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The medical community acknowledges the presence of thyroid disorders and nonalcoholic fatty liver disease (NAFLD). Nevertheless, the interconnection between these two circumstances is complex. Thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), and thyroid-stimulating hormone (TSH), are essential for maintaining metabolic balance and controlling the metabolism of lipids and carbohydrates. The therapeutic potential of THs, especially those that target the TRβ receptor isoform, is generating increasing interest. The review explores the pathophysiology of these disorders, specifically examining the impact of THs on the metabolism of lipids in the liver. The purpose of this review is to offer a thorough analysis of the correlation between thyroid disorders and NAFLD, as well as suggest potential therapeutic approaches for the future., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Intrauterine growth restriction (IUGR) is a pregnancy complication impairing fetal growth and development. The compromised development is often attributed to disruptions of oxygen and nutrient supply from the placenta, resulting in a number of unfavourable physiological outcomes with impaired brain and organ growth. IUGR is associated with compromised development of both grey and white matter, predisposing the infant to adverse neurodevelopmental outcomes, including long-lasting cognitive and motor difficulties. Cerebral thyroid hormone (TH) signalling, which plays a crucial role in regulating white and grey matter development, is dysregulated in IUGR, potentially contributing to the neurodevelopmental delays associated with this condition. Notably, one of the major TH transporters, monocarboxylate transporter-8 (MCT8), is deficient in the fetal IUGR brain. Currently, no effective treatment to prevent or reverse IUGR exists. Management strategies involve close antenatal monitoring, management of maternal risk factors if present and early delivery if IUGR is found to be severe or worsening in utero. The overall goal is to determine the most appropriate time for delivery, balancing the risks of preterm birth with further fetal compromise due to IUGR. Drug candidates have shown either adverse effects or little to no benefits in this vulnerable population, urging further preclinical and clinical investigation to establish effective therapies. In this review, we discuss the major neuropathology of IUGR driven by uteroplacental insufficiency and the concomitant long-term neurobehavioural impairments in individuals born IUGR. Importantly, we review the existing clinical and preclinical literature on cerebral TH signalling deficits, particularly the impaired expression of MCT8 and their correlation with IUGR. Lastly, we discuss the current evidence on MCT8-independent TH analogues which mimic the brain actions of THs by being metabolised in a similar manner as promising, albeit underappreciated approaches to promote grey and white matter development and improve the neurobehavioural outcomes following IUGR., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Background: Thyroid hormone (TH) appears to have a reparative action on the postinfarcted myocardium. This novel action was recently tested in a pilot, randomized, double-blind, placebo-controlled trial (ThyRepair). The present study performed a post-hoc analysis of data from the ThyRepair study to provide further insights into the novel actions of TH on the human postischemic myocardium., Methods: Data from 41 patients participating in the ThyRepair study (n = 20 placebo and n = 21 LT3) were included in the analysis. LT3 treatment started after stenting and continued intravenously for 48 h. All patients had cardiac magnetic resonance (CMR) at hospital discharge; left ventricular (LV) ejection fraction (LVEF%), LV end-diastolic volume index (LVEDVi; mL/m 2 ), LV end-systolic volume index (LVESVi; mL/m 2 ), infarct volume (IV), left ventricular mass index (LVMi) as edema index, and microvascular obstruction (MVO) were assessed. Patients were divided into two groups based on the median value of the IV: patients with IV ≤ 20% of the LV (group A) and patients with IV > 20% (group B). CMR measurements at discharge are expressed as mean ± SD., Results: In group A, the placebo and T3-treated groups had similar LVEF% (56.8 ± 10.2 vs. 52.2 ± 10.5), LVEDVi (90.9 ± 19.8 vs. 92.8 ± 14.5), and LVESVi (40.8 ± 18.2 vs. 44.9 ± 14.1) at discharge. In group B, LVEDVi and LVESVi were 112 ± 23.8 and 68.3 ± 21.5 for placebo vs. 91.8 ± 18.6 and 49.0 ± 14.0 for the T3-treated group, respectively, p < 0.05. LVEF% was significantly increased in the T3-treated group vs. placebo, 47.3 ± 6.5 vs. 39.9 ± 8.7, p < 0.05. In group B, CMR LVMi was lower in T3-treated patients vs. placebo but did not reach statistical significance (p = 0.1). MVO was 1.95 ± 2.2 in placebo vs. 0.84 ± 0.9 in the LT3-treated group, p = 0.15., Conclusion: The present study suggests that acute LT3 treatment may exert more favorable effects on the recovery of cardiac function in patients with large infarct size. Furthermore, it signals a potential effect of LT3 on myocardial edema and microvascular obstruction. These novel findings merit further investigation in large trials., Competing Interests: The following patent is relevant to the work in this manuscript: PCT/EP2019/087056. L-triiodothyronine T3 for use in limiting microvascular obstruction. CP and IM are the inventors and hold royalties in relation to this patent. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pantos, Grigoriou, Trikas, Alexopoulos and Mourouzis.)

Cardiovascular disease (CVD) remains the leading cause of death worldwide, representing a major health issue of social and economic relevance. Both hyperthyroidism and hypothyroidism are very common in the adult population, and both disorders may contribute to the onset and progression of CVD. After a brief description of the role of thyroid hormones (THs) on the physiology of the cardiovascular system and the potential mechanism that links THs alterations with changes in cardiac function, blood pressure, endothelial function, and lipid levels, we review updated data about the clinical impact of overt hypothyroidism (OH) and subclinical hypothyroidism (SCH) on CV risk, CVD, and mortality. Furthermore, we summarize the current evidence for treating SCH with levothyroxine (L-T4). Several guidelines of distinguished endocrine societies recommend treatment for SCH with TSH higher than 10 mIU/L, where the benefit of L-T4 therapy is more evident for younger people, but still controversial in those aged over 65 years. Based on current knowledge, more research efforts are needed to better address the clinical management of CV risk and CVD in the elderly affected by SCH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Patrizio, Ferrari, Elia, Ragusa, Balestri, Botrini, Rugani, Mazzi, Antonelli, Fallahi and Benvenga.)

Background: Thyroid hormones were reported to exert neuroprotective effects after ischemic stroke by reducing the burden of brain injury and promoting post-ischemic brain remodeling., Objective: We aimed to analyze the value of thyroid hormone replacement therapy (THRT) due to pre-existing hypothyroidism on the clinical course and outcome of aneurysmal subarachnoid hemorrhage (SAH)., Methods: SAH individuals treated between January 2003 and June 2016 were included. Data on baseline characteristics of patients and SAH, adverse events and functional outcome of SAH were recorded. Study endpoints were cerebral infarction, in-hospital mortality and unfavorable outcome at 6 months. Associations were adjusted for outcome-relevant confounders., Results: 109 (11%) of 995 individuals had THRT before SAH. Risk of intracranial pressure- or vasospasm-related cerebrovascular events was inversely associated with presence of THRT (p = 0.047). In multivariate analysis, THRT was independently associated with lower risk of cerebral infarction (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.41-0.99, p = 0.045) and unfavorable outcome (aOR = 0.50, 95% CI = 0.28-0.89, p = 0.018), but not with in-hospital mortality (aOR = 0.69, 95% CI = 0.38-1.26, p = 0.227)., Conclusion: SAH patients with THRT show lower burden of ischemia-relevant cerebrovascular events and more favorable outcome. Further experimental and clinical studies are required to confirm our results and elaborate the mechanistic background of the effect of THRT on course and outcome of SAH., (© 2024. The Author(s).)

