influences the impact of carrying the Thr92Ala-DIO2 polymorphism in the male mouse.

About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased BMI and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice⸺fed chow or high fat diet⸺behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin-tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice. Carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30°C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some of the clinical studies performed in different populations across the globe have obtained inconsistent results.

TSH Trajectories During Levothyroxine Treatment in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) Cohort.

CONTEXT: Thyroid-stimulating hormone (TSH) trajectory classification represents a novel approach to defining the adequacy of levothyroxine (LT4) treatment for hypothyroidism over time. OBJECTIVE: This is a proof of principle study that uses longitudinal clinical data, including thyroid hormone levels from a large prospective study to define classes of TSH trajectories and examine changes in cardiovascular (CV) health markers over the study period. METHODS: Growth mixture modeling (GMM), including latent class growth analysis (LCGA), was used to classify LT4-treated individuals participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) based on serial TSH levels. Repeated measure analyses were then utilized to assess within-class changes in blood pressure, lipid levels, hemoglobin A1c, and CV-related medication utilization. RESULTS: From the 621 LT4-treated study participants, the best-fit GMM approach identified 4 TSH trajectory classes, as defined by their relationship to the normal TSH range: (1) high-high normal TSH, (2) normal TSH, (3) normal to low TSH, and (4) low to normal TSH. Notably, the average baseline LT4 dose was lowest in the high-high normal TSH group (77.7 µg, P < .001). There were no significant differences in CV health markers between the classes at baseline. At least 1 significant difference in CV markers occurred in all classes, highlighted by the low to normal class, in which total and high-density lipoprotein cholesterol, triglycerides, and A1c all increased significantly (P = .049, P < .001, P < .001, and P = .001, respectively). Utilization of antihypertensive, antihyperlipidemic, and antidiabetes medications increased in all classes. CONCLUSION: GMM/LCGA represents a viable approach to define and examine LT4 treatment by TSH trajectory. More comprehensive datasets should allow for more complex trajectory modeling and analysis of clinical outcome differences between trajectory classes.

A Scholarly Dialog on Recent Trends in National Institutes of Health's Funding for the Thyroid Field.

Background: The National Institutes of Health (NIH) is the major funding agency for biomedical research in the United States. To initiate a scholarly dialog about research and career development in the thyroid field, here we reviewed recent trends in NIH funding for this area. We used the Research Portfolio Online Reporting Tool database to estimate the level of NIH extramural support during 2013-2022 (number of active grants/year and $amount/year weighed by the total number of active grants/year and $amount/year), provided by the NIH to the thyroid field. We determined that in 2013, the NIH supported ∼140 grants/year, totaling almost $50 million/year, the majority in the form of R01 grants. Within the thyroid field, support was evenly split between thyroid cancer and thyroid hormone metabolism and action subareas. In the subsequent years (2014-2022), the total number of active grants peaked at 150/year ($55 million) in 2014 but progressively decreased to about 100 active grants/year ($30 million) in 2022. This trend occurred while the NIH budget increased from $29 to $46 billion/year. Globally, the number of thyroid-related publications increased by ∼70% during the study period, and the fractional contribution of several countries remained relatively stable, except for China which increased by ∼600%. Remarkably, the fraction of thyroid-related publications in the United States sponsored by the NIH decreased from 5.5% to 3.1% of the global number. Conclusion: These results constitute a very concerning scenario for research and education in the thyroid field. We appeal to the NIH, the professional societies in endocrinology and thyroidology, and all other relevant stakeholders such as thyroid-related professionals and thyroid patients to engage in further discussions to identify the root causes of this trend and implement an action plan to stabilize and eventually reverse this situation.

Thyroid hormone homeostasis in levothyroxine-treated patients: Findings from ELSA-Brasil.

