BACKGROUND:Suboptimal treatment of hypothyroidism with levothyroxine (LT4) is common and associated with adverse cardiovascular outcomes. Patients treated with LT4 doses >100 µg may be at increased risk of under- and overtreatment and therefore may benefit from more frequent thyroid stimulating hormone (TSH) surveillance. Our study aim was to determine the association between LT4 dose and the occurrence of suboptimal treatment within 6 months of a normal TSH value. METHODS:A total of 4449 LT4-treated adults were included in a 6-month longitudinal study. All included patients were required to have at least 2 TSH collections over the study period at least 30 days apart. Patients were grouped according to LT4 dose (≤50, 51-100, 101-150, and >150 µg), which served as the primary exposure. Outcomes included the occurrence of TSH values outside an age-adjusted normal range and a wide range (0.1-10.0 mIU/L). Model covariates included sociodemographics, index TSH value, and a range of codiagnoses and comedications that were prevalent in the population and/or known to impact LT4 treatment. Longitudinal data were analyzed using both repeated measures (generalized estimating equations) and time-to-event (Cox proportional hazards models) methodologies. Kaplan-Meier curves were plotted to examine the incidence of out-of-range TSH values stratified by LT4 dose class. RESULTS:The incidence of at least one out-of-range TSH value approached 25% across the entire population and exceeded 45% in the LT4 > 150 µg group. In the repeated measures analysis, a dose-dependent relationship between LT4 dose and the occurrence of TSH outside the age-adjusted range (OR: 1.98, 3.39, and 5.65 for LT4 doses of 51-100, 101-150, and >150 µg, respectively, p-values <0.001). Results were similar when the outcome was defined as a TSH outside 0.1-10.0 mIU/L. In the time-to-event analysis, the hazard ratios were 1.58, 2.73, and 3.08, respectively (p-values <0.001). CONCLUSIONS:We identified a dose-dependent relationship between LT4 dose and suboptimal treatment over a 6-month study period. It may be beneficial for medically complex patients taking high doses of LT4 to increase TSH surveillance, in particular for those with a history of suboptimal treatment.

CONTEXT:Time-in-range (TIR) using sequential TSH levels during levothyroxine (LT4) treatment could serve as a measure of chronic disease control in hypothyroidism. OBJECTIVES:Primary objectives: (1) develop a method of estimating TIR and (2) determine the impact of patient sociodemographic characteristics on TIR. Secondary objective: investigate the relationship between TIR and time to cardiovascular event. METHODS:The study was conducted using longitudinal clinical data (2016-2022) from a single academic institution. Study participants were ≥18 years old, LT4-treated, and had ≥3 unique TSH levels collected over a minimum of 2 years. For each patient, TIR, time-above-range (TAR) and time-below-range (TBR) were estimated using linear interpolation of log-transformed TSH levels. Fitted linear regression was used to evaluate the relationship between TIR/TAR/TBR and LT4 dose over the study period. Generalized estimating equations were used to model annualized TIR/TAR/TBR with sociodemographic and clinical covariates. Survival analysis was used to characterize the relationship between TIR and occurrence of cardiovascular events. RESULTS:A total of 2752 LT4-treated patients had a median TIR of 86% over the study enrollment period (median, 3.8 years). For both males and females, LT4 dose was negatively correlated with TIR (R = -0.23 and -0.30, respectively; P < .001 for both). Male sex and Black race were associated with TIR <75% (OR, 1.30; P < .001; OR, 1.37; P < .001). The association between TAR and cardiovascular events approached significance (OR, 1.03 per +10% TAR; P = .078). CONCLUSION:We used TIR estimation to identify differences in disease control between sociodemographic groups and the impact of LT4 dose. In future studies, we aim to better characterize the association between TIR and clinically meaningful outcomes.