Objective: Hypothyroidism is a common endocrine condition usually managed with levothyroxine (LT4). However, controversy remains around the use of liothyronine (LT3). We aimed to investigate the practices of Australian endocrinologists when managing patients with hypothyroidism, their use of LT3 + LT4 combination therapy and use of thyroid hormones in euthyroid patients., Design and Participants: Members of the Endocrine Society of Australia (ESA) were invited to participate in an online questionnaire., Measurements: We analysed questionnaires that had complete demographic data., Results: Eighty-seven questionnaires fulfilled the criteria. LT4 was used as first line treatment for hypothyroidism by all respondents. Only 45% reported that their patients were dispensed the brand of LT4 that they recommend. LT3 (alone or in combination) was prescribed by 44% in their clinical practice. Although 49% of respondents would consider LT3 + LT4 in patients with normal TSH who had ongoing symptoms of hypothyroidism, the inability of LT4 to restore normal physiology was ranked the least likely explanation for persistent symptoms and only 32% would consider it for themselves if they were diagnosed with hypothyroidism. The majority (55%), in accordance with evidence, would not prescribe thyroid hormone to euthyroid individuals but 39% would consider use in euthyroid female infertility with high levels of thyroid antibodies and 11% in euthyroid patients with a simple goitre growing over time. LT4 use in pregnancy was variable among members., Conclusions: Australian endocrinologists mostly follow international guidelines when prescribing thyroid hormone therapy and many prescribe combination LT3 and LT4 therapy, particularly for patients who remain symptomatic on LT4 monotherapy. Prescribing practices are largely similar to other countries who have completed similar questionnaires., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Objective: Thyroid hormone under-replacement and over-replacement are associated with adverse health outcomes. This systematic review aimed to evaluate the extent of thyroid hormone replacement adequacy for patients with known hypothyroidism in real-word settings, excluding those receiving thyroid hormone suppressive therapy as thyroid cancer treatment., Design: Four electronic databases (Embase [Ovid], Medline [Ovid], PubMed and SCOPUS) were searched for published and unpublished observational studies until 12 December 2022. The results of the studies were meta-analysed to calculate pooled prevalence estimates for thyroid hormone supplementation adequacy, over-replacement and under-replacement. Quality assessment of studies was performed using the Joanna-Briggs appraisal tool for prevalence studies., Results: Seven studies with a total of 4230 patients were eligible for quantitative synthesis. The pooled prevalence estimates of adequate thyroid replacement, over-replacement and under-replacement were 0.55 (95% confidence interval [CI]: 0.49-0.60, p = .001), 0.20 (95% CI: 0.14-0.27, p = .001) and 0.24 (95% CI: 0.13-0.36, p = .001), respectively. Four studies subclassified hypothyroidism and hyperthyroidism into overt and subclinical. The pooled prevalence of overt and subclinical hyperthyroidism was 0.04 (95% CI: 0.00-0.11, p = .01) and 0.17 (95% CI: 0.09-0.27 p = .001), respectively. For overt and subclinical hypothyroidism, the pooled prevalence was 0.02 (95% CI: 0.01-0.03, p = .001) and 0.20 (95% CI: 0.12-0.29, p = .001), respectively., Conclusions: On average, approximately half of patients with hypothyroidism are only treated to target euthyroidism. In real-world practice, a significant number of patients are over-treated or under-treated, leading to adverse healthcare outcomes. It is imperative that more effective thyroid monitoring strategies be implemented, with an emphasis on primary care thyroid function monitoring, to minimise inappropriate thyroid replacement treatments and optimise healthcare outcomes at a population level., (© 2023 John Wiley & Sons Ltd.)

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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Dyslipidemia is one of the most common disorders worldwide, which, if left untreated, results in a multitude of complications. Thus proper diagnostics, which includes identifying of secondary causes of dyslipidemia is crucial. Endocrine disorders are an important cause of secondary dyslipidemia. This paper aims to review the publications on lipoprotein alterations in endocrine disorders from the past two years and provide an overview of the recent discoveries in this dynamically developing and large field. Significant changes in lipoprotein serum concentrations are present in most endocrinological diseases and can be modified with proper treatment. Some lipoproteins have also been proposed as markers in some endocrine diseases, e.g., thyroid carcinoma. From the scope of endocrine disorders, the largest number of studies explored the lipoprotein changes in polycystic ovary syndrome and in women during the menopausal and peri-menopausal period. Even though the association of thyroid disorders with dyslipidemia is already well studied, new research has delivered some exciting findings about lipoprotein alterations in euthyroid patients with either positive antithyroid peroxidase antibodies or reduced sensitivity to thyroid hormones. The problem of the adverse metabolic profile, including dyslipidemia in hypoprolactinemia has been recognized. Moreover, this review describes other significant discoveries encompassing lipoprotein alterations in disorders of the adrenals, thyroid, parathyroid glands, pituitary, and gonads. The up-to-date knowledge of the influence of endocrine disorders and hormonal changes on serum lipoproteins is prudent as it can significantly impact therapeutic decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Olejarz, Szczepanek-Parulska and Ruchala.)

Background: To assess 28-day survival in two pilot groups of septic shock patients with euthyroid sick syndrome (ESS) supplemented with triiodothyronine (T3)., Methods: A total of 95 septic shock patients with ESS were divided according to values of the thyroid hormones into low T3 and low T3T4 groups. Among 48 patients with low T3, 24 (50%) were randomized to T3 for 4 days and 24 (50%) to placebo. Among 47 patients with low T3T4, 24 (51%) were randomized to T3 for 4 days and 23 (49%) to placebo. The analysis included 28-day survival as the primary outcome and laboratory with hemodynamics as the secondary outcomes. Laboratory data were analyzed on the day of admission (T0), on the first (T1), third (T2) and seventh day (T3) with hemodynamics analyzed for the first four days., Results: In the low T3 population, 18 (75%) patients receiving T3 died at day 28 compared with 8 (33.3%) patients receiving placebo (p = 0.004). In the low T3T4 population, 6 (25%) patients receiving T3 died in ICU compared with 12 (52.1%) patients receiving placebo (p = 0.039). Oral T3 treatment increased mean arterial pressure values at day 1, day 3 and day 7 in the low T3T4 population, (p = 0.015, =0.005 and =0.042 respectively), and had no significant effect on these values in the low T3 population., Conclusion: T3 supplementation was associated with a low 28-day mortality rate in patients with low T3T4 but with increased mortality in patients with low T3 ESS. These results suggest caution before initiating thyroid supplementation in septic patients., Registration: ClinTrials.gov (NCT05270798)., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: This meta-analysis and systematic review aimed to evaluate the therapeutic efficacy and advantages associated with the use of recombinant human thyroid-stimulating hormone (rhTSH) for radioactive iodine (RAI) therapy in patients with intermediate- to high-risk differentiated thyroid cancer., Patients and Methods: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles reporting clinical outcomes of rhTSH compared with thyroid hormone withdrawal (THW) in patients with intermediate- to high-risk differentiated thyroid cancer published between January 2012 and June 2023. Meta-analyses were performed (PROSPERO registration number: CRD42022340915) to assess the success rate of radioiodine remnant ablation (RRA) in patients with intermediate to high risk and determine the disease control rate among patients with distant metastases, evaluated using the RECIST criteria., Results: Thirteen studies involving 1858 patients were included in the meta-analysis. Pooled analyses revealed significantly higher overall RRA success rate in the rhTSH group compared with the THW group, with a risk ratio (RR) of 1.12 (95% confidence interval [CI], 1.01-1.25). However, in the subgroup analysis of high-risk patients, pooled analyses showed no significant differences in RRA success rate between the rhTSH group compared with the THW group with a pooled RR of 1.05 (95% CI, 0.88-1.24). In patients with distant metastases, there were no significant differences in the disease control rate between groups, with a pooled RR of 1.06 (95% CI, 0.78-1.44)., Conclusions: rhTSH for RAI therapy is a practical option for RAI therapy in patients with intermediate- to high-risk thyroid cancer, including those with distant metastases., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This review focuses on post-operative thyroid hormone replacement and thyrotropin suppression therapy in patients with differentiated thyroid cancer., Methods: A clinical review., Results: Differentiated thyroid cancers (DTC), including papillary and follicular thyroid cancers, have an excellent prognosis and their management leverages a unique set of clinical tools arising from homology to the normal thyroid follicular cell. Surgery is the cornerstone of initial management, and post-operative care often requires thyroid hormone replacement therapy, which may be approached with the intent of physiologic normalization or used pharmacologically to suppress TSH as part of a DTC treatment., Conclusion: Management of DTC and approaches to TSH suppression are tailored to an individual's risk of DTC recurrence and are adjusted to a patient's clinical status and comorbidities over time with the goal of mitigating risk and maximizing benefit., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