CONTEXT: The effectiveness of levothyroxine (LT4) in restoring thyroid hormone (TH) homeostasis, particularly serum thyroxine (T4) and triiodothyronine (T3) levels, remains debatable. OBJECTIVE: To assess TH homeostasis in LT4-treated individuals using data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil) study. METHODS: The ELSA-Brasil study follows 15,105 adult Brazilians (aged 35 to 74 years) over 8.2 years (2008-2019) with 3 observation points assessing health parameters including serum thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels. We analyzed 186 participants that initiated treatment with LT4 during the study, and 243 individuals continuously treated with LT4 therapy. RESULTS: Initiation of therapy with LT4 resulted in a 11-19% decrease in TSH, a ∼19% increase in FT4, and a 7% reduction in FT3 serum levels (FT3 dropped >10% in ∼40% of the LT4-treated patients). This was associated with an increase in triglyceride levels and utilization of hypolipidemic and anti-diabetic medications. Participants continuously treated with LT4 exhibited a stable elevation in serum FT4 and, a reduction in serum FT3 and TSH levels. While 115 participants (47.3%) had at least one serum FT4 levels above the control reference range (>1.52 ng/dL), 38 participants (15.6%) had at least one serum FT3 below the reference range (<0.23 ng/dL). CONCLUSION: The present results challenge the dogma that treatment with LT4 for hypothyroidism restores TH homeostasis in all patients. A substantial number of LT4-treated patients exhibit repeated FT4 and FT3 levels outside the normal reference range, despite normal TSH levels. Further studies are needed to define the clinical implications of these findings.

Impaired T3 uptake and action in MCT8-deficient cerebral organoids underlie Allan-Herndon-Dudley syndrome.

Patients with mutations in the thyroid hormone (TH) cell transporter monocarboxylate transporter 8 (MCT8) gene develop severe neuropsychomotor retardation known as Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human induced pluripotent stem cells (iPSCs) from MCT8-deficient patients. MCT8-deficient COs exhibited (i) altered early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired triiodothyronine (T3) transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3 inducibility of TH-regulated genes. In contrast, the TH analogs 3,5-diiodothyropropionic acid and 3,3',5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting proof of concept that lack of T3 transport underlies the pathophysiology of AHDS and demonstrating the clinical potential for TH analogs to be used in treating patients with AHDS. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for patients with AHDS.

Emerging Therapies in Hypothyroidism.

Levothyroxine (LT4) is effective for most patients with hypothyroidism. However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels. Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone. Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3. For these patients, new slow-release LT3 formulations that provide stable serum T3 levels are being tested. In addition, progress in regenerative technology has led to the development of human thyroid organoids that restore euthyroidism after being transplanted into hypothyroid mice. Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved. This is seen, for example, in patients with metabolic (dysfunction)-associated fatty liver disease, for whom liver-selective T3-like molecules have been utilized successfully in clinical trials.

A Cross-Sectional Analysis of Cardiovascular and Bone Health Care Utilization During Treatment With Thyroid Hormone.

CONTEXT: Combination therapy with levothyroxine and liothyronine (LT4 + LT3) and desiccated thyroid extract (DTE) make up >10% of new thyroid hormone (TH) prescriptions in the United States. OBJECTIVE: To assess health care utilization related to cardiovascular disease (CVD) and bone health (BH) events (atrial fibrillation [AF], heart failure [HF], myocardial infarction [MI], stroke, and osteoporosis/fractures [FX]) in participants taking LT4+LT3 or DTE surveyed in the Medical Expenditure Panel Survey database. MATERIALS AND METHODS: Multi-year cross-sectional analysis examining 5437 participants (≥18 years old) treated with LT4, LT4+LT3, or DTE between 2016 and 2020. Health care utilization was assessed through outpatient, emergency, and hospital visits for AF, HF, MI, stroke, FX, and a composite index. A weighted analysis provided national estimates of health care utilization parameters. Utilization was re-analyzed following propensity score-based matching to balance sociodemographic and clinical covariates between treatment groups. Additionally, provider type and specialty data were obtained from visits associated with TH prescriptions. RESULTS: 5106 participants were treated with LT4 monotherapy, 252 with DTE, and 79 with LT4 + LT3. Prevalence of combined outpatient CVD and BH-related care utilization was lower among DTE/LT4+LT3 vs LT4 users (3.5% vs 7.7%; P = .008). There were no differences in emergency/hospital events. After covariate balancing, CVD and BH-related care utilization was similar between groups in outpatient and emergency/hospital settings. LT3 and DTE made up 7.6% of all TH prescriptions. For visits associated with DTE prescriptions, nurse practitioners and alternative medicine professionals were more likely to be identified as the primary provider type. CONCLUSION: No significant differences in CVD- and BH-related health care utilization were identified between LT4 and DTE/LT4+LT3 users after covariate balancing. Non-MD providers were more likely to prescribe DTE.

Localized T3 production modifies the transcriptome and promotes the hepatocyte-like lineage in iPSC-derived hepatic organoids.

Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here, we studied human induced pluripotent stem cell-derived (iPSC-derived) hepatic organoids and identified a robust induction of DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in DIO2-T3 (the deiodinase that activates thyroxine [T4] to triiodothyronine [T3]) persists until the hepatoblasts differentiate into hepatocyte- or cholangiocyte-like cells, neither of which expresses DIO2. Preventing the induction of the DIO2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by ~60%, and increased the number of cholangiocyte-like cells by ~55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not fully restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in DIO2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implications for how the liver handles energy substrates.

Sustained Pituitary T3 Production Explains the T4-mediated TSH Feedback Mechanism.

The regulation of thyroid activity and thyroid hormone (TH) secretion is based on feedback mechanisms that involve the anterior pituitary TSH and medial basal hypothalamus TSH-releasing hormone. Plasma T3 levels can be "sensed" directly by the anterior pituitary and medial basal hypothalamus; plasma T4 levels require local conversion of T4 to T3, which is mediated by the type 2 deiodinase (D2). To study D2-mediated T4 to T3 conversion and T3 production in the anterior pituitary gland, we used mouse pituitary explants incubated with 125I-T4 for 48 hours to measure T3 production at different concentrations of free T4. The results were compared with cultures of D1- or D2-expressing cells, as well as freshly isolated mouse tissue. These studies revealed a unique regulation of the D2 pathway in the anterior pituitary gland, distinct from that observed in nonpituitary tissues. In the anterior pituitary, increasing T4 levels reduced D2 activity slightly but caused a direct increase in T3 production. However, the same changes in T4 levels decreased T3 production in human HSkM cells and murine C2C12 cells (both skeletal muscle) and mouse bone marrow tissue, which reached zero at 50 pM free T4. In contrast, the increase in T4 levels caused the pig kidney LLC-PK1 cells and kidney fragments to proportionally increase T3 production. These findings have important implications for both physiology and clinical practice because they clarify the mechanism by which fluctuations in plasma T4 levels are transduced in the anterior pituitary gland to mediate the TSH feedback mechanism.

Gene polymorphisms and thyroid hormone signaling: implication for the treatment of hypothyroidism.

INTRODUCTION: Mutations and single nucleotide polymorphisms (SNPs) in the genes encoding the network of proteins involved in thyroid hormone signaling (TH) may have implications for the effectiveness of the treatment of hypothyroidism with LT4. It is conceivable that loss-of-function mutations or SNPs impair the ability of LT4 to be activated to T3, reach its targets, and ultimately resolve symptoms of hypothyroidism. Some of these patients do benefit from therapy containing LT4 and LT3. METHODS: Here, we reviewed the PubMed and examined gene mutations and SNPs in the TH cellular transporters, deiodinases, and TH receptors, along with their impact on TH signaling, and potential clinical implications. RESULTS: In some mechanisms, such as the Thr92Ala-DIO2 SNP, there is a compelling rationale for reduced T4 to T3 activation that limits the effectiveness of LT4 to restore euthyroidism. In other mechanisms, a potential case can be made but more studies with a larger number of individuals are needed. DISCUSSION/CONCLUSION: Understanding the clinical impact of the genetic makeup of LT4-treated patients may help in the preemptive identification of those individuals that would benefit from therapy containing LT3.

The D2D3 form of uPAR acts as an immunotoxin and may cause diabetes and kidney disease.

Soluble urokinase plasminogen activator receptor (suPAR) is a risk factor for kidney diseases. In addition to suPAR, proteolysis of membrane-bound uPAR results in circulating D1 and D2D3 proteins. We showed that when exposed to a high-fat diet, transgenic mice expressing D2D3 protein developed progressive kidney disease marked by microalbuminuria, elevated serum creatinine, and glomerular hypertrophy. D2D3 transgenic mice also exhibited insulin-dependent diabetes mellitus evidenced by decreased levels of insulin and C-peptide, impaired glucose-stimulated insulin secretion, decreased pancreatic ß cell mass, and high fasting blood glucose. Injection of anti-uPAR antibody restored ß cell mass and function in D2D3 transgenic mice. At the cellular level, the D2D3 protein impaired ß cell proliferation and inhibited the bioenergetics of ß cells, leading to dysregulated cytoskeletal dynamics and subsequent impairment in the maturation and trafficking of insulin granules. D2D3 protein was predominantly detected in the sera of patients with nephropathy and insulin-dependent diabetes mellitus. These sera inhibited glucose-stimulated insulin release from human islets in a D2D3-dependent manner. Our study showed that D2D3 injures the kidney and pancreas and suggests that targeting this protein could provide a therapy for kidney diseases and insulin-dependent diabetes mellitus.

