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Purpose: Patients undergoing head and neck cancer surgery after prior radiation or chemoradiation are at high risk for wound complications. Hypothyroidism is a known risk factor for wound complications, especially fistulae after salvage total laryngectomy. The purpose of this phase II clinical trial is to investigate the effect of perioperative intravenous levothyroxine supplementation on wound complications in patients undergoing salvage total laryngectomy., Patients and Methods: Euthyroid patients previously treated with radiation/chemoradiation undergoing total laryngectomy were prospectively recruited (n = 72). Postoperatively, intravenous levothyroxine was administered at a weight-based dose (1.3 mcg/kg/d) and transitioned to enteral dosing on day 7. Free T3, T4, and thyroid-stimulating hormones were collected, and dosing was adjusted accordingly. The primary endpoints were rates of fistula formation and fistula requiring reoperation, compared with matched historic controls. All patients were monitored for adverse effects., Results: The rate of postoperative hypothyroidism was 21% compared with 49% in a matched historic cohort. The rate of fistula formation was 18.1%, whereas the rate of fistula requiring reoperation was 4.2%, significantly lower than rates in our historic cohort (34.6% and 14.8%, respectively; P = 0.02 and 0.01). Postoperative hypothyroidism and recurrent clinical stage predicted fistula requiring reoperation in multivariate analysis; other acute phase reactants were not predictive. There were no observed adverse events related to levothyroxine supplementation., Conclusions: Postoperative intravenous levothyroxine supplementation reduced rates of acute hypothyroidism, fistula formation, and fistula requiring reoperation in patients undergoing salvage total laryngectomy without adverse effects. Intravenous levothyroxine is a viable strategy to reduce wound complications in this high-risk patient population., (©2024 American Association for Cancer Research.)

Amiodarone-induced thyrotoxicosis (AIT) is a common condition in patients who are receiving amiodarone for cardiac arrhythmia. This risk is elevated in iodine-deficient regions. Levothyroxine is the standard treatment for patients with hypothyroidism. This investigation is concerned with the evaluation of the possible pharmacokinetic interaction between amiodarone and levothyroxine upon co-therapy in rats and to investigate the cause of thyrotoxicosis. A selective, sensitive and precise RP-HPLC method was developed for the simultaneous determination of levothyroxine and amiodarone in rat plasma. A stationary phase of C18 Xterra RP column and a mobile phase consisting of acetonitrile: acidified water with 0.1% trifluoracetic acid (pH = 4.8) with gradient elution were used. The experiment was conducted at ambient temperature with flow rate of 1.5 mL/min for the chromatographic separation and quantitation of the investigated drugs. Protein precipitation with methanol was applied for the analysis of the two drugs in rat plasma. The method was linear over concentration range of 5-200 μg/mL for both levothyroxine and amiodarone. The European Medicines Agency guideline was applied for the validation of the developed bioanalytical method. The method was successfully applied to in vivo pharmacokinetic study in which levothyroxine and amiodarone were quantified in plasma of rats after receiving an oral dose of levothyroxine and amiodarone. After the calculation of the pharmacokinetic parameters, a statistical analysis was performed to elucidate the existence of significant difference between test and control groups in rats. The combination of levothyroxine and amiodarone significantly decreased levothyroxine bioavailability in rats, making the therapeutic drug monitoring mandatory in patients receiving levothyroxine and amiodarone. In addition, the increased clearance of levothyroxine upon the co-administration with amiodarone may explain the reported hypothyroidism., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction and Objective: The risk of seizure in offspring following prenatal exposure to levothyroxine is not well investigated. This study aimed to evaluate the association between levothyroxine treatment among pregnant women and the risk of seizure in their offspring., Methods: This population-based cohort study included all pregnant women who delivered a live birth between January 2001 to January 2018, with a follow-up to December 2020, using data from the Hong Kong Clinical Data Analysis and Reporting System. Propensity score fine-stratification weighted hazard ratios (wHR) with 95% confidence intervals (CIs) were presented to assess the association between maternal levothyroxine use during pregnancy and seizures in children., Results: Among 528,343 included mother-child pairs, 3044 children were prenatally exposed to levothyroxine at any time during the pregnancy period. A significantly increased risk of seizure was observed in children of the prenatally exposed group compared with the prenatally unexposed group (wHR 1.12, 95% CI 1.02-1.22). An increased risk of seizure was observed when comparing the prenatally exposed group with euthyroid mothers who had no history of thyroid-related diagnosis or prescriptions (wHR 1.12, 95% CI 1.02-1.23). However, no significant difference was observed between the prenatally exposed group and those previously exposed to levothyroxine but had stopped during pregnancy (wHR 0.97, 95% CI 0.66-1.44). No significant difference was observed in the sibling-matched analysis either (wHR 1.23, 95% CI 0.76-2.01)., Conclusion: The observed increased risk of seizure in children born from mothers exposed to levothyroxine during pregnancy might be due to residual confounding by maternal thyroid disease. The findings support the current guidelines on the safe use of levothyroxine treatment during pregnancy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