Thyroid hormones have vital roles in development, growth and energy metabolism. Within the past two decades, disturbances in thyroid hormone action have been implicated in ageing and the development of age-related diseases. This Review will consider results from biomedical studies that have identified the importance of precise temporospatial regulation of thyroid hormone action for local tissue maintenance and repair. Age-related disturbances in the maintenance of tissue homeostasis are thought to be important drivers of age-related disease. In most iodine-proficient human populations without thyroid disease, the mean, median and 97.5 centile for circulating concentrations of thyroid-stimulating hormone are progressively higher in adults over 80 years of age compared with middle-aged (50-59 years) and younger (20-29 years) adults. This trend has been shown to extend into advanced ages (over 100 years). Here, potential causes and consequences of the altered thyroid status observed in old age and its association with longevity will be discussed. In about 5-20% of adults at least 65 years of age, thyroid-stimulating hormone concentrations are elevated but circulating concentrations of thyroid hormone are within the population reference range, a condition referred to as subclinical hypothyroidism. Results from randomized clinical trials that have tested the clinical benefit of thyroid hormone replacement therapy in older adults with mild subclinical hypothyroidism will be discussed, as well as the implications of these findings for screening and treatment of subclinical hypothyroidism in older adults., (© 2023. Springer Nature Limited.)

Levothyroxine or l-thyroxine is artificially manufactured thyroxine, which is used as a drug to treat underactive thyroid conditions in humans. The drug, levothyroxine, is consumed daily in a prescribed dose to replace the missing thyroid hormone thyroxine in an individual with an underactive thyroid, and it helps to maintain normal physiological conditions. Though it is a life-maintaining drug, it replaces the missing thyroid hormone and performs the necessary daily metabolic functions in our body. Like all other allopathic drugs, it comes with certain side effects, which include joint pain, cramps in muscle, weight gain/loss, hair loss, etc . The thyroid hormone, thyroxine, is known to mobilize fat in our body, including the ones from the hepatic system. An underactive thyroid may cause an accumulation of fat in the liver, leading to a fatty liver, which is clinically termed Non-Alcoholic Fatty Liver Disease (NAFLD). The correlation between hypothyroidism and NAFLD is now well-studied and recognized. As levothyroxine performs the functions of the missing thyroxine, it is anticipated, based on certain preliminary studies, that the drug helps to mobilize hepatic fat and thus may have a crucial role in mitigating the condition of NAFDL., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Subclinical hypothyroidism is an early, mild form of hypothyroidism that may progress to overt hypothyroidism if untreated. The current study aimed to assess the effects of vitamin D supplementation on hormonal (thyroid stimulating hormone [TSH], triiodothyronine, thyroxine, and free thyroxine) parameters, lipid profiles, serum irisin, and obesity indices in women with subclinical hypothyroidism., Methods: The present randomized, double-blind, placebo-controlled clinical trial was carried out on 44 women with subclinical hypothyroidism. The participants were allocated to two groups (22 patients in each group) that received vitamin D (50,000 IU/week) or placebo for 12 weeks. Fasting blood samples, anthropometric and body composition measurements, physical activity levels, and dietary intakes were collected at baseline and at the end of the study., Results: Vitamin D supplementation significantly decreased TSH, total cholesterol, and fat mass percentage, and significantly increased serum vitamin D and irisin levels and fat-free mass percentage compared to the control group (all, p<0.05). Changes in thyroid hormones, other lipid profiles, and anthropometric indices were not significantly different between the groups., Conclusion: Our study indicates that vitamin D administration improves serum TSH, total cholesterol, irisin, and body composition in women with subclinical hypothyroidism. More well-designed clinical trials are required to confirm these findings and clarify the effects of vitamin D supplementation on both genders of patients. Clinical trial registration: https://www.irct.ir/trial/57482, Identifier IRCT20100408003664N25., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Safari, Rafraf, Malekian, Molani-Gol, Asghari-Jafarabadi and Mobasseri.)

Context: Recent studies suggest that hypothyroidism is a risk factor for dementia. Based on existing literature, it is unclear if treatment or compliance to treatment is associated with decreased dementia risk in hypothyroidism patients., Objective: To determine the association between thyroid hormone medication adherence and risk of dementia., Methods: A population-based cohort study following patients with newly diagnosed hypothyroidism until incidence of dementia, death, or December 31, 2020, whichever came earliest. The study comprised 41 554 older adults age 50 and above with newly diagnosed hypothyroidism between 2004 and 2008 who underwent health screening. Risk of dementia was evaluated using multivariable-adjusted Cox proportional hazards regression., Results: Among 5188 men (12.5%) and 36 366 (87.5%) women, 2120 cases of incident dementia were identified. After stratification of the participants according to the interquartile range of the medication possession ratio (MPR), the fourth quartile (highest adherence) showed a 14% lower risk of overall dementia compared with the first quartile (lowest adherence) (adjusted hazard ratio 0.86; 95% CI 0.76-0.97). No consistent association was observed between thyroid hormone medication adherence and vascular dementia. After a dichotomous stratification of the MPR, higher MPR (≥0.8) showed a lower risk of Alzheimer disease (adjusted hazard ratio 0.91; 95% CI 0.84-0.99) than lower MPR (<0.8)., Conclusion: Better adherence to thyroid hormone medication may be beneficial in preventing incident dementia, especially Alzheimer disease, in older adults with newly diagnosed hypothyroidism. Along with the resolution of hypothyroid symptoms and the reduction of cardiovascular risk factors, the reduction of dementia risk may be another potential benefit of thyroid hormone medication., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.