INTRODUCTION:Standard levothyroxine (LT4) therapy may not fully address all risks associated with hypothyroidism-especially cognitive decline, dementia, and mortality-even when TSH levels are normalized. Observational studies link hypothyroidism to higher dementia rates; the role of LT4 plus T3 therapies remains uncertain. METHODS:This retrospective cohort study analyzed TriNetX data, comparing 1.26 million patients with hypothyroidism (on LT4, LT4 + T3, or desiccated thyroid extract) to 3.32 million controls. Outcomes included dementia, atrial fibrillation, and mortality over 20 years of follow-up. Propensity score matching was used to balance covariates for age, sex, and comorbidities. Adjusted hazard ratios were obtained via Cox proportional hazard modeling. A parallel systematic review and meta-analysis of 12 studies evaluated dementia risk in hypothyroidism. RESULTS:Patients with hypothyroidism showed a ∼1.4-fold higher risk of dementia and a >2.0-fold increase in mortality-even with normal TSH-and these risks were most pronounced when TSH levels were off-target. A parallel meta-analysis indicated a 1.4-fold heightened dementia risk. In cohorts formed by propensity score matching comparing LT4 monotherapy vs combination therapy, relative risk analysis indicated 27% and 31% lower dementia and mortality risks, respectively, with combination therapy. The adjusted Cox model (hazard ratio) showed 16% and 25% reductions in these outcomes for combination therapy patients. CONCLUSION:Despite standard LT4 therapy, hypothyroidism remains associated with heightened risks of dementia and mortality. Adding T3 may more effectively mitigate these risks than LT4 alone, but further studies are needed to confirm the cognitive and survival benefits of T3-containing regimens.

Thyroid hormones are produced in the thyroid gland and metabolized in the peripheral tissues. The major pathway of thyroid hormone metabolism is the removal of an iodine atom from the phenolic or tyrosyl ring by deiodinating enzymes, the so-called deiodinases. Three distinct types of deiodinase have been identified, namely type 1 (D1), type 2 (D2) and type 3 (D3), which differ in main function and expression profile. Measuring the activities of D1, D2 and D3 is an indispensable tool in research on thyroid hormone metabolism. At present, only a limited number of research laboratories worldwide measure deiodinase activity using a variety of assays and protocols. Unlike diagnostic labs, research labs rarely participate in external quality control due to limited availability for most analytes or enzymes. However, implementing a quality assurance program for deiodinase assays is crucial to ensure consistent enzyme activity across laboratories. The present study provides the results of a method comparison between five established laboratories with experience in measuring deiodinase activity. The results showed that there are considerable differences in deiodinase activity levels determined by participating laboratories, which could be partially explained by differences in techniques and protocols. We therefore concluded that in most cases, absolute deiodinase activities can only be compared within the same laboratory. External quality control only adds value when all the laboratories use the same technique with their own optimized protocols. The use of internal controls is recommended to ensure that the correct enzymatic activity is being measured over time in the same laboratory.

Introduction:Hypothyroidism is a widespread chronic condition in the U.S. Gaining a comprehensive understanding of where patients with hypothyroidism seek care is critical. This study aims to estimate national trends in outpatient care visits for U.S. adults with hypothyroidism. Methods:We analyzed data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey from 2010 to 2019. Our analysis included visits for adults that were categorized by setting: primary care, medical specialty care, surgical specialty care, and emergency care. All visits associated with a diagnosis of hypothyroidism or a prescription for thyroid hormone were included. We examined 2 primary outcomes: (1) the annual mean count of visits for patients with hypothyroidism, and (2) the subset of those visits for which thyroid disease was listed as a reason for the visit. Results:An estimated 30 million primary care annual visits took place for patients with hypothyroidism, and another 15.4 million annual visits to medical specialists. Of those primary care visits, thyroid disease was a reason for visit for approximately 3.3 million visits (10.8%). Approximately 65% of all outpatient visits for patients with hypothyroidism for which thyroid disease was a reason for visit occurred in the primary care setting. Conclusion:The majority of outpatient visits for U.S. adults with hypothyroidism took place in primary care settings. These findings highlight the need to focus on primary care as a key intervention point to improve disease control in hypothyroidism.