An excess of thyroid hormones in the blood characterizes hyperthyroidism. Long-term use of prescription medications to treat hyperthyroidism has substantial adverse effects and when discontinued, the symptoms frequently recur. Several plant species have been utilized to cure hyperthyroidism. In the present work, we investigated the impact of polyherbal extract (POH) of four medicinal plants to treat hyperthyroidism. Biochemical analysis revealed the presence of a high concentration of phytochemicals in the POHs. The in vitro antioxidant study revealed their antioxidant and free radical scavenging capacity. The gas chromatography coupled mass spectrometry analysis of the POHs showed the presence of 13 bioactive phytochemical compounds. The effect of various concentrations of POHs on L-thyroxine-induced hyperthyroidism in Wistar albino rats was evaluated for 18 days. The TSH, T3 and T4 levels increased significantly and reduced the increase of liver enzymes caused by hyperthyroidism in POH-treated rats. The data showed that POH therapy could restore thyroid function to normal. The injection of POH increased the size comprising vacuolated cells, columnar follicular cells and highly coloured nuclei with increasing POH content and the number of normal thyroid follicles rose. The findings indicate that polyherbal formulations of these medicinal plants include credible antithyroid compounds that may offer a protective and an effective alternative treatment to synthetic thyroid medications., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: We examined the association between levothyroxine use and longitudinal MRI biomarkers for thigh muscle mass and composition in at-risk participants for knee osteoarthritis (KOA) and their mediatory role in subsequent KOA incidence., Methods: Using the Osteoarthritis Initiative (OAI) data, we included the thighs and corresponding knees of participants at risk but without established radiographic KOA (baseline Kellgren-Lawrence grade (KL) < 2). Levothyroxine users were defined as self-reported use at all annual follow-up visits until the 4th year and were matched with levothyroxine non-users for potential confounders (KOA risk factors, comorbidities, and relevant medications covariates) using 1:2/3 propensity score (PS) matching. Using a previously developed and validated deep learning method for thigh segmentation, we assessed the association between levothyroxine use and 4-year longitudinal changes in muscle mass, including cross-sectional area (CSA) and muscle composition biomarkers including intra-MAT (within-muscle fat), contractile percentage (non-fat muscle CSA/total muscle CSA), and specific force (force per CSA). We further assessed whether levothyroxine use is associated with an 8-year risk of standard KOA radiographic (KL ≥ 2) and symptomatic incidence (incidence of radiographic KOA and pain on most of the days in the past 12 months). Finally, using a mediation analysis, we assessed whether the association between levothyroxine use and KOA incidence is mediated via muscle changes., Results: We included 1043 matched thighs/knees (266:777 levothyroxine users:non-users; average ± SD age: 61 ± 9 years, female/male: 4). Levothyroxine use was associated with decreased quadriceps CSAs (mean difference, 95%CI: - 16.06 mm 2 /year, - 26.70 to - 5.41) but not thigh muscles' composition (e.g., intra-MAT). Levothyroxine use was also associated with an increased 8-year risk of radiographic (hazard ratio (HR), 95%CI: 1.78, 1.15-2.75) and symptomatic KOA incidence (HR, 95%CI: 1.93, 1.19-3.13). Mediation analysis showed that a decrease in quadriceps mass (i.e., CSA) partially mediated the increased risk of KOA incidence associated with levothyroxine use., Conclusions: Our exploratory analyses suggest that levothyroxine use may be associated with loss of quadriceps muscle mass, which may also partially mediate the increased risk of subsequent KOA incidence. Study interpretation should consider underlying thyroid function as a potential confounder or effect modifier. Therefore, future studies are warranted to investigate the underlying thyroid function biomarkers for longitudinal changes in the thigh muscles., (© 2023. The Author(s).)

Medications are known to affect the thyroid physiology and are a known cause of hypothyroidism. There is an ever-growing list of medications that affect the thyroid by 1 or more mechanisms. Mifepristone is presently used for the treatment of mild autonomous cortisol secretion (MACS). Hypothyroidism is not a known side effect of this medication. We present a 71-year-old woman with newly diagnosed impaired fasting glucose, dyslipidemia, and osteopenia presenting with a 3-year history of unintentional 15-pound weight gain (despite exercise and a good diet) and increased anxiety. Her physical examination was pertinent for mild lower extremity edema, easy bruising, and skin thinning. Workup revealed adrenocorticotropic hormone (ACTH)-independent MACS from bilateral micronodular hyperplasia of the adrenals. Since she was not a surgical candidate, medical management with mifepristone was chosen. While on mifepristone, she complained of excessive fatigue, a workup done revealed new-onset hypothyroidism. Given her symptoms and bloodwork, she was started on levothyroxine. After stopping mifepristone, she was biochemically and clinically euthyroid and was eventually off levothyroxine. The mechanism by which mifepristone induces hypothyroidism is unknown. Except for a multicenter case series suggesting that mifepristone increases thyroid hormone requirements in patients with central hypothyroidism, to the best of our knowledge, the literature on euthyroid patients developing hypothyroidism secondary to mifepristone is scarce. In conclusion, while the hypothyroidism seems reversible our case highlights the importance of getting baseline thyroid function tests (TFTs) and repeating them while on the medication. Treatment of hypothyroidism is based on symptoms and bloodwork.

Both metformin and statins reduce thyroid antibody titers in individuals with Hashimoto thyroiditis. The present study compared the impact of low-grade systemic inflammation and insulin resistance on levothyroxine action in subjects with this disorder. The study included 3 groups of women with autoimmune subclinical hypothyroidism matched for thyroid antibody titers and hormone levels: patients receiving atorvastatin (group A) or metformin (group B) and statin- and metformin-naïve women (group C). Over the entire study period (6 months), all individuals received levothyroxine. Titers of thyroid antibodies, as well as concentrations of thyrotropin, free thyroid hormones, prolactin, lipids, glucose, insulin, high-sensitivity C-reactive protein (hsCRP), and 25-hydroxyvitamin D were assessed at baseline and 6 months later. At baseline, the study groups differed in plasma lipids, insulin sensitivity, and hsCRP. In all groups of patients, levothyroxine decreased thyroid antibody titers, reduced thyrotropin levels and increased free thyroid hormone levels. Treatment-induced changes in antibody titers and free thyroid hormone levels were strongest in group A, while the changes in thyrotropin were most pronounced in group B. The decrease in antibody titers correlated to a greater degree with hsCRP levels than with insulin sensitivity. The obtained results suggest that low-grade systemic inflammation is a more important factor determining the impact of levothyroxine on thyroid autoimmunity and thyroid hormone levels than insulin resistance., (© 2022, The American College of Clinical Pharmacology.)