Background: Treatment with proton pump inhibitors (PPIs) and antacids affects the gastrointestinal absorption of levothyroxine sodium (LT4) tablets. Patients with hypothyroidism taking LT4 and PPIs or antacids, thus, require appropriate monitoring. The objective of this study was to determine whether a soft gelatin capsule of LT4 (Tirosint ® ) would obviate the effect of PPIs on LT4 absorption. The objective was achieved by assessing the effects of a switch from a conventional LT4 tablet form to the same dose as soft capsules in thyroidectomized patients on treatment with LT4 and PPIs. Methods: Patients with history of hypothyroidism due to total thyroidectomy on stable treatment with LT4 tablets, and with gastrointestinal disease treated with PPIs, were switched to a 12-week treatment with Tirosint at the same dose of the LT4 tablets, while maintaining treatment with PPIs. Serum thyrotropin (TSH) levels were the primary endpoint of the study. Secondary efficacy endpoints were: serum levels of free thyroxine (fT4), total thyroxine (TT4), free triiodothyronine (fT3), total triiodothyronine (TT3), creatine-phosphokinase (CPK), sex-hormone binding globulin, ferritin, angiotensin converting enzyme, and a lipid panel. Results: Forty-seven patients (36 females and 11 males, mean age 55.4 years) were enrolled and 45 of them completed the study (2 patients withdrew consent). During treatment with Tirosint, mean TSH levels demonstrated a statistically significant decrease (mean changes from baseline: -0.32 mIU/L at week 6 and -0.68 mIU/L at week 12) and concomitant increases in thyroid hormone (TH) levels from baseline to week 12, which were statistically significant for fT3 and TT3 (mean changes from baseline: 0.26 pmol/L and 0.10 nmol/L, respectively). Significant decreases of serum low-density lipoprotein, total cholesterol, and CPK levels were observed at week 12. No signs/symptoms arose during the study that could be specifically correlated to either hypo- or hyperthyroidism. Conclusions: In thyroidectomized patients taking PPIs and replacement LT4, a switch from conventional LT4 tablets to LT4 soft capsules at the same dose was associated with a significant decrease in TSH and increase in TH, indicating that LT4 absorption may be less affected by PPIs when given in the form of soft capsules. Clinical Trial Registration: NCT03094416.

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Approximately 10%-15% of subjects with hypothyroidism on L-thyroxine (LT4) alone have persistent symptoms affecting their quality of life (QoL). Although the cause is unclear, there is evidence that "tissue T3 lack" may be responsible. If so, combining liothyronine (LT3) with LT4 would be helpful. However, randomized controlled trials (RCT), have not established greater efficacy for the LT3 + LT4 combination in these subjects than for LT4 alone. While the trial design may have been responsible, the use of unphysiological, short-acting LT3 preparations and non-thyroid-specific patient-reported outcome measures (PROMs) may have contributed. We recommend attention to the following aspects of trial design for future RCTs of LT3 + LT4 compared to LT4 alone: (a) Subject selection-(i) measurable symptoms (disadvantages should be recognized); (ii) using a validated thyroid specific PROM such as ThyPRO39 or the Composite scale derived from it; (iii) those taking over 1.2 μg/day or 100 μg/day (for pragmatic reasons) of LT4 defining a population likely without intrinsic thyroid activity who depend on exogenous LT4; (iv) recruiting a preponderance of subjects with autoimmune thyroiditis increasing generalisability; and (v) those with a high symptom load with a greater response to combination therapy e.g. those with the deiodinase 2 polymorphism. (b) The use of physiological LT3 preparations producing pharmacokinetic similarities to T3 profiles in unaffected subjects: two long-acting LT3 preparations are currently available and must be tested in phase 2b/3 RCTs. (c) The superiority of a crossover design in limiting numbers and costs while maintaining statistical power and ensuring that all subjects experienced the investigative medication., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Premawardhana, Taylor, Okosieme, Adlan, Obuobie and Dayan.)

Background: The monocarboxylate transporter 8 (MCT8) plays a vital role in maintaining brain thyroid hormone homeostasis. This transmembrane transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene (SLC16A2) cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders. The underlying pathophysiological mechanisms of AHDS remain unclear, and no effective treatments are available for the neurological symptoms of the disease., Methods: Neurovascular unit ultrastructure was studied by means of transmission electron microscopy. BBB permeability and integrity were evaluated by immunohistochemistry, non-permeable dye infiltration assays and histological staining techniques. Brain blood-vessel density was evaluated by immunofluorescence and magnetic resonance angiography. Finally, angiogenic-related factors expression was evaluated by qRT-PCR. The studies were carried out both in an MCT8 deficient subject and Mct8/Dio2KO mice, an AHDS murine model, and their respective controls., Results: Ultrastructural analysis of the BBB of Mct8/Dio2KO mice revealed significant alterations in neurovascular unit integrity and increased transcytotic flux. We also found functional alterations in the BBB permeability, as shown by an increased presence of peripheral IgG, Sodium Fluorescein and Evans Blue, along with increased brain microhemorrhages. We also observed alterations in the angiogenic process, with reduced blood vessel density in adult mice brain and altered expression of angiogenesis-related factors during brain development. Similarly, AHDS human brain samples showed increased BBB permeability to IgG and decreased blood vessel density., Conclusions: These findings identify for the first time neurovascular alterations in the MCT8-deficient brain, including a disruption of the integrity of the BBB and alterations in the neurovascular unit ultrastructure as a new pathophysiological mechanism for AHDS. These results open a new field for potential therapeutic targets for the neurological symptoms of these patients and unveils magnetic resonance angiography as a new non-invasive in vivo technique for evaluating the progression of the disease., (© 2023. The Author(s).)

Acquired hypothyroidism is generally also referred to as juvenile hypothyroidism. Hypothyroidism is due to the deficient secretion of thyroid hormones causing metabolic and neurological sequelae at the cellular level. It can present as overt hypothyroidism wherein the thyroid hormones (T4 and T3) secretion fall and thyrotropin (TSH) rises. Acquired hypothyroidism frequently presents between 9 and 11 y of age and is rarely seen before 4 y of age. Approximately 80% of the children and adolescents are asymptomatic at the time of diagnosis. Children with moderate to severe hypothyroidism often present for evaluation of poor growth, constipation, lethargy and/or dry skin. A detailed history and examination will provide us with enough clues for diagnosing hypothyroidism. Primary hypothyroidism can be diagnosed with raised TSH with subnormal levels of T3 and T4. Titres of thyroid antibodies - Anti-thyroperoxidase (TPO) and anti-thyroglobulin (ATG) antibodies, will be high in autoimmune hypothyroidism. Subclinical hypothyroidism is diagnosed with mildly elevated or high normal levels of TSH with free T4 being in the normal range. Insufficient secretion of thyrotropin from the pituitary causes central hypothyroidism. Acquired hypothyroidism is treated by replacement with levothyroxine. Regular monitoring of thyroid profile is necessary for adjusting doses of levothyroxine. Close monitoring and individualization of levothyroxine therapy is essential for normal growth and development of the child., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Background: Preterm infants presented a high prevalence of congenital hypothyroidism (CH), while the optimal screening pattern is still under debate. This study aimed at evaluating the characteristics of thyroid function by conducting weekly screening during the first month of life in very preterm infants (VPIs) to achieve timely diagnosis and treatment of CH. Methods: A prospective cohort study was carried out on VPIs born with gestational age (GA) <32 weeks (w) and admitted to the participating institutes from January 1, 2019 to December 31, 2022. Serial serum thyroid hormone levels were measured weekly within the first month after birth, and at 36 w of corrected age, or before discharge. Datasets for serial thyroid hormone levels and general information were obtained. Results: A total of 5992 VPIs were enrolled in this study, of which 456 (7.6%) [95% confidence interval (CI), 6.9-8.3%] were diagnosed with CH. The incidence of CH increased with lower GA, moving from 4.8% [CI, 3.4-6.1%] at GA 31 w to 16.9% [CI, 8.3-25.4%] at GA <26 w. Among the CH subjects, 57.7% [CI, 53.1-62.2%] were identified after the first screening and classified as delayed thyrotropin elevation (dTSH). With the decrease of GA, the proportion of dTSH also increased, moving from 38.1% [CI, 27.5-48.7%] at GA 31 w to 82.6% [CI, 65.8-99.4%] at GA <26 w. Through conducting weekly screening of thyroid function, it was remarkable that only 42.3% [CI, 37.8-46.9%] of CH subjects were diagnosed during the first screening. The cumulative rate of CH identified by rescreening performed at the second, third, and fourth week was 76.1% [CI, 72.2-80.0%], 90.6% [CI, 87.9-93.3%], and 98.9% [CI, 97.9-99.9%], respectively. Conclusion: The incidence of CH and dTSH both increase with lower GA in VPIs. Dynamic screening of thyroid function by weeks within the first month of life is crucial for the timely diagnosis and treatment of CH in VPIs, and it might effectively reduce the implications of missed diagnosis and delayed treatment. Clinical Trials Registration: ChiCTR1900025234 and ChiCTR2000037918 (Registration number).