The Effects of Patient Characteristics on the Management of Subclinical Hypothyroidism: A Survey of Faculty and Trainees.

OBJECTIVE: There is no universal approach to the management of subclinical hypothyroidism (SCH). This study was designed to determine the impact of patient characteristics on management decisions in SCH amongst physician faculty members and trainees. METHODS: An online survey was distributed to faculty members and medical trainees (ie, interns, residents, and fellows) at multiple academic medical centers. The survey included 9 clinical scenarios describing women with SCH with 5 management options sequenced from most "conservative" (no further treatment or monitoring) to most "aggressive" (treatment with levothyroxine). RESULTS: Of the 194 survey respondents, 95 (49.0%) were faculty members and 99 (51.0%) were trainees. Faculty members were more likely to report being "confident" or "very confident" in making the diagnosis of SCH compared to trainees (95.8% vs 46.5%, P < .001). Faculty members were also more likely to consider patient preference for treatment (60.0% vs 32.3%, P < .001). Among all respondents, the clinical factors that resulted in the highest predicted probability of treatment were hypothyroid symptoms (predicted probability [PP] 68.8%, 95% CI [65.7%-71.9%]), thyroid stimulating hormone >10 mIU/L in a 31-year-old (PP 63.9%, 95% CI [60.3%-67.3%]), and the desire for fertility (PP 52.2%, 95% CI [48.6%-56.0%]). In general, faculty members favored more aggressive treatment across all clinical scenarios. CONCLUSION: The presence of symptoms, thyroid stimulating hormone >10 mIU/L, and desire for fertility were most predictive of the decision to treat in SCH. In several clinical scenarios, both trainee and faculty decision-making demonstrated discordance with general SCH management principles.

Are We Restoring Thyroid Hormone Signaling in Levothyroxine-Treated Patients With Residual Symptoms of Hypothyroidism?

INTRODUCTION: Levothyroxine (LT4) at doses that maintain the serum thyroid-stimulating hormone levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates the signs and symptoms of overt hypothyroidism in the majority of patients, owing to the endogenous activation of thyroxine to triiodothyronine, the biologically active thyroid hormone. Still, a small percentage of the patients (10%-20%) exhibit residual symptoms, despite having normal serum thyroid-stimulating hormone levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life. OBJECTIVE: To provide a summary of progress in the approach of patients with hypothyroidism that exhibit residual symptoms despite treatment. METHODS: We reviewed the current literature and here we focused on the mechanisms leading to a deficiency of T3 in some LT4-treated patients, the role of residual thyroid tissue and the rationale for combination therapy with LT4 + liothyronine (LT3). RESULTS: A score of clinical trials comparing therapy with LT4 versus LT4 + LT3 concluded that both are safe and equally effective (neither is superior); however, these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4 + LT3; desiccated thyroid extract has also been used with similar results. A practical approach to patients with residual symptoms and on initiation of combination therapy with LT4 + LT3 is provided. CONCLUSION: A recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4.

Demographic, Healthcare Access, and Dietary Factors Associated With Thyroid Hormone Treatments for Hypothyroidism.

CONTEXT: Clinical guidelines have recommended a trial of liothyronine (LT3) with levothyroxine (LT4) in select patients with hypothyroidism. However, little is known about the real-world use of LT3 and desiccated thyroid extract (DTE) and the characteristics of patients treated with LT3 and DTE. OBJECTIVES: (1) Determine national trends of new LT4, LT3, and DTE prescriptions in the United States; (2) determine whether sociodemographic, healthcare access, and dietary factors are associated with different thyroid hormone (TH) therapies. METHODS: Parallel cross-sectional studies were conducted using 2 datasets: (1) a national patient claims dataset (2010-2020) and (2) the National Health and Nutrition Examination Study (NHANES) dataset (1999-2016). Included participants had a diagnosis of primary or subclinical hypothyroidism. Study outcomes included the impact of demographics and healthcare access on differences in the proportion of TH therapies consisting of LT4, LT3, and DTE (patient claims) and differences in dietary behaviors between DTE-treated participants and LT4-treated matched controls (NHANES). RESULTS: On an average annual basis, 47 711 adults received at least 1 new TH prescription, with 88.3% receiving LT4 monotherapy, 2.0% receiving LT3 therapy, and 9.4% receiving DTE therapy. The proportion receiving DTE therapy increased from 5.4% in 2010 to 10.2% in 2020. In the analysis between states, high primary care and endocrinology physician densities were associated with increased use of LT4 monotherapy (odds ratio 2.51, P < .001 and odds ratio 2.71, P < .001). DTE-treated NHANES participants (n = 73) consumed more dietary supplements compared to LT4-treated participants (n = 146) (4.7 vs 2.1, P < .001). CONCLUSIONS: The proportion of new TH therapies containing DTE for hypothyroidism doubled since 2010 while LT3 therapies remained stable. DTE treatment was associated with decreased physician density and increased dietary supplement use.