Background: The influence of maternal levothyroxine treatment during pregnancy remains unclear. This study aimed to evaluate the associations of maternal levothyroxine treatment during pregnancy with the birth and neurodevelopmental outcomes in offspring., Methods: This population-based cohort study was conducted among pregnant women using the Hong Kong Clinical Data Analysis and Reporting System. Mother-child pairs in Hong Kong from 2001 to 2015 were included and children were followed up till 2020. We defined the exposure group as mothers who were exposed to levothyroxine during pregnancy. Preterm birth and small for gestational age (SGA) were included as birth outcomes. Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) were included as neurodevelopmental outcomes. Odds ratios (OR) or hazard ratios (HRs) with a 95% confidence interval (CI) were evaluated to assess the association of gestational levothyroxine use with offspring birth and neurodevelopmental outcomes respectively, using propensity score fine-stratification weighting and a Cox proportional hazards regression model., Results: Among 422,156 mother-child pairs, 2125 children were born from mothers exposed to levothyroxine during pregnancy. A significantly increased risk of preterm birth was observed in children with maternal levothyroxine exposure during pregnancy, when compared to mothers who had no history of thyroid-related diagnoses or prescriptions (weighted OR [wOR]: 1.22, 95% CI: 1.07, 1.39). Similarly, an increased risk of preterm birth was found among children of gestational levothyroxine users, when compared to children of mothers who had used levothyroxine before but stopped during pregnancy (wOR: 2.16, 95% CI: 1.09, 4.25). Sensitivity analysis, by excluding mothers exposed to psychotropic or antiepileptic medications before or during pregnancy, also indicated a similar increased risk of preterm birth regarding the gestational use of levothyroxine (wOR: 1.26, 95% CI: 1.10, 1.45). No significant association was observed for the risk of SGA, ADHD, and ASD., Conclusions: There is no evidence that gestational use of levothyroxine is associated with SGA, ADHD, or ASD in offspring. Gestational levothyroxine treatment is associated with a higher risk of preterm birth. Such risk might be confounded by the underlying maternal thyroid disease itself, however, we cannot completely exclude the possible effect of gestational L-T4 treatment on offspring preterm birth. Our findings provided support to the current guidelines on the cautious use of levothyroxine treatment during pregnancy., (© 2022. The Author(s).)

Hypothyroidism is a common health problem among elder women. However, conflicting results were observed regarding the association between levothyroxine treatment and osteoporosis risk. Therefore, the current study aimed to evaluate the effect of levothyroxine replacement therapy on osteoporosis risk in the Saudi population. This study was a matched case-control study conducted from June to August 2020. Data were extracted from the electronic medical records and included sociodemographic, clinical characteristics, comorbid conditions, levothyroxine replacement therapy dose, duration, concomitant therapy, and bone mineral density. Cases were matched with controls (1:1 basis) by age; the study included 256 cases and 256 controls. In the multivariate conditional logistic regression analysis, thyroxine use was independently associated with an increased likelihood of osteoporosis. Therefore levothyroxine use in elderly females was associated with an increased risk of osteoporosis, and hence, clinicians must be aware of the levothyroxine replacement therapy outcomes in postmenopausal females at risk of osteoporosis.

Hypothyroidism disturbs redox homeostasis and takes part in cardiovascular system dysfunction. Considering antioxidant and cardio-protective effects of PPAR-γ agonists including pioglitazone (POG) and rosiglitazone (RSG), the present study was aimed to determine the effect of POG or RSG on oxidants and antioxidants indexes in the heart and aorta tissues of Propylthiouracil (PTU)-induced hypothyroid rats., Materials and Methods: The animals were divided into six groups: (1) Control; (2) propylthiouracil (PTU), (3) PTU-POG 10, (4) PTU-POG 20, (5) PTU-RSG 2, and (6) PTU-RSG 4. Hypothyroidism was induced in rats by giving 0.05% propylthiouracil (PTU) in drinking water for 42 days. The rats of PTU-POG 10 and PTU-POG 20 groups received 10 and 20 mg/kg POG, respectively, besides PTU, and the rats of PTU-RSG 2 and PTU-RSG 4 groups received 2 and 4 mg/kg RSG, respectively, besides PTU. The animals were sacrificed, and the serum of the rats was collected to measure thyroxine level. The heart and aorta tissues were also removed for the measurement of biochemical oxidative stress markers., Results: Hypothyroidism was induced by PTU administration, which was indicated by lower serum thyroxine levels. Hypothyroidism also was accompanied by a decrease of catalase (CAT), superoxide dismutase (SOD) activities, and thiol concentration in the heart and aorta tissues while increased level of malondialdehyde (MDA). Interestingly, administration of POG or RSG dramatically reduced oxidative damage in the heart and aorta, as reflected by a decrease in MDA and increased activities of SOD, CAT, and thiol content., Conclusion: The results of this study showed that administration of POG or RSG decreased oxidative damage in the heart and aorta tissues induced by hypothyroidism in rats.

Thyroid gland has a key role in maintaining the body homeostasis. Thyroxine is the main hormone secreted from the thyroid gland, its effect being predominantly achieved after the intracellular conversion of thyroxine to triiodothyronine, which exhibits a higher affinity for the receptor complex, thus modifying gene expression of the target cells. Amiodarone is one of the most commonly used antiarrhythmics in the treatment of a broad spectrum of arrhythmias, usually tachyarrhythmias. Amiodarone contains a large proportion of iodine, which is, in addition to the intrinsic effect of the medication, the basis of the impact on thyroid function. It is believed that 15%-20% of patients treated with amiodarone develop some form of thyroid dysfunction. Amiodarone may cause amiodarone-induced hypothyroidism (AIH) or amiodarone-induced thyrotoxicosis (AIT). AIT is usually developed in the areas with too low uptake of iodine, while AIH is developed in the areas where there is a sufficient iodine uptake. Type 1 AIT is more common among patients with an underlying thyroid pathology, such as nodular goiter or Graves' (Basedow's) disease, while type 2 mostly develops in a previously healthy thyroid. AIH is more common in patients with previously diagnosed Hashimoto's thyroiditis. Combined types of the diseases have also been described. Patients treated with amiodarone should be monitored regularly, including laboratory testing and clinical examinations, to early detect any deviations in the functioning of the thyroid gland. Supplementary levothyroxine therapy is the basis of AIH treatment. In such cases, amiodarone therapy quite often need not be discontinued. Type 1 AIT is treated with thyrostatic agents, like any other type of thyrotoxicosis. If possible, the underlying amiodarone therapy should be discontinued. In contrast to type 1 AIT, the basic pathophysiological substrate of which is the increased synthesis and release of thyroid hormones, the basis of type 2 AIT is destructive thyroiditis caused by amiodarone, desethylamiodarone as its main metabolite, and an increased iodine uptake. Glucocorticoid therapy is the basis of treatment for this type of disease.