BACKGROUND:Thyroid dysfunction has been associated with adverse postoperative outcomes, but little is known about its effects on patients undergoing coronary artery bypass grafting (CABG). Here, our goals were (1) to evaluate the incidence of CABG in patients with hypothyroidism receiving thyroid hormone replacement therapy, and (2) to assess short-term and long-term outcomes in patients with hypothyroidism undergoing CABG compared with controls without thyroid disease, and (3) to determine whether abnormal preoperative thyroid-stimulating hormone (TSH) levels modify postoperative surgical risk in this patient population. METHODS:Retrospective longitudinal study using the TriNetX Global Collaborative Network database. The incidence of CABG was evaluated in about 1.23 million patients with hypothyroidism during a 20-year observation period (median of 4.4 ± 5.9). Post-CABG outcomes, including mortality, cardiovascular events, and postsurgical complications, were evaluated in 6557 patients with hypothyroidism over 10 years after 1:1 propensity score-matching. RESULTS:Over 20 years, patients with a diagnosis of hypothyroidism had a higher incidence of CABG compared with controls (0.27% vs. 0.22%; hazard ratio [HR] 1.08; confidence interval [CI]: 1.03-1.14). Among patients who underwent CABG, the diagnosis of hypothyroidism was associated with mild increased risk of short-term postsurgical infections (HR:1.10, CI:1.01-1.20), CABG-specific complications (HR: 1.24, CI: 1.08-1.42), and critical care utilization (HR:1.14, CI:1.07-1.21). During long-term follow-up, these patients were at increased risk of incident heart failure (HR:1.15, CI:1.04-1.28), stroke (HR:1.18, CI:1.01-1.39), and major adverse cardiovascular events (MACE) (HR:1.15, CI:1.01-1.29). Sensitivity analysis, including only patients with hypothyroidism diagnosis, showed that abnormal preoperative TSH levels, particularly those with elevated TSH, had a higher risk of short-term mortality and long-term embolic events. CONCLUSIONS:Hypothyroidism is associated with a higher incidence of coronary disease requiring CABG and increased risks of postoperative complications, heart failure, stroke, and MACE. These findings support the potential value of preoperative thyroid function assessment and optimization to mitigate postoperative complications and improve surgical outcomes in this high-risk group.

OBJECTIVE:Pediatric hypothyroidism is an endocrine disorder where early thyroid replacement therapy is recommended to support healthy development. This study characterized prevalence and treatment patterns of pediatric hypothyroidism among children in the US. METHODS:Children aged 0 to 17 years with hypothyroidism were identified from 2 large US claims databases from 2013 to 2022, using age-specific algorithms based on diagnosis and prescription claims. Annual prevalence of hypothyroidism and treated hypothyroidism were analyzed separately by database and as a pooled dataset, and stratified by age group, sex, and calendar year. Two-sample tests of proportion were used to compare prevalence across groups. RESULTS:Among 7 214 633 children, the overall hypothyroidism prevalence (per 1000 children) was 3.49 in 2022. From 2013 to 2022, annual hypothyroidism prevalence (per 1000 children) increased by 43% in children <1 year (0.62 to 0.88) and by 33% in children aged 1 to 3 years (0.70 to 0.94), but decreased by 9% to 18% in children aged 4-17 years. Prevalence was higher in female than male children, and differences between sexes increased with age. In 2022, approximately two-thirds of children with hypothyroidism received thyroid replacement therapy. Female children were significantly more likely than males to receive treatment, with the largest difference among those aged 8 to 11 years (70.1% vs 61.5%). CONCLUSION:Distinct age- and sex-dependent trends in pediatric hypothyroidism prevalence were observed over time. A substantial subpopulation of patients did not receive treatment despite known developmental risks. Enhanced efforts to identify and treat pediatric hypothyroidism are warranted to ensure optimal developmental outcomes for affected children.