Levothyroxine Treatment Adequacy and Formulation Changes in Patients with Hypothyroidism: A Retrospective Study of Real-World Data from the United States.

Background: The prevalence of hypothyroidism (HT) has increased over time. To assess the effectiveness of treatment, we (1) studied thyrotropin (TSH) levels among patients receiving levothyroxine (LT4) and (2) determined the percentages of patients switching among LT4 formulations. Methods: Data on patients with HT receiving LT4 from the Optum™ Clinical and Claims Database were analyzed from March 2013 through February 2020. Eligible adult patients had ≥1 medical claim with an HT diagnosis and all patients were observed for ≥12 months. Patients included in Objective 1 were indexed on a randomly selected TSH result and had ≥2 results for TSH 1-15 months apart. Patients included in Objective 2 were indexed on a randomly selected LT4 pharmacy claim and had ≥2 LT4 claims ≥1 month apart and ≥1 claim during follow-up. Outcomes were the proportion of patients with low, normal, or high (<0.45, 0.45-4.5, or >4.5 mIU/L, respectively) TSH levels and the proportion of patients switching LT4 formulations, respectively. Data were stratified by age group, sex, and insurance type. All data reported were analyzed using descriptive statistics. Results: Of patients who were in the indexed TSH group, 81.1% [confidence intervals: 80.4-81.8; n/N = 9130/11,259] achieved normal TSH values. When stratified by age group, sex, and insurance type, ≥70% of patients in each of these subgroups exhibited normal mean TSH values at follow-up. For Objective 2 (N = 25,076), 24.9% (N = 6238) of the LT4-indexed group had ≥1 formulation switch in 12 months, of which 67.3% only switched once, and 41.4% (N = 10,370) had ≥1 formulation switch in up to 24 months. A significantly higher proportion of Medicare vs. commercially insured patients had switched formulations (26.2% vs. 23.1%, p < 0.001). Conclusions: Most LT4-treated patients maintain normal TSH levels, which is an improvement vs. previous reports. Continued physician engagement and patient education are advised to further reduce the number of patients who maintain off-target TSH levels. Contrary to clinical recommendations, about 25% of patients receiving LT4 switched formulations within 1 year, with >40% switching within 2 years; among patients who switched, most only switched once.

Axonal T3 uptake and transport can trigger thyroid hormone signaling in the brain.

The development of the brain, as well as mood and cognitive functions, are affected by thyroid hormone (TH) signaling. Neurons are the critical cellular target for TH action, with T3 regulating the expression of important neuronal gene sets. However, the steps involved in T3 signaling remain poorly known given that neurons express high levels of type 3 deiodinase (D3), which inactivates both T4 and T3. To investigate this mechanism, we used a compartmentalized microfluid device and identified a novel neuronal pathway of T3 transport and action that involves axonal T3 uptake into clathrin-dependent, endosomal/non-degradative lysosomes (NDLs). NDLs-containing T3 are retrogradely transported via microtubules, delivering T3 to the cell nucleus, and doubling the expression of a T3-responsive reporter gene. The NDLs also contain the monocarboxylate transporter 8 (Mct8) and D3, which transport and inactivate T3, respectively. Notwithstanding, T3 gets away from degradation because D3's active center is in the cytosol. Moreover, we used a unique mouse system to show that T3 implanted in specific brain areas can trigger selective signaling in distant locations, as far as the contralateral hemisphere. These findings provide a pathway for L-T3 to reach neurons and resolve the paradox of T3 signaling in the brain amid high D3 activity.