Following minor changes of excipients of Levothyrox®, the French Pharmacovigilance Database was overwhelmed by patients' spontaneous reports of adverse drug reactions associated with the new formula. After noticing that most of these reports differed from those related to other drugs, we aimed to characterize their features and compared them with spontaneous reports associated with other chronic treatments as comparators. We randomly sampled patient reports associated with either Levothyrox® new formula (n = 200) or comparator drugs (n = 200) from March 2017 till March 2018 from the National Pharmacovigilance Database. We evaluated the number of incriminated drugs and adverse drug reactions per report and verified whether they were "expected" or not according to the Summary of Product Characteristics. Levothyrox®-associated reports included, on average, more adverse drug reactions (8 ± 4) than comparators (2 ± 2, P < 0.01) and mentioned mostly one drug (98.5% of reports), whereas comparators mentioned two at least (P < 0.001). The quantitative distribution of adverse drug reactions per report differed quite significantly, appearing almost Gaussian for Levothyrox® whereas Poisson-like for comparators (P < 0.0001). Age did not differ significantly in the two groups (54.2 vs. 49.7, NS), but female predominated in Levothyrox® group (94.5%) as compared with comparators (60.8%, P < 0.001). A mere third of the Levothyrox®-associated adverse drug reactions were deemed "expected," versus two thirds for comparators (P < 0.001). The pattern of spontaneous reports associated with Levothyrox®, whether fueled by media or influenced by social networks, appears atypical, as compared with that of comparators. Such reports, by their abundance, may impair the automatic detection of relevant concomitant signals., (© 2022 Société Française de Pharmacologie et de Thérapeutique.)

Hypothyroidism affects up to 5% of the global population. Incidence increases with age and is more common in women and individuals with prolonged estrogen exposure when compared with people who have not been exposed to estrogen. Symptoms can develop slowly and often mimic symptoms of other disorders, including menstrual cycle abnormalities. Understanding risk factors and common presenting symptoms is important in providing high-quality primary and reproductive care. Diagnosis relies on simple-to-obtain, fairly inexpensive testing of thyroid-stimulating hormone (TSH) levels and confirmation with levels of thyroxine. Management of hypothyroidism usually involves monotherapy with levothyroxine taken on an empty stomach. There are 2 methods for beginning levothyroxine treatment, and outpatient primary care clinicians can use shared decision-making to determine the best initiation method for each individual. Follow-up involves regular assessment of levels of TSH and symptom relief. Although some patients may need referral for specialist treatment, the majority of individuals with hypothyroidism can be diagnosed and treated by their outpatient primary care providers., (© 2022 by the American College of Nurse-Midwives.)

Aims: Hypothyroxinaemia might be easily ignored, because attention is typically paid to individuals with elevated thyroid stimulating hormone (TSH). In this study, we aimed to evaluate the association of oxcarbazepine use as adjuvant for treatment of schizophrenia with hypothyroxinaemia and central set point of thyroid homeostasis., Methods: This retrospective cohort study was conducted in the Second Affiliated Hospital of Xinxiang Medical University. Inpatients with a diagnosis of schizophrenia admitted between January 2016 and October 2019 with normal thyroid function at admission were included. Oxcarbazepine use was the exposure measure. Newly developed hypothyroxinaemia was the primary outcome measure and parameters of thyroid homeostasis central set point as measured by TSH index and thyroid feedback quantile-based index (TFQI) were the secondary outcome measures., Results: In total, 1207 eligible patients were included. The occurrence of hypothyroxinaemia in patients who received oxcarbazepine was higher (35/107, 32.7%) than in those patients who did not (152/1099, 13.8%), with adjusted relative risk of 2.24 and 95% confidence interval of 1.57 and 3.17. Oxcarbazepine use was associated with greater reduction in TSH index (adjusted β -0.33 and 95% confidence interval -0.48, -0.19) and TFQI (adjusted β -0.24 and 95% confidence interval -0.31, -0.16)., Conclusion: Oxcarbazepine use was independently associated with increased risk of developing hypothyroxinaemia, and greater reduction in TSH index and TFQI, suggesting that impaired central set point of thyroid homeostasis might be involved in the mechanism of oxcarbazepine-induced hypothyroxinaemia., (© 2021 British Pharmacological Society.)

Background: In bipolar disorder (BD), depression is the most difficult-to-treat dimension and available evidence suggests that add-on supraphysiological doses of levothyroxine may be an effective augmenting agent., Aim: This systematic review has been conducted to evaluate the efficacy and safety of supraphysiologic doses of levothyroxine in bipolar depression in adults., Methods: After a comprehensive literature search on MEDLINE/PubMed, Scopus, Cochrane databases and International Clinical Trial Registry Platform (ICTRP), reviewers extracted data from eight relevant articles. PRISMA guidelines were followed in the selection, analysis and reporting of findings. Quality assessment was done using the risk of bias assessment and a random effects model was used to estimate effect size. Meta-analysis could not be done due to the lack of randomized, placebo-controlled trials and adequate data. A systematic review was done on eight studies and analysis on the pre-post change in Hamilton depression rating scale score (HDRS) was done for six studies., Results: The random model analysis of pooled effects showed a standardized mean difference of HDRS score by 2.62 (95% CI: 2.21-3.04; p  < 0.0001). The responder and remission rates were not significant as reported in one study. Markov chain analysis performed in one study revealed that patients in the levothyroxine group had a significantly greater increase in time in the euthymic state and a decrease in the mixed state. In most of the studies, levothyroxine therapy was well tolerated, with no serious adverse events., Conclusion: Add-on supraphysiological dose of levothyroxine has a potential role in attenuating depressive symptoms in bipolar depression, especially in therapy-resistant BD., Prospero Registration Number: CRD42020218456.