CONTEXT:Bariatric surgery (BS) effectively reduces obesity-related risks, but its outcomes in patients with preexisting hypothyroidism are unclear. OBJECTIVE:To evaluate the impact of preexisting hypothyroidism on adverse health outcomes following BS. METHODS:In this retrospective cohort study utilizing the TriNetX Global Collaborative Network database, patients with obesity who underwent BS or not, with and without hypothyroidism, were propensity score-matched. Short-term outcomes comprised mortality, readmission, ICU admission, and surgical and systemic complications. Long-term outcomes included mortality, major adverse events, bone health, and metabolic, renal, and neurological outcomes. RESULTS:There were 5700 patients in each cohort (46.7 ± 12 years, 88% female). In the short term, patients with hypothyroidism exhibited higher risks of readmission (risk ratio [RR]: 1.25; CI: 1.14-1.36), incisional hernia (RR: 1.56; CI: 1.12-2.18), and biliary diseases (RR: 1.39; CI: 1.05-1.86). In the long term, patients with hypothyroidism had higher risks of incident cerebrovascular events (hazard ratio [HR]: 1.25; CI: 1.00-1.55), diabetes (HR: 1.39; CI: 1.12-1.74), and dyslipidemia (HR: 1.20; CI: 1.02-1.42). There were also higher risks of fall (HR: 1.20; CI: 1.02-1.40), osteoporosis (HR: 1.30; CI: 1.07-1.58), polyneuropathy (HR: 1.34; CI: 1.08-1.66), hypoglycemia (HR: 1.51; CI: 1.23-1.87), as well as iron (HR: 1.17; CI: 1.04-1.31) and vitamin B (HR: 1.34; CI: 1.20-1.49) deficiencies. Hypothyroidism-associated risks of poor outcomes were higher in patients who underwent gastric bypass. Compared to the nonsurgical care, patients with hypothyroidism who underwent BS showed a lower risk of obesity-related outcomes but a higher risk of iron and vitamin B deficiencies, osteoporosis, and hypoglycemia. CONCLUSION:Preexisting hypothyroidism in bariatric patients increases the risks of adverse outcomes. However, the risk of obesity-related outcomes is decreased in this population when compared to nonsurgical care.

BACKGROUND:The standard of care for hypothyroidism treatment worldwide is daily oral levothyroxine (LT4) sodium. Limitations associated with daily oral administration highlight the need for alternative formulations to address challenges in maintaining euthyroidism. XP-8121 (LT4 sodium for subcutaneous [SC] administration) is a ready-to-use, liquid formulation of LT4 intended for once-weekly administration, offering an alternative hormone replacement approach by bypassing the gastrointestinal tract. This study assessed the safety, tolerability, and target dose conversion factor from oral LT4 to XP-8121 SC in adult participants. PARTICIPANTS AND METHODS:This Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled study (NCT05823012) evaluated XP-8121 SC in 46 adults with hypothyroidism receiving a consistent dose of oral LT4 for at least 3 months prior to screening, with documented normal thyrotropin (TSH) levels at least 3 months prior to screening and normal free thyroxine (fT4) at screening. The weekly XP-8121 SC dose was initiated at 50% of the target dose and titrated every 2 weeks for up to 8 weeks based on individual response using fT4 trough concentrations. Following titration, participants continued the established dose during a 4-week maintenance period. RESULTS:Of the 46 participants enrolled, 39 completed the study. The majority were female (37; 80.4%) and identified as White (44; 95.7%). The final dose conversion factor point estimate ranged from 4.02 (90% confidence interval [CI]: 3.79-4.27) to 4.24 (90% CI: 4.06-4.42), supporting a conversion factor of approximately four times the daily oral LT4 dose when transitioning to XP-8121 SC. Although participants were initially underdosed during titration, TSH normalization was observed in 79.5% and fT4 normalization in 100% among those who completed the study on a consistent dose (unchanged for 6 weeks) at the end of maintenance. Overall, 78 treatment-emergent adverse events (TEAEs) were reported in 30 participants (65.2%) who received at least one dose of XP-8121 SC; fatigue (21.7%) and injection-site pain (10.9%) were the most common TEAEs. A majority of participants who completed the study reported higher satisfaction, convenience, and perceived effectiveness with once-weekly XP-8121 SC and expressed preference over daily oral LT4. CONCLUSIONS:Once-weekly XP-8121 SC was generally well-tolerated in all treated participants and supported a dose conversion factor of four times the daily oral LT4 dose.