Serum Thyrotropin and Triiodothyronine Levels in Levothyroxine-treated Patients.

CONTEXT: Small adjustments in levothyroxine (LT4) dose do not appear to provide clinical benefit despite changes in thyrotropin (TSH) levels within the reference range. We hypothesize that the accompanying changes in serum total triiodothyronine (T3) levels do not reflect the magnitude of the changes in serum TSH. OBJECTIVE: This work aims to characterize the relationships of serum free thyroxine (FT4) vs T3, FT4 vs TSH, and FT4 vs the T3/FT4 ratio. METHODS: This cross-sectional, observational study comprised 9850 participants aged 18 years and older treated with LT4 from a large clinical database from January 1, 2009, to December 31, 2019. Patients had been treated with LT4, subdivided by serum FT4 level. Main outcome measures included model fitting of the relationships between serum FT4 vs TSH, FT4 vs T3, and FT4 vs T3/FT4. Mean and median values of TSH, T3, and T3/FT4 were calculated. RESULTS: The relationships T3 vs FT4 and TSH vs FT4 were both complex and best represented by distinct, segmented regression models. Increasing FT4 levels were linearly associated with T3 levels until an inflection point at an FT4 level of 0.7 ng/dL, after which a flattening of the slope was observed following a convex quadratic curve. In contrast, increasing FT4 levels were associated with steep declines in TSH following 2 negative sigmoid curves. The FT4 vs T3/FT4 relationship was fit to an asymptotic regression curve supporting less T4 to T3 activation at higher FT4 levels. CONCLUSION: In LT4-treated patients, the relationships between serum FT4 vs TSH and FT4 vs T3 across a range of FT4 levels are disproportionate. As a result, dose changes in LT4 that robustly modify serum FT4 and TSH values may only minimally affect serum T3 levels and result in no significant clinical benefit.

Different Hypothalamic Mechanisms Control Decreased Circulating Thyroid Hormone Levels in Infection and Fasting-Induced Non-Thyroidal Illness Syndrome in Male Thyroid Hormone Action Indicator Mice.

Background: Non-Thyroidal Illness Syndrome (NTIS) caused by infection or fasting is hallmarked by reduced circulating thyroid hormone (TH) levels. To better understand the role of local TH-action in the development of NTIS, we assessed tissue-specific changes of TH signaling in Thyroid Hormone Action Indicator (THAI) mice. Methods: NTIS was induced in young adult THAI mice by bacterial lipopolysaccharide (LPS)-administration or by 24 or 48 hours' fasting. Tissue-specific TH-action was assessed by the detection of changes of the Luciferase reporter of THAI mice with quantitative polymerase chain reaction along with tissue-specific examination of regulators of TH metabolism and signaling. Age dependence of revealed alterations of hypothalamic TH-action was also studied in 1-year-old male THAI mice. Results: LPS-treatment increased TH-action in the hypothalamic arcuate nucleus-median eminence (ARC-ME) region preceded by an increase of type 2 deiodinase (D2) expression in the same region and followed by the suppression of proTrh expression in the hypothalamic paraventricular nucleus (PVN). In contrast, LPS decreased both TH-action and D2 activity in the pituitary at both ages. Tshß expression and serum free thyroxine (fT4) and free triiodothyronine (fT3) levels decreased in LPS-treated young adults. Tshß expression and serum fT4 levels were not significantly affected by LPS treatment in aged animals. In contrast to LPS treatment, TH-action remained unchanged in the ARC-ME of 24 and 48 hours fasted animals accompanied with a modest decrease of proTrh expression in the PVN in the 24-hour group. Tshß expression and fT3 level were decreased in both fasted groups, but the fT4 decreased only in the 48 hours fasted animals. Conclusions: Although the hypothalamo-pituitary-thyroid (HPT) axis is inhibited both in LPS and fasting-induced NTIS, LPS achieves this by centrally inducing local hyperthyroidism in the ARC-ME region, while fasting acts without affecting hypothalamic TH signaling. Lack of downregulation of Tshß and fT4 in LPS-treated aged THAI mice suggests age-dependent alterations in the responsiveness of the HPT axis. The LPS-induced tissue-specific hypo-, eu-, and hyperthyroidism in different tissues of the same animal indicate that under certain conditions TH levels alone could be a poor marker of tissue TH signaling. In conclusion, decreased circulating TH levels in these two forms of NTIS are associated with different patterns of hypothalamic TH signaling.