Background: Immunotherapy has revolutionized the treatment of solid malignancies, but is associated with endocrine-related adverse events. This study aims to dissect the natural course of immunotherapy-induced hypothyroidism and provide guidance regarding diagnosis and management in patients with and without pre-existing hypothyroidism., Methods: A retrospective analysis was conducted using patients who received immunotherapy between 2010-2019 within a multicenter hospital system. Participants were separated in three groups-those with pre-existing hypothyroidism, those who developed primary hypothyroidism and those with hypophysitis within a year of their first immunotherapy. Serial effects of immunotherapy on thyroid function tests (TFTs) and levothyroxine dosing were evaluated., Results: 822 patients were screened, with 85 determined to have pre-existing hypothyroidism, 48 de-novo primary hypothyroidism and 12 de-novo hypophysitis. All groups displayed fluctuations in TFTs around weeks 6-8 of treatment. In the pre-existing hypothyroidism group, the levothyroxine dose was higher at 54 weeks than at baseline with the difference showing a trend towards statistical significance (p=0.06). The observed mean levothyroxine dose was significantly lower than the mean calculated weight-based dose for all groups. This finding was most clinically significant for the de-novo hypophysitis group (mean difference: -58.3 mcg, p<0.0001). The mean 0.9 mcg/kg levothyroxine dose at week 54 for the de-novo hypophysitis group was statistically lower than the other groups (p=0.009)., Conclusion: It is reasonable to screen with TFTs every 4 weeks, and space out TFTs surveillance to every 12 weeks after week 20. Our findings suggest a more conservative approach for levothyroxine dosing in those developing de-novo hypothyroidism, especially hypophysitis, such as initiating at 0.9-1.2 mcg/kg., 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 Kristan, Toro-Tobon, Francis, Desale, Bikas, Jonklaas and Goyal.)

Context: Abnormal thyroid function after thyroidectomy and subsequent thyroid-stimulating hormone suppression can have detrimental effects on glucose homeostasis in patients with thyroid cancer., Objective: To investigate whether thyroidectomy increases the risk of type 2 diabetes in patients with thyroid cancer and to explore the association between levothyroxine dosage and type 2 diabetes risk., Methods: A retrospective population-based cohort study using the Korean National Health Insurance database. We included 36 377 thyroid cancer patients without known diabetes who underwent thyroidectomy between 2004 and 2013. Matched subjects with nonthyroid cancer were selected using 1:1 propensity score matching. The main outcome measure was newly developed type 2 diabetes mellitus., Results: Patients with thyroid cancer who underwent thyroidectomy had a higher risk of developing type 2 diabetes mellitus than the matched controls (hazard ratio [HR] 1.43, 95% CI 1.39-1.47). Among patients with thyroid cancer, when the second quartile group (in terms of the mean levothyroxine dosage; 101-127 μg/day) was considered the reference group, the risk of type 2 diabetes mellitus increased in the first quartile (<101 μg/day; HR 1.45, 95% CI 1.36-1.54) and fourth quartile groups (≥150 μg/day; HR 1.37, 95% CI 1.29-1.45); meanwhile, the risk decreased in the third quartile group (128-149 μg/day; HR 0.91, 95% CI 0.85-0.97)., Conclusion: Patients with thyroid cancer who underwent thyroidectomy were more likely to develop type 2 diabetes mellitus than the matched controls. There was a U-shaped dose-dependent relationship between the levothyroxine dosage and type 2 diabetes mellitus risk., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The current regulatory criterion for bioequivalence of narrow therapeutic index (NTI) drugs in the European Union requires that the 90% confidence interval for the ratio of the population geometric means of the test product compared with the reference for area under the plasma concentration-time curve (AUC), and in certain cases maximum plasma drug concentration (C max ), to be included within the tighter acceptance range of 90.00-111.11%. As a consequence, sponsors need to recruit a higher number of subjects to demonstrate bioequivalence and this may be seen as increasing the burden for the development of generics. This "one-size-fits-all" criterion is particularly questionable when the within-subject variability of the reference product is moderate to high. As an alternative, we propose a further refined statistical approach where the acceptance range is narrowed based on the within-subject variability of the reference product of the NTI drug, similar to the one used for widening the standard 80.00-125.00% acceptance range for highly variable drugs. The 80.00-125.00% acceptance range is narrowed, only if the within-subject variability is lower than 30%, down to the current NTI acceptance range of 90.00-111.11% when the within-subject variability is 13.93% or lower. Examples within the current European Medicines Agency list of NTI drugs show a considerable reduction in required sample size for drugs like tacrolimus and colchicine, where the predicted within-subject variability is 20-30%. In these cases, this approach is less sample size demanding without any expected increase in the therapeutic risks, since patients treated with reference products with moderate to high within-subject variability are frequently exposed to bioavailability differences larger than 10%., (© 2021 The Authors. Clinical Pharmacology & Therapeutics © 2021 American Society for Clinical Pharmacology and Therapeutics.)