Thyroid hormones (THs [T3 and T4] ) are key regulators of metabolic rate and nutrient metabolism. They are controlled centrally and peripherally in a coordinated manner to elegantly match T3-mediated energy expenditure (EE) with energy availability. Hypothyroidism reduces EE and has long been blamed for obesity; however, emerging evidence suggests that, instead, obesity may drive thyroid dysfunction. Thus, we used a mouse model of diet-induced obesity to determine its direct effects on thyroid histopathology and function, deiodinase activity, and T3 action. Strikingly, overnutrition induced hypothyroidism within 3 weeks. Levels of thyroidal THs and their precursor protein thyroglobulin decreased, and ER stress was induced, indicating that thyroid function was directly impaired. We also observed pronounced histological and vascular expansion in the thyroid. Overnutrition additionally suppressed T4 activation, rendering the mice resistant to T4 and reducing EE. Our findings collectively show that overnutrition deals a double strike to TH biosynthesis and action, despite large efforts to adapt - but, fortunately, thyroid dysfunction in mice can be reversed by weight loss. In humans, BMI correlated with thyroidal vascularization, importantly demonstrating preliminary translatability. These studies lay the groundwork for obesity therapies that tackle hypothyroidism, which are much needed, as no current obesity treatment works for everyone.

OBJECTIVE:Levothyroxine (LT4) is the standard treatment for hypothyroidism; yet many patients show reduced triiodothyronine (T3) levels despite normal thyrotropin (TSH). The clinical impact of the incomplete normalization of T3 homeostasis, including potential metabolic consequences, remains uncertain This study aimed to determine whether lower serum free T3 (FT3) levels in LT4-treated individuals constitute an independent risk factor for dyslipidemia. METHODS:We analyzed data from the Longitudinal Study of Adult Health in Brazil (ELSA-Brasil), which followed 15 105 civil servants aged 35-74 over 3 study waves (2008-2019). Participants with preexisting dyslipidemia were excluded. Participants were categorized based on FT3 levels (≤0.28 ng/dL vs >0.28 ng/dL), and the incidence of dyslipidemia (defined as non-high-density lipoprotein cholesterol ≥160 mg/dL or statins use) was assessed. Multivariable logistic regression was used to determine the association between low FT3 level and development of dyslipidemia. RESULTS:We identified 105 participants who developed hypothyroidism, initiated LT4 therapy, and achieved TSH normalization. Participants with FT3 ≤0.28 ng/dL had a significantly higher incidence of dyslipidemia (47.5% vs 27.3%, P = .036). FT3 ≤0.28 ng/dL remained a significant independent predictor of dyslipidemia after adjusting for confounders (adjusted OR: 3.558, 95% confidence interval: 1.173-12.045; P = .031). Other factors, including TSH, free thyroxine, body mass index, and smoking, were not significant. CONCLUSION:Low FT3 levels in LT4-treated patients represent an independent risk factor for dyslipidemia, even with normal TSH levels. This challenges the adequacy of TSH-centric management and supports the need for therapeutic strategies that ensure T3 homeostasis to mitigate dyslipidemia and cardiovascular risk.