Background: Hypothyroidism is clinically characterized by a decrease in levels of the circulating thyroid hormones namely thyroxine and triiodothyronine. The main treatment for hypothyroidism is thyroid hormone replacement using levothyroxine to normalize serum thyroid hormone levels., Objectives: In this study, we explored the metabolic changes in the plasma of patients with hypothyroidism after reaching a euthyroid state with levothyroxine treatment., Methods: Plasma samples from 18 patients diagnosed as overt hypothyroidism were collected before and after levothyroxine treatment upon reaching a euthyroid state and were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate and univariate analyses evaluated data to highlight potential metabolic biomarkers., Results: Liquid chromatography-mass spectrometry-based metabolomics revealed a significant decrease in the levels of ceramide, phosphatidylcholine, triglycerides, acylcarnitine, and peptides after levothyroxine treatment; this could indicate a change in the fatty acid transportation system and an enhanced β-oxidation, compared with a hypothyroid state. At the same time, the decrease in the peptides suggested a shift in protein synthesis. In addition, there was a considerable rise in glycocholic acid following therapy, suggesting the involvement of thyroid hormones in stimulating bile acid production and secretion., Conclusions: A metabolomic analysis of patients with hypothyroidism revealed significant changes in several metabolites and lipids after treatment. This study showed the value of the metabolomics technique in providing a complementary understanding of the pathophysiology of hypothyroidism and as a crucial tool for examining the molecular impact of levothyroxine treatment on hypothyroidism. It was an important tool for investigating the therapeutic effects of levothyroxine on hypothyroidism at the molecular level.

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., Competing Interests: Disclosure A.C.B. is a consultant for AbbVie, Acella, Synthonics, Thyron, and Madrigal. The other authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Aim: To determine whether thyroid hormone levels are associated with a specific clinical phenotype in patients with first-episode psychosis (FEP)., Methods: Ninety-eight inpatients experiencing FEP and with less than 6 weeks of antipsychotic treatment were included in the study and were followed up for one year. Baseline psychiatric evaluation included assessment of prodromal symptoms, positive and negative symptoms, depressive symptoms, stressful life events and cycloid psychosis criteria. Thyroid function (thyroid-stimulating hormone (TSH) and free thyroxin (FT4)) was determined at admission. Partial correlation analysis was conducted to analyse the correlation between levels of TSH/FT4 and symptoms. Logistic regression was performed to explore the association between psychopathological symptoms, 12-month diagnoses and thyroid hormones while adjusting for covariates., Results: Patients with prodromal symptomatology showed lower baseline FT4 levels (OR = 0.06; p  = 0.018). The duration of untreated psychosis (DUP) was inversely associated with FT4 concentrations ( r  =  - 0.243; p  = 0.039). FEP patients with sudden onset of psychotic symptoms (criteria B, cycloid psychosis) showed higher FT4 levels at admission (OR = 10.49; p  = 0.040). Patients diagnosed with affective psychotic disorders (BD or MDD) at the 12-month follow-up showed higher FT4 levels at admission than patients diagnosed with nonaffective psychosis (schizophrenia, schizoaffective) (OR = 8.57; p  = 0.042)., Conclusions: Our study suggests that higher free-thyroxine levels are associated with a specific clinical phenotype of FEP patients (fewer prodromal symptoms, shorter DUP duration and sudden onset of psychosis) and with affective psychosis diagnoses at the 12-month follow-up., Competing Interests: The authors declare there are no competing interests., (©2023 Gine-Serven et al.)

Background: Thyroid hormones (active form T3) are naturally potent compounds that influence energy expenditure, cholesterol metabolism, and fat oxidation. T3 would be an effective anti-obesity drug if it would not be delivered to the heart and bones, which leads to serious side effects, such as cardiovascular and bone thyrotoxicity, muscle wasting, and so on., Methods: In this study, we designed a targeted drug delivery system that is a glucagon-modified liposome to deliver T3 to the liver and adipose tissues., Results: The liposomes exhibited excellent properties, including uniform nanoscale particle size, good physicochemical stability, and adequate drug release behavior. More importantly, the glucagon-modified liposomes were enriched in the liver, which minimized the undesired bone and cardiovascular thyrotoxicity of T3. Compared to the control group, T3-loading glucagon-modified liposomes could effectively decrease body weight, reverse hepatic steatosis, and correct hyperlipidemia and hyperglycemia in ob/ob mice, without the undesired cardiovascular and bone thyrotoxicity., Conclusion: These findings indicate that delivery of thyroid hormone by glucagon-modified liposomes may provide an effective strategy for anti-obesity therapy., Competing Interests: Conflict of Interests The authors declare that they have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Searching for aging key points is one of the main problems in geriatrics. More and more research in recent years has been devoted to the study of geroprotective mechanisms, the impact of various conditions and diseases on aging in general. Of particular importance is the determination of age-related involutive processes in the human body, whether they are part of normal aging or a condition that needs to be corrected to improve the functioning of organs and systems. An important mechanism of aging starts is a change in hormonal activity of endocrine glands, in particular in hormonal activity of thyroid. Frequency of hypothyroidism in advanced age explains relevance of the chosen topic. The aim of the review was to find out the role hypothyroidism in aging. The main task was to define, whether thyroid hormones decrease in older age was a protective factor or pathological process. A review of the literature over the past 10 years on subclinical treatment was carried out and we identified the most pressing issues associated with hypothyroidism and aging. We studied data on the relationship between hypothyroidism and major geriatric syndromes, with special attention paid to cognitive diseases and emotional disorders.

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

Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3'-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.

Common symptoms of overt hypothyroidism are non-specific and include fatigue, lethargy, and dry skin. Although the diagnosis is considered to be straightforward, no single symptom can be used to identify patients with overt hypothyroidism, while many patients with subclinical hypothyroidism are asymptomatic. A large population-based study on the spectrum of symptoms in subclinical hypothyroidism showed similar rates of thyroid disease-related symptoms compared with euthyroid subjects, while the TSH concentration had no impact on symptom score. Together, these findings make it challenging to attribute symptoms to their underlying cause. This is also true in the case of unexplained persistent symptoms in levothyroxine-treated patients. Although generally considered a life-long replacement therapy, successful thyroid hormone discontinuation resulting in euthyroidism has been reported in approximately one third of patients. Thus, we overtreat patients with (subclinical) hypothyroidism, highlighting the importance of reliable diagnostic criteria. The diagnostic process, including the implementation of robust TSH and FT4 reference intervals, is especially challenging in specific situations including aging, pregnancy, non-thyroidal illness, and central hypothyroidism. There is a clear need for improved adherence to current guidelines from scientific societies and for willingness to manage symptoms without a clear pathological correlate, especially in the case of mild TSH elevations. This review will highlight recent literature on this topic and offers some practice points., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jansen, Boelen, Heijboer, Bruinstroop and Fliers.)