Background: Thyroid disorders are among the most common metabolic disorders worldwide. Thyroid dysfunction affects salivary glands function, causing hyposalivation. It also provokes physiological and histological changes in parotid, submandibular, and in particular the sublingual gland., The Aim of This Work: The aim of this work was to clarify the histological and ultrastructural changes that occur in the parotid gland following carbimazole-induced hypothyroidism in adult male albino rats. The study also aims to investigate the possible protective role of L-thyroxin supplementation on the rat parotid glands after long and short duration of hypothyroidism., Material and Methods: Fifty-five adult male albino rats of Sprague Dawley strain; were divided into four groups and eleven subgroups, five rats each. G І received nothing. G П given normal saline orally daily. G Ш (medical Hypothyroidism, short duration - long duration - recovery group) given Carbimazole orally by gastric tube in a dose of 0.05 mg/kg daily for 3,6 successive weeks for group (a, b) and for 6 successive weeks then were left without any medication for another 3 weeks in recovery group c. G IV-b, c (L-Thyroxine supplemented group, short duration-long duration) given Carbimazole orally daily for 3,6 successive weeks then L-thyroxine was given orally in a dose of (10 μg/100 g/B.W) daily for another 3 successive weeks. Animals were sacrificed 24 hours after the last dose of Carbimazole in G III-a, b and 3 weeks after stoppage the drug in G III-c. Animals were sacrificed 24 hours after the last dose of L- Thyroxine in G IV-b, c. The parotid specimens were processed for histopathological examination by light and electron microscopy. The medically induced Hypothyroidism resulted in significant parotid gland damage which was more obvious with longer duration; as follow: a) most of the acini had irregular outlines and were widely separated with narrow lumen and cytoplasmic vacuoles. b) some acinar cells contained ill defined, irregular, pyknotic or hyperchromatic nuclei. c)Vascular changes: dilated and engorged with blood. d) the interlobular and striated ducts appeared disrupted and dilated. e) extravasated blood with cellular infiltration were seen in the interstitial space., In Conclusion: Thyroid hormones (THs) had a significant effect in protection of parotid gland against damage induced by carbimazole, as it preserved the normal histological architecture of the parotid gland. This beneficial effect of THs was mostly related to its antioxidant properties. The expression of BCL-2 has certain regularity in apoptosis after drug administration. Regulation of glandular atrophy and apoptosis are closely related. The molecular mechanism of the apoptosis of the gland is not clear, and further study is needed in the future.

Background: Levothyroxine sodium marketed in France was reformulated following a French National Agency for Medicines and Health Products Safety request for a more stringent potency specification. Despite previously established purity and bioequivalence of the new and old formulations, reports of adverse events substantially increased following reformulation. This analysis evaluated the nature and relevance of the medically confirmed safety reports., Methods: Spontaneous and solicited individual case safety reports in France were retrieved from 26 March 2015 to 30 June 2016 (old formulation) and 26 March 2017 to 30 June 2018 (new formulation). Rates of reports and adverse events were calculated for the overall patient population and for at-risk subgroups. Adverse events delineated by thyroid-stimulating hormone levels were evaluated., Results: A total of 295 and 42 775 reports for the old formulation and new formulation, respectively, were retrieved, with 149 and 5503 medically confirmed. The most common medically confirmed adverse events were consistent with the known safety profile of levothyroxine, with generally comparable rates between both formulations (range of differences, 1.8-4.1%). Most cases were not serious (old formulation, 65.8%; new formulation, 78.7%). Reporting rates were similar or higher for the old formulation within subgroups of at-risk patients. Nature/distributions of adverse events by thyroid-stimulating hormone levels as determined by both the marketing authorization holder of levothyroxine and the French National Agency for Medicines and Health Products Safety were similar., Conclusions: The new formulation safety profile aligns with the established profile of the old formulation of levothyroxine. The benefit-risk profile is unchanged, such that the benefits of using the new formulation in the approved indications outweigh the risks associated with the treatment., Competing Interests: H.L. has no conflict of interest to declare. C.C.-B. and K.M. are employees of the affiliate company Merck Santé S.A.S. in France. B.C. and S.H. are employees of Merck KGaA. J-L.W. discloses receipt of speaker honoraria and/or congress invitations from Genévrier, HAC Pharma, Merck, and Novartis., (Thieme. All rights reserved.)

Objectives: A new LT4 formulation (Euthyrox [LT4 NF]) was developed to meet new regulatory standards, and has replaced the older formulation (LT4 OF) in a number of countries. We evaluated the possibility of tolerability/safety concerns associated with the switch by analysing spontaneous adverse event (AE) reports before and after switching., Methods: We examined spontaneous reports of adverse events (AE) from 18 countries generated from individual case safety reports (ICSRs) submitted to the pharmaceutical sponsor's global safety database, over one year before/one year after the switch., Results: There was no clear pattern relating to the numbers of ICSRs received before and after the switch across the countries. ICSRs contained a total of 634 AE relating to thyroid imbalance (82 serious) with LT4 OF over the period of one year; 343 such AE (60 serious) were reported for LT4 NF. The most common thyroid imbalance AE for LT4 OF concerned hypothyroidism or hyperthyroidism, unspecified thyroid function test abnormalities, and dosing issues. More AE of any aetiology were reported for LT4 NF (5098) vs. LT4 OF (4439), although the number of serious AE was lower for LT4 NF vs. LT4 OF (457 and 580, respectively). Fatigue, dizziness, headache, palpitations, and nausea were among the most common AE reported for each formulation. The nature of AE was comparable between formulations., Conclusions: No new safety concerns arose concerning the updated LT4 formulation in the 18 countries. Careful counselling of patients and adherence to routine thyroid care is important.

Objective: Oral solution and tablet formulations of levothyroxine (L-T4) are both used in the treatment of congenital hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children., Design: The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age., Methods: Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (group D) or tablets (group T). Auxological parameters, thyroid-stimulating hormone (TSH) and free thyroxine (FT4) values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The developmental quotient (DQ) at 1 and 3 years of age was evaluated using Griffiths' Scale., Results: In this study, 254 children were enrolled among which 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (P = 0.002) and 1 month (P = 0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (P = 0.03). No statistical difference was detected between the median DQ; however, group D showed lower values in the language subscale at 12 months and in eye-hand coordination at 36 months., Conclusions: Both therapeutic strategies are effective in the treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects on cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.

Aim of the study : To assess the occurrence of cardiac arrhythmias caused by high doses of levothyroxine in patients with thyroid cancer with subclinical hyperthyroidism. Materials and Methods : This prospective study included 98 women divided into three groups according to plasma thyroid stimulating hormone (TSH) concentration: <0.1 µU/mL, 0.1-0.39 µU/mL, or 0.4-4.0 µU/mL (control group). All participants underwent laboratory tests and an electrocardiography (ECG) Holter test to assess their heart rate and the occurrence of arrhythmias. Statistical analysis assessed differences between groups in all clinical parameters and factors influencing the occurrence of arrhythmias. Results : There were no differences between groups in the maximum, average, or minimum heart rate or in the incidence of the studied cardiac arrhythmias. Heart rate in women with a TSH concentration of <0.1 µU/mL depended on age and the presence of arterial hypertension, and heart rate in women with a TSH concentration of 0.4-4.0 µU/mL depended on free triiodothyronine concentration and the presence of arterial hypertension; no relationship was identified for women with a TSH concentration of 0.1-0.39 µU/mL. One-way logistic regression analysis did not identify any factors influencing the occurrence of arrhythmias. Conclusions : While maintaining normal free triiodothyronine levels, the use of suppressive doses of levothyroxine after thyroidectomy for differentiated thyroid cancer does not induce clinically significant arrhythmias or affect average heart rate. None of the studied clinical parameters influenced the risk of arrhythmia.