L-thyroxine (L-T4) monotherapy is the standard treatment for hypothyroidism, administered daily to normalize TSH levels. Once absorbed, T4 is converted to T3 to alleviate most symptoms. However, this treatment abnormally elevates plasma T4 levels in over 50% of patients. Using L-T4-treated Thyroid Hormone (TH) Action Indicator mice, which express a T3-regulated luciferase (Luc) reporter, we examined whether these T4 elevations disrupt TH signaling. Hypothyroid mice exhibited reduced Luc expression across brain regions, and L-T4 treatment failed to restore T3 signaling uniformly. There was also variability in the activity of type 2 deiodinase (D2), the enzyme that generates most brain T3. Intracerebroventricular T4 administration achieved higher elevation of Luc expression in the mediobasal hypothalamus compared to the cortex, and studies on cultured cortical astrocytes and hypothalamic tanycytes revealed cell-type-specific responses to T4. In tanycytes, exposure to T4 sustained D2 activity, leading to progressive T3 signaling, whereas in astrocytes, T4 exposure triggered a drop in D2 activity, limiting T3 production through a ubiquitin-dependent, self-limiting mechanism. The sustained D2 activity in tanycytes was linked to rapid deubiquitination by USP33, as confirmed using a ubiquitin-specific protease (USP) pan-inhibitor and USP33 knockout mice. In conclusion, the brain's response to L-T4 treatment is heterogeneous, influenced by cell-specific regulation of D2-mediated T3 production. While cortical astrocytes exhibit limited T3 signaling due to D2 ubiquitination, tanycytes coexpressing USP33 amplify T3 signaling by rescuing ubiquitinated D2 from proteasomal degradation. These findings provide mechanistic insights into the limitations of L-T4 therapy and highlight the need for tailored approaches to managing hypothyroidism.

Maternal low thyroxine (T4) serum levels during the first trimester of pregnancy correlate with cerebral cortex volume and mental development of the progeny, but why neural cells during early fetal brain development are vulnerable to maternal T4 levels remains unknown. In this study, using iPSCs obtained from a boy with a loss-of-function mutation in MCT8 - a transporter previously identified as critical for thyroid hormone uptake and action in neural cells - we demonstrate that thyroid hormone induces transcriptional changes that promote the progression of human neural precursor cells along the dorsal projection trajectory. Consistent with these findings, single-cell, spatial, and bulk transcriptomics from MCT8-deficient cerebral organoids and cultures of human neural precursor cells underscored the necessity for optimal thyroid hormone levels for these cells to differentiate into neurons. The controlled intracellular activation of T4 signaling occurs through the transient expression of the enzyme type 2 deiodinase, which converts T4 into its active form, T3, alongside the coordinated expression of thyroid hormone nuclear receptors. The intracellular activation of T4 in neural precursor cells results in transcriptional changes important for their division mode and cell cycle progression. Thus, T4 is essential for fetal neurogenesis, highlighting the importance of adequate treatment for mothers with hypothyroidism.

CONTEXT:Levothyroxine (L-T4) monotherapy is the standard of care for the treatment of hypothyroidism. A minority of L-T4-treated patients remain symptomatic and report better outcomes with combination therapy that contains liothyronine (L-T3) or with desiccated thyroid extract (DTE). OBJECTIVE:This work aimed to assess patient preferences in the treatment of hypothyroidism. METHODS:A systematic review, meta-analysis, meta-regression, and network meta-analysis of randomized controlled trials (RCTs) comparing treatments for adults with hypothyroidism (L-T4 vs L-T4 + L-T3 or DTE). Searches were conducted in PubMed, Embase, and Cochrane databases up to April 10, 2024. Data extraction and quality assessment were independently performed by 4 researchers. RESULTS:Eleven RCTs (8 cross-over studies) with a total of 1135 patients were considered. Overall, 24% of patients preferred L-T4 vs 52% who preferred L-T4 + L-T3 or DTE; 24% had no preference. The meta-analysis confirmed the preference for combination therapy over L-T4 monotherapy (relative risk [RR]: 2.20; 95% CI, 1.38-3.52; P = .0009). Excluding 4 studies reduced the high heterogeneity (I2 = 81%) without affecting the results (RR: 1.97; 95% CI, 1.52-2.54; P < .00001; I2 = 24%). This preference profile remained when only crossover studies were considered (RR: 2.84; 95% CI, 1.50-5.39; P < .00001). Network meta-analysis confirmed the preference for DTE and L-T3 + L-T4 vs L-T4 alone. CONCLUSION:Patients with hypothyroidism prefer combination therapy (L-T3 + L-T4 or DTE) over L-T4 monotherapy. The strength of these findings justifies considering patient preferences in the setting of shared decision-making in the treatment of hypothyroidism.