Purpose: Previous studies demonstrated decreased quality of life (QoL) in differentiated thyroid cancer (DTC) survivors and suggested QoL variability related to time from thyroidectomy and levothyroxine dosage. The aims of this study were to evaluate QoL in thyroidectomized subjects in different levothyroxine states and to evaluate the association between TSH and thyroid hormones and QoL., Methods: Prospective 5-year study enrolling 208 patients thyroidectomized for DTC, studied in one to four times according to levothyroxine dosage: withdrawal (WITHD), complete (C-SUPP) and mild TSH-suppression (M-SUPP), replacement (REPL). Each patient was allowed to participate into the study more than one time. A total of 300 evaluations were collected, consisting of detailed thyroid hormone profile and QoL assessment through the ThyPRO questionnaire., Results: Comparing the four groups, significant differences were found for anxiety, impaired social and daily life and item 12 (overall impact of thyroid disease) domains (p < 0.05). Interestingly, C-SUPP subjects reported the best scores in almost all ThyPRO scales. Significant correlations were found between QoL and pituitary-thyroid axis function, as well as between QoL and gender, being females more affected. At multiple regression analyses fT3 demonstrated to be the best explanatory factor for overall impact of thyroid disease on the patient's life, followed by gender., Conclusions: TSH-suppressive doses of levothyroxine are more effective in improving QoL in DTC patients after thyroidectomy. These results confirm the urgent need of further studies aimed to define the best treatment of hypothyroidism, effective on well-being and harmless for patients., (© 2022. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: During treatment for differentiated thyroid carcinoma (DTC), patients go from euthyroidism to severe hypothyroidism to subclinical hyperthyroidism induced by thyroid hormone suppression therapy (THST). Severe hypothyroidism may induce a tendency toward bleeding, whereas hyperthyroidism is thrombogenic. Therefore, treatment for DTC may increase the risk of bleeding during thyroid hormone withdrawal, and thrombosis during THST. This study aims to provide prospective analysis of changes in the hemostatic system from euthyroidism to hypothyroidism, and during THST, in patients treated for DTC. Methods: This is a secondary study in a larger Dutch prospective cohort. Consecutive samples were obtained from 20 patients (18 female [90%]; median age 48 [interquartile range 35.8-56.5] years) throughout their treatment for DTC during euthyroidism ( n  = 5), severe hypothyroidism ( n  = 20), and THST ( n  = 20). We measured selected hemostatic proteins and C-reactive protein (CRP), performed functional tests of hemostasis (a thrombin generation test and a plasma-based clot lysis test), and assessed markers of in vivo activation of hemostasis (thrombin-antithrombin complexes, plasmin-antiplasmin [PAP] complexes, and D-dimer levels). Results: During hypothyroidism, the majority of measured parameters did not change. During THST, plasma levels of nearly all measured hemostatic proteins were higher than during hypothyroidism. Additionally, CRP significantly increased from 1.3 (0.5-3.3) to 3.2 (1.3-5.1) mg/L during THST ( p  < 0.01). Ex vivo thrombin generation increased from 626.0 (477.0-836.3) to 876.0 (699.0-1052.0) nM × min ( p  = 0.02), and ex vivo clot lysis time increased from 60.6 (55.6-67.4) to 76.0 (69.7-95.0) minutes during THST ( p  < 0.01). PAP levels reduced from 266.5 (211.8-312.0) to 192.0 (161.0-230.0) μg/L during THST ( p  < 0.01); other markers of in vivo activation of coagulation remained unaffected. Conclusions: During THST-induced hyperthyroidism, a shift toward a more hypercoagulable and hypofibrinolytic state occurred. However, in vivo activation of hemostasis did not increase. The rise in CRP levels suggests the presence of a low-grade inflammation in patients during THST. Both a hypercoagulable and hypofibrinolytic state and a low-grade inflammation are associated with an increased risk of cardiovascular diseases (CVD). Therefore, the subtle changes found during THST could potentially play a role in the pathogenesis of CVD as observed in DTC patients. Clinical Trial Registration: This study is part of a larger clinical trial registered at the Netherlands Trial Register (NTR ID 7228).

Objective: Management of hypothyroidism is controversial because of medication cost pressures and scientific uncertainty on how to address treatment dissatisfaction experienced by some patients. The objective was to investigate the experience and preferences of UK endocrinologists in use of thyroid hormones., Design: Web-based survey., Patients: UK endocrinologists were invited to participate., Measurements: Responses to questionnaire., Results: The response rate was 21% (272/1295). While levothyroxine monotherapy is regarded as the treatment of choice for hypothyroidism, 51% of respondents stated that combined treatment with levothyroxine and liothyronine could be considered for levothyroxine-treated patients whose symptoms persist despite normalisation of serum thyroid stimulating hormone (TSH) concentration. However, only 40% are currently prescribing such treatment, and just 23% would consider taking it themselves. A small minority prescribe desiccated thyroid extract, and those most likely to do so are aged over 60 years. Most respondents stated that they have no influence over brand or formulation of levothyroxine dispensed to their patients and expect no major differences in efficacy between different formulations. A total of 9% would prescribe levothyroxine for euthyroid enlarging goitre, and 29% for euthyroid female infertility with high titre thyroid peroxidase antibodies, despite recent trials finding no benefit., Conclusions: UK endocrine practice in management of hypothyroidism is broadly in line with international guidance. However, a minority of respondents would consider thyroid hormone supplementation in euthyroid individuals for female infertility, enlarging goitre, and other indications in which evidence of efficacy is lacking. Willingness to consider prescribing combined levothyroxine and liothyronine, for hypothyroid symptoms which persist despite normalised TSH, has increased in comparison to previous international surveys, despite inconsistent evidence of benefit., (© 2022 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