Background: Brain death frequently induces hemodynamic instability and cardiac stunning. Impairments in cardiac performance are major contributors to hearts from otherwise eligible organ donors not being transplanted. Deficiencies in pituitary hormones (including thyroid-stimulating hormone) may contribute to hemodynamic instability, and replacement of thyroid hormone has been proposed as a means of improving stability and increasing hearts available for transplantation. Intravenous thyroxine is commonly used in donor management. However, small controlled trials have not been able to demonstrate efficacy., Methods: This multicenter study will involve organ procurement organizations (OPOs) across the country. A total of 800 heart-eligible brain-dead organ donors who require vasopressor support will be randomly assigned to intravenous thyroxine for at least 12 h or saline placebo. The primary study hypotheses are that thyroxine treatment will result in a higher proportion of hearts transplanted and that these hearts will have non-inferior function to hearts not treated with thyroxine. Additional outcome measures are the time to achieve hemodynamic stability (weaning off vasopressors) and improvement in cardiac ejection fraction on echocardiography., Discussion: This will be the largest randomized controlled study to evaluate the efficacy of thyroid hormone treatment in organ donor management. By collaborating across multiple OPOs, it will be able to enroll an adequate number of donors and be powered to definitively answer the critical question of whether intravenous thyroxine treatment increases hearts transplanted and/or provides hemodynamic benefits for donor management., Trial Registration: ClinicalTrials.gov NCT04415658 . Registered on June 4, 2020., (© 2021. The Author(s).)

Levothyroxine (LT4) is used to treat frequently encountered endocrinopathies such as thyroid diseases. It is regularly used in clinical (overt) hypothyroidism cases and subclinical (latent) hypothyroidism cases in the last decade. Suppressive LT4 therapy is also part of the medical regimen used to manage thyroid malignancies after a thyroidectomy. LT4 treatment possesses dual effects: substituting new-onset thyroid hormone deficiency and suppressing the local and distant malignancy spreading in cancer. It is the practice to administer LT4 in less-than-high suppressive doses for growth control of thyroid nodules and goiter, even in patients with preserved thyroid function. Despite its approved safety for clinical use, LT4 can sometimes induce side-effects, more often recorded with patients under treatment with LT4 suppressive doses than in unintentionally LT4-overdosed patients. Cardiac arrhythmias and the deterioration of osteoporosis are the most frequently documented side-effects of LT4 therapy. It also lowers the threshold for the onset or aggravation of cardiac arrhythmias for patients with pre-existing heart diseases. To improve the quality of life in LT4-substituted patients, clinicians often prescribe higher doses of LT4 to reach low normal TSH levels to achieve cellular euthyroidism. In such circumstances, the risk of cardiac arrhythmias, particularly atrial fibrillation, increases, and the combined use of LT4 and triiodothyronine further complicates such risk. This review summarizes the relevant available data related to LT4 suppressive treatment and the associated risk of cardiac arrhythmia., 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 © 2021 Gluvic, Obradovic, Stewart, Essack, Pitt, Samardzic, Soskic, Gojobori and Isenovic.)