The Thr92Ala-Dio2 polymorphism is prevalent worldwide, with about 50% of the population carrying at least 1 allele. The Ala92-Dio2 allele encodes a less active type 2 deiodinase enzyme and has been associated with neurodegenerative diseases, hypertension, and insulin resistance. To understand why its phenotypic effects are variable across different populations, in this study we examined the impact of genetic background on the Thr92Ala-Dio2 polymorphism. We focused on the thyroid gland of 2 genetically distant mouse strains, the C57BL/6J (B6) and the FVB/N (FVB). While the B6-Ala92-Dio2 mice have no meaningful phenotype, the FVB-Ala92-Dio2 exhibit a goiter (about 2.3-fold heavier thyroid) with an about 1.7-fold enlarged thyroid follicular area and impaired hormonogenesis with reduced thyroglobulin content of T4 and T3, 35% to 50% lower serum T4, and about 3-fold elevated serum TSH levels. Notably, the FVB-Ala92-Dio2 thyroid glands showed transcriptional evidence of endoplasmic reticulum stress, unfolded protein response, autophagy, and apoptosis. Female FVB-Ala92-Dio2 mice exhibited a more pronounced thyroid phenotype than males. These findings underscore the critical role of genetic background in modulating the phenotype outcomes of the Thr92Ala-Dio2 polymorphism and highlight its potential implications for understanding variable disease susceptibility in human populations.

INTRODUCTION:Over 10 million thyroid function tests (TFTs) are carried out in England each year, most requests coming from primary care. Our previous work showed that only 25% of results for patients being treated with Levothyroxine fell within the TSH/FT4 boundary circumscribing 75% of untreated individuals. This study aimed to investigate further the differences in thyroid hormone levels, taking into account both diagnostic code and amounts prescribed. METHODS:Using a city-wide population record, we analysed TSH/FT4 simultaneous results from 47,869 consecutive diagnosed hypothyroid individuals by medication dose and 393,101 untreated/euthyroid individuals over 14 years. For those on medication, we only included those who were diagnosed over 2 years ago, had no more than two tests per year and more than 2 years of test results available. For those not on medication, we included results from those patients who had a single test or two tests with more than 4 years between tests. RESULTS:The FT4 distribution for Levothyroxine-treated individuals was similar in shape versus untreated individuals but shifted towards higher FT4 even at the lowest dose of Levothyroxine, with an increasing separation of the distributions as Levothyroxine dose increased (F value = 1.5 increasing to F value = 4.2). In contrast, the distribution of TSH was substantially different for untreated individuals versus those on Levothyroxine, where the distribution was massively skewed to low or undetectable TSH with a 'hockey stick' configuration, with increasing skewness as doses of Levothyroxine rose. For those not on thyroid hormone replacement, 90.3% of individuals were within the TSH reference range and of these, 0.8% were recorded with a low FT4. For those on medication, only 43.8% were within the TSH reference range. For men versus women, the median Levothyroxine dose was higher in all decades, with the highest median daily dose at age 50-59 years (men: 107 mcg/day; women 93 mcg/day). Median T4 rose (women > men) and TSH fell progressively (women > men) by age in treated individuals. The levels of TSH in treated and untreated populations were only similar at around FT4 = 20pmol/L: below this treated patients have a higher TSH and above it, treated have a lower TSH for the same FT4. CONCLUSION:We have here described that distribution of FT4/TSH is different in people on and off Levothyroxine treatment. For those on Levothyroxine, only 43.8% were within the TSH reference range and the degree of difference increased in treated individuals with Levothyroxine daily dose. The potential implication of our findings is that clinicians must be mindful as they diagnose and treat hypothyroidism that the administration of Levothyroxine, while in most but not all individuals is clinically beneficial does not return the individual to the same balance of TSH and FT4 as seen in euthyroid individuals.

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 similar to 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 similar to 70% during the study period, and the fractional contribution of several countries remained relatively stable, except for China which increased by similar to 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.