This retrospective study was designed to compare the treatment response of patients with differentiated thyroid cancer (DTC) prepared for radioiodine ablation (RIA) with thyroid hormone withdrawal (THW) or recombinant human thyrotropin (rhTSH) stimulation. Patients with DTC were followed-up retrospectively between 2013 and 2018 in Kaohsiung Chang Gung Memorial Hospital, Taiwan. We compared the excellent response ratios between THW (49.9%) and rhTSH (50.1%) stimulation. Patients were then divided into subgroups, on the basis of age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage, for analysis. In all, 647 patients were followed-up after RIA. The ratios of THW or rhTSH use in the different subgroups were not statistically significant. In all the patients, the excellent response rate with THW and rhTSH was 80% and 76.5%, respectively, which was not statistically significant. The subgroup analysis, including age, sex, extrathyroidal extension, lymph node metastasis, and tumor-node-metastasis stage (low and high risk), showed similar results. Furthermore, the logistic regression analysis revealed no statistically significant differences among the subgroups. The multivariate analysis showed extrathyroidal extension, lymph node metastasis, and high I 131 dose were the prognostic factors affecting the excellent response rate. In conclusion, the THW and rhTSH preparations for RIA were similar in terms of the excellent response rates and subgroup clinical outcomes., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: loss of skeletal muscle function, strength and mass is common in older adults, with important socioeconomic impacts. Subclinical hypothyroidism is common with increasing age and has been associated with reduced muscle strength. Yet, no randomized placebo-controlled trial (RCT) has investigated whether treatment of subclinical hypothyroidism affects muscle function and mass., Methods: this is an ancillary study within two RCTs conducted among adults aged ≥65 years with persistent subclinical hypothyroidism (thyrotropin (TSH) 4.60-19.99 mIU/l, normal free thyroxine). Participants received daily levothyroxine with TSH-guided dose adjustment or placebo and mock titration. Primary outcome was gait speed at final visit (median 18 months). Secondary outcomes were handgrip strength at 1-year follow-up and yearly change in muscle mass., Results: we included 267 participants from Switzerland and the Netherlands. Mean age was 77.5 years (range 65.1-97.1), 129 (48.3%) were women, and their mean baseline TSH was 6.36 mIU/l (standard deviation [SD] 1.9). At final visit, mean TSH was 3.8 mIU/l (SD 2.3) in the levothyroxine group and 5.1 mIU/l (SD 1.8, P < 0.05) in the placebo group. Compared to placebo, participants in the levothyroxine group had similar gait speed at final visit (adjusted between-group mean difference [MD] 0.01 m/s, 95% confidence interval [CI] -0.06 to 0.09), similar handgrip strength at one year (MD -1.22 kg, 95% CI -2.60 to 0.15) and similar yearly change in muscle mass (MD -0.15 m2, 95% CI -0.49 to 0.18)., Conclusions: in this ancillary analysis of two RCTs, treatment of subclinical hypothyroidism did not affect muscle function, strength and mass in individuals 65 years and older., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: Although Graves' disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe., Methods: A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions., Results: A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and β-blockers and adjunctive ATD-treatment during RAI in the APAC-group., Conclusion: Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The decision to pursue lobectomy versus total thyroidectomy is highly individualized. The rate of thyroid hormone replacement therapy after lobectomy varies considerably (15%-48%) and studies are limited by short-term follow-up. We sought to assess long-term thyroid hormone replacement therapy-requirement for lobectomy., Methods: Patients undergoing lobectomy from January 2005 to July 2010 at an academic institution were reviewed. Demographic, laboratory, pathology, and thyroid hormone replacement therapy use were compared., Results: In total, 235 patients were included. The rate of thyroid hormone replacement therapy after lobectomy was 46.8% (110/235). The majority were female (84.7%), with a mean age of 52 ± 1 years, 97% with benign pathology, and the median duration of follow-up was 7.2 years. Among the 110 thyroid hormone replacement therapy, the mean postoperative thyroid stimulating hormone level 9.08 ± 0.96m IU/L and the time to thyroid hormone replacement therapy-initiation was 621 days; 24% started therapy ≥2 years after surgery. There was no difference in age, sex, or malignancy. Hashimoto thyroiditis was diagnosed in 21.8% patients who underwent thyroid hormone replacement therapy versus 8.0% of those without thyroid hormone replacement therapy (odds ratio 3.2; 95% confidence interval, 1.43-6.79; P < .001). On multivariate analysis, only Hashimoto thyroiditis was independently associated with thyroid hormone replacement therapy use (odds ratio 2.88; 95% confidence interval, 1.3-6.6; P = .012)., Conclusion: With long-term follow-up, nearly 50% of patients who underwent lobectomy for benign disease required thyroid hormone replacement therapy and nearly one-quarter of these patients not starting until ≥2 years after surgery. Therefore, patients who undergo thyroid lobectomy should be counseled appropriately and thyroid function followed for a minimum of 2 years., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to conduct a systematic review and meta-analysis evaluating the role of thyroid hormone therapy in patients with heart failure and low-triiodothyronine syndrome., Methods: The electronic databases PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Science and Technology Journal Database, Wanfang Database, and China Biology Medicine disc were systematically searched to identify eligible studies published before November 27, 2021. The mean difference was pooled for randomized controlled trials using a random-effects model., Results: The meta-analysis showed that thyroid hormone treatment improved the left ventricular ejection fraction (weighted mean difference [WMD] 5.61, 95% confidence interval [CI]: 4.38 to 6.85, I 2  = 63.12%, P < 0.01). The cardiac output improved with thyroid hormone therapy (WMD 0.65, 95% CI: 0.42 to 0.89, I 2  = 84.28%, P < 0.01). The early-to-late diastolic transmitral flow velocity in the thyroid hormone group was also improved compared to the control group (WMD 0.29, 95% CI: 0.15 to 0.42, I 2  = 95.08%, P < 0.01). The left ventricular diastolic dysfunction was decreased with thyroid hormone treatment (WMD -5.17, 95% CI: -7.47 to -2.88, I 2  = 90.18%, P < 0.01). The brain natriuretic peptide decreased with thyroid hormone treatment (standardized mean difference -1.49, 95% CI: -2.15 to -0.84, I 2  = 90.18%, P < 0.01). Noradrenaline decreased with thyroid hormone therapy (WMD -349.86, 95% CI: -401.05 to -298.67, I 2  = 0%, P < 0.01). Free triiodothyronine increased with thyroid hormone treatment (standardized mean difference 2.18, 95% CI: 0.75 to 2.60, I 2  = 98.20%, P < 0.01)., Conclusion: This meta-analysis showed that thyroid hormone replacement therapy was effective in patients with heart failure and low-triiodothyronine syndrome., (Copyright © 2022. Published by Elsevier Inc.)

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3-4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.

Clinical hypothyroidism is defined by the inadequate production of thyroid hormone from the thyroid gland to maintain normal organ system functions. For nearly all patients with clinical hypothyroidism, lifelong treatment with thyroid hormone replacement is required. The primary goal of treatment is to provide the appropriate daily dose of thyroid hormone to restore normal thyroid function for each individual patient. In current clinical practice, normalization of thyrotropin (TSH) level is the primary measure of effectiveness of treatment, however the use of a single biomarker to define adequate thyroid hormone replacement is being reevaluated. The assessment of clinical health outcomes and patient-reported outcomes (PROs), often within the context of intensity of treatment as defined by thyroid function tests (i.e., undertreatment, appropriate treatment, or overtreatment), may play a role in evaluating the effectiveness of treatment. The purpose of this narrative review is to summarize the prominent health outcomes literature in patients with treated hypothyroidism. To date, overall mortality, cardiovascular morbidity and mortality, bone health and cognitive function have been evaluated as endpoints in clinical outcomes studies in patients with treated hypothyroidism. More recent investigations have sought to establish the relationships between these end results and thyroid function during the treatment course. In addition to clinical event outcomes, patient-reported quality of life (QoL) has also been considered in the assessment of adequacy of hypothyroidism treatment. From a health care quality perspective, treatment of hypothyroidism should be evaluated not just on its effectiveness for the individual patients but also to the extent to which patients of different sociodemographic groups are treated equally. Ultimately, more research is needed to explore differences in health outcomes between different sociodemographic groups with hypothyroidism. Future prospective studies of treated hypothyroidism that integrate biochemical testing, PROs, and end result clinical outcomes could provide a more complete picture into the effectiveness of treatment of hypothyroidism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor JJ declared a past co-authorship with the author ME., (Copyright © 2022 Ettleson and Papaleontiou.)

Objective: To investigate the effect of radioactive iodine therapy under thyroid hormone withdrawal in differentiated thyroid cancer patients on health-related quality of life., Methods: Patients who were diagnosed with differentiated thyroid cancer after thyroidectomy were involved in this study. All of them were managed with thyroid hormone withdrawal. Health-related quality of life was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and its thyroid cancer module at three different time points. Changes in health-related quality of life were evaluated by Wilcoxon and Kruskal-Wallis tests. Univariable logistic regression analysis was used to determine social-demographic and clinical factors associated with worse health-related quality of life., Results: A total of 99 differentiated thyroid cancer patients were involved in this study. Changes in health-related quality of life at different time points showed that 1 month post-radioactive iodine treatment, an improvement in nausea and vomiting, insomnia and appetite loss was observed. Impairments of global health, role, cognitive and social function and problems of discomfort in the head and neck, voice concerns, dry mouth, fatigue, pain, dyspnea, thyroid fatigue, fear, tingling or numbness, joint pain and shoulder function increased after radioactive iodine treatment. Univariable logistic regression analysis demonstrated potential factors associated with worse health-related quality of life. Thyroid stimulating hormone and parathyroid hormone levels were more sensible to changes in functional domain. Patients aged ≥55-year-old, with annual income under ¥50 000, low parathyroid hormone and pT4 tumour stage experienced higher changes in symptom scales after radioactive iodine treatment., Conclusion: After radioactive iodine treatment, differentiated thyroid cancer patients experienced negative health-related quality of life, and most of these impairments might not recover in the short term. Thyroid stimulating hormone and parathyroid hormone levels, annual income and pT tumours stage were independent risk factors for decreased health-related quality of life., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Primary hypothyroidism severely impacts the quality of life of patients through a decrease in the production of the thyroid hormones T3 and T4, leading to symptoms affecting cardiovascular, neurological, cognitive, and metabolic function. The incidence rate of primary hypothyroidism is expected to increase in the near future, partially due to increasing survival of patients that have undergone radiotherapy for head and neck cancer, which induces this disease in over half of those treated. The current standard of care encompasses thyroid hormone replacement therapy, traditionally in the form of synthetic T4. However, there is mounting evidence that this is unable to restore thyroid hormone signaling in all tissues due to often persistent symptoms. Additional complications are also present in the form of dosage difficulties, extensive drug interactions and poor patience compliance. The alternative therapeutic approach employed in the past is combination therapy, which consists of administration of both T3 and T4, either synthetic or in the form of desiccated thyroid extract. Here, issues are present regarding the lack of regulation concerning formulation and lack of data regarding safety and efficacy of these treatment methods. Tissue engineering and regenerative medicine have been applied in conjunction with each other to restore function of various tissues. Recently, these techniques have been adapted for thyroid tissue, primarily through the fabrication of regenerative scaffolds. Those currently under investigation are composed of either biopolymers or native decellularized extracellular matrix (dECM) in conjunction with either primary thyrocytes or stem cells which have undergone directed thyroid differentiation. Multiple of these scaffolds have successfully restored an athyroid phenotype in vivo . However, further work is needed until clinical translation can be achieved. This is proposed in the form of exploration and combination of materials used to fabricate these scaffolds, the addition of peptides which can aid restoration of tissue homeostasis and additional in vivo experimentation providing data on safety and efficacy of these implants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Heim, Nixon, Emmerson and Callanan.)

Purpose of Review: Among pregnant women on thyroid hormone replacement therapy undertreatment is common, while overtreatment is rare. Both deficient and excessive maternal thyroid hormone have been related to adverse maternofetal and long-term offspring outcomes, although studies' results are inconsistent. This review aims to discuss recent evidence regarding the effects of under- and overtreatment with thyroid hormone replacement during pregnancy and how current practices could be improved., Recent Findings: Whether or not thyroid hormone therapy needs to be initiated for maternal subclinical hypothyroidism remains unclear, but recent meta-analyses have confirmed associations between adverse maternal, neonatal, and offspring outcomes in both overt and subclinical hypothyroidism. Subclinical hyperthyroidism in pregnancy is related to fewer adverse outcomes. Current adherence to levothyroxine during pregnancy and medication counseling by healthcare providers are suboptimal., Summary: Undertreatment of maternal hypothyroidism may increase risks for adverse maternofetal and offspring effects more than overtreatment does. If thyroid hormone replacement therapy is indicated and initiated in pregnancy, frequent thyroid function monitoring is required to avoid under- or overtreatment. Effective communication between clinicians and patients is imperative to increase medication adherence., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

It is well known that ionizing radiation can induce genetic damage and that oxidative stress is a major factor inducing it. Our aim was to investigate whether thyroid remnant ablation with low activities of 131 I (1,850 MBq) is associated with DNA damage by evaluating the CometAssay, micronuclei, and chromosome aberrations with multicolor fluorescent in situ hybridization. Methods: We studied 62 patients prepared with recombinant human thyroid-stimulating hormone (rhTSH) or by thyroid hormone withdrawal. In both groups, we analyzed stable and unstable genetic alterations before 131 I therapy and 1 wk and 3 mo after 131 I administration. We also correlated the genetic damage with several variables, including the degree of radiation-induced oxidative stress, genetic polymorphisms of enzymes involved in DNA repair, and antioxidative stress. Results: We found a comparable amount of DNA breaks evaluated by CometAssay and micronuclei testing in both groups of patients at different time points, but there was a significant increase in stable chromosome aberrations evaluated by multicolor fluorescent in situ hybridization (breaks and translocations) in patients prepared with thyroid hormone withdrawal. Overall, high chromosome damage was associated with higher retained body radioactivity and unfavorable gene polymorphism. A high level of free oxygen radicals and a low level of antioxidants were found in all patients at any time point. In particular, patients prepared with thyroid hormone withdrawal, at 3 mo, had significantly higher levels of free oxygen radicals than those prepared with rhTSH. Conclusion: An increase in stable chromosome aberrations with respect to baseline is detectable after administration of low doses of 131 I in patients prepared with thyroid hormone withdrawal but not in patients prepared with rhTSH. The clinical significance of these chromosomal alterations remains to be determined., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: We designed a multicentre open prospective randomized trial to evaluate the risk-benefit profile of two different initial treatment schemes with levothyroxine (L-T4), 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, on growth and neurodevelopmental outcomes in children with congenital hypothyroidism (CH) detected by neonatal screening to identify the best range dose to achieve optimal neurocognitive development., Design Patients and Methods: Children detected by neonatal screening were randomly assigned to receive an initial L-T4 dose of 10-12.5 μg/kg/day (Low) or 12.6-15 μg/kg/day (High). All patients underwent periodical clinical examination with measurement of growth parameters and measurement of TSH and FT4. Neurocognitive development was evaluated at the age of 24 months using Griffiths Mental Development Scales (GMDS) and cognitive and behavioral assessment was performed at 48 months of age using Wechsler Preschool and Primary scale of Intelligence (WIPPSI-III). The study was registered with clinicaltrials.gov (NCT05371262)., Results: Treatment schemes below or above 12.5 μg/kg/day were both associated with rapid normalization of TSH and thyroid hormone levels in most patients with no differences in the risk of over- and under-treatment episodes in the first months of life. Growth parameters were normal and comparable between the two groups. Developmental quotients at 24 months of age were normal in both groups (Low 100.6 ± 15.5 vs High 96.9 ± 16.6). Likewise, at 4 years of age IQ and subtest scores were comparable between patients from Low and High (Total IQ 104.2 ± 11.4 vs 101.0 ± 20.3, Verbal IQ 103.9 ± 11.5 vs 98.7 ± 15.1, Performance IQ 105.3 ± 10.4 vs 100.3 ± 19.8). 6/45 CH patients (13.3%) showed a total IQ below 85 (73.7 ± 5.9) regardless of age at diagnosis, L-T4 starting dose, time of FT4 and TSH normalization and episodes of over and undertreatment. Worse socioeconomic status and delayed bone age at diagnosis were the only predictors of an increased risk of having suboptimal IQ at 24 and IQ at 48 months., Conclusions: Our results indicate that initial treatment with L-T4, 10-12.5 μg/kg/day vs 12.6-15 μg/kg/day, are both associated with normal growth and neurodevelopmental outcomes in children with CH detected by neonatal screening. Further studies with a long-term follow-up on a larger number of patients are needed to confirm these results., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05371262?term=NCT05371262&draw=2&rank=1 identifer NCT05371262., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Esposito, Vigone, Polizzi, Wasniewska, Cassio, Mussa, Gastaldi, Di Mase, Vincenzi, Pozzi, Peroni, Bravaccio, Capalbo, Bruzzese and Salerno.)