Background/aim: Thyroid lobectomy may cause post-lobectomy hypothyroidism. We investigated the difference in levothyroxine (LT4) supplementation and cessation between patients with benign disease and those with papillary thyroid carcinoma (PTC) and found that the rate of LT4 cessation could be decreased after thyroid-stimulating hormone (TSH) suppression in PTC., Patients and Methods: We retrospectively reviewed 88 patients with benign tumor and 463 patients with PTC and investigated the risk factors for LT4 supplementation after thyroid lobectomy., Results: During the median follow-up of 73.0 months, 207 (37.6%) patients maintained the euthyroid state, while 344 (62.4%) patients continued LT4 supplementation for LT4 replacement or TSH suppression. In patients with benign tumors, only high pre-TSH level (>1.98 mIU/l) was a significant risk factor (odds ratio [OR]=10.09). However, in patients with PTC, pre-TSH level ≥1.98 mIU/l (OR=3.28), pregnancy planning (OR=2.97), and age ≥42.5 years (OR=1.94) were significant risk factors. Moreover, the most potent risk factor was tumor aggressiveness (OR=4.00), which was found to be more significant than high pre-TSH. The overall rate of LT4 cessation in all patients was 37.6%; however, in the 303 patients who underwent the LT4-Off trial, there was no difference in the rate in the benign tumor, low-risk PTC, and intermediate-risk PTC groups (66.2%, 68.8%, and 70.8%, respectively; p=0.886)., Conclusion: When post-lobectomy TSH levels were adequate and the risk of recurrence was reduced, LT4 cessation in PTC could be achieved at the same rate as that in benign tumors, regardless of the duration of TSH suppression., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The aim of the current prospective randomized control study was to assess efficacy, safety, and non-inferiority of a new liquid L-thyroxine formulation dissolved in glycerol and water (T4 ® drops, produced by a Greek pharmaceutical Company, Uni-Pharma, Athens, Greece) in comparison to the standard Tablets form (T4 ® tablets, Uni-Pharma, Athens, Greece) in the substitutive treatment of children with congenital hypothyroidism (CH)., Methods: Thirty-nine children with CH, aged 3-12 years old, were enrolled in the study, after parental Informed Consent has been obtained, while three patients were lost from follow-up. At baseline, all participants had normal thyroid-stimulating hormone (TSH) and Free T4 values. Patients were randomly subdivided according to the assigned treatment in Group A (n=17)-Tablet Form and Group B (n=19)-Liquid Form. TSH and Free T4 levels were evaluated at 0, 2, 4, and 6 months., Results: TSH values showed a statistically significant difference (p=0.017) between groups only at six months (Group A having higher TSH levels than Group B, albeit within the normal range), while Free T4 levels had no statistical difference throughout the six month study period and were always within the normal range. Moreover, dose adjustments were more frequent in Group A (p=0.038) during the six months. Liquid L-thyroxine substitutive treatment exhibited no statistically significant adverse effects in comparison to the widely used tablets., Conclusions: Levothyroxine (LT4) as liquid solution formulation is safe and noninferior to the widely used L-thyroxine Tablets, with less need for dose adjustment, and can therefore be safely used in the treatment of children with CH., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Introduction: Thyrotropin stimulating hormone (TSH) suppression in patients with differentiated thyroid cancer (DTC) aims to decrease the growth and proliferation of thyroid cancer cells. However, the effect of TSH-suppressive therapy on bone microarchitecture remains undefined., Methods: Cross-sectional study including 43 women with DTC undergoing TSH-suppressive therapy (sTSH) compared to 20 women also on levothyroxine (LT4) therapy but with TSH in the low-normal range (nTSH) since the thyroid surgery. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA), and trabecular bone score (TBS) was evaluated using the TBS iNsigth software. Fracture risk assessed by FRAX, with and without TBS, was calculated. The relationship between suppressive therapy-related parameters and bone parameters was investigated., Results: The TBS mean values were not significantly different in the sTSH and nTSH groups (1.273 ± 0.12 vs 1.307 ± 0.14, p = 0.7197). In both groups, postmenopausal women had degraded microarchitecture (TBS 1.216 ± 0.11 vs 1.213 ± 0.09, p = 0.9333), while premenopausal women had normal microarchitecture (1.328 ± 0.11 vs 1.401 ± 0.12, p = 0.195). The percentage of all postmenopausal women with degraded TBS was 54.7%, while the percentage of osteoporosis diagnoses was 16.1%. The TBS-adjusted FRAX-probability of fracture was similar in sTSH and nTSH groups. Body mass index (BMI) and menopausal status were the only variables associated with TBS and BMD., Conclusion: Trabecular microarchitecture assessed by TBS was similar between women on long-term suppressive therapy in DTC and those on LT4 replacement therapy aiming at a TSH level within the low-normal reference range. Low TBS values were observed in postmenopausal women of both groups, suggesting that not only suppressed TSH levels but also a low-normal TSH is associated with deteriorated bone microarchitecture in postmenopausal women following total thyroidectomy., (© 2021. Italian Society of Endocrinology (SIE).)

In differentiated thyroid cancer (DTC), the standard treatment includes total thyroidectomy and lifetime levothyroxine (LT4) replacement. However, long-term exogenous LT4 has become controversial due to the adverse effects of oversuppression. The study included 191 patients (aged 18-76 years) with a prospective diagnosis of non-metastatic DTC and 79 healthy individuals. The patients with DTC were stratified into three groups according to their TSH levels: suppressed thyrotropin if TSH was below 0.1 μIU/ml, mildly suppressed thyrotropin if TSH was between 0.11 and 0.49 μIU/ml, and low-normal thyrotropin if THS was between 0.5 and 2 μIU/ml. The Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Anxiety Sensitivity Index (ASI), Short Symptom Inventory (SSI), and Pittsburgh Sleep Quality Index (PSQI) were administered to all participants. It was found that the BDI, BAI, SSI and PSQI scores were worse in patients with DTC (p=0.024, p=0.014, p=0.012, and p=0.001, respectively). According to theTSH levels, the mean ASI was found to be higher in the suppressed and mildly suppressed thyrotropin groups (19±14.4 vs. 10.6±11.1; 16.4±14.9 vs. 10.6±11.1, p=0.024, respectively), the mean SSI was found higher in the suppressed group (61.0±55.5 vs. 35.1±37.0, p=0.046), and the mean PSQI was higher in all three groups (7.94±3.97 vs. 5.35±4.13; 7.21±4.59 vs. 5.35±4.13; 7.13±4.62 vs. 5.35±4.13, p=0.006) when compared with the controls. No significant difference was found between the groups. A positive correlation was detected in the duration of LT4 use and BDI and SSI, and a weak, negative correlation was detected between TSH levels and ASI and PSQI. Based on our study, it was found that depression, anxiety disorders, and sleep problems were more prevalent in patients with DTC, being more prominent in the suppressed TSH group. These results were inversely correlated with TSH values and positively correlated with the duration of LT4 use. Unnecessary LT4 oversuppression should be avoided in patients with DTC., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Thyroid hormone (TH) metabolism and cellular TH action are influenced by ageing. To investigate the response to thyroxine (T4) overtreatment, a kinetic study was conducted in young and aged mice with chronic hyperthyroidism and hormone withdrawal. Five and 22 months old male mice were treated with T4 or PBS over 5 weeks, followed by observation for up to 12 days. Serial analysis was performed for thyroid function parameters, transcript levels of TH target genes, deiodinase type 1 (DIO1) activity as well as serum lipids at 12, 24, 72, 144, 216, and 288 h after cessation of T4 administration. Higher FT3 concentrations and higher renal DIO1 activities were noted in aged mice 12 h after T4 withdrawal and marked thyroid-stimulating hormone elevation was found in aged mice after 12 days compared to respective controls. A biphasic expression pattern occurred for TH target genes in all organs and a hypothyroid organ state was observed at the end of the study, despite normalization of TH serum concentrations after 72 h. In line with this, mirror-image kinetics were detected for serum cholesterol and triglycerides in aged and young mice. Recovery from TH overtreatment in mice involves short- and medium-term adaption of TH metabolism on systemic and organ levels. Increased renal DIO1 activity may contribute to higher T3 concentrations and prolonged thyrotoxicosis followed by hypothyroidism in an aged-mouse organism. Translation of these findings in the clinical setting seems warranted and may lead to better management of hyperthyroidism and prevention of T4 overtreatment in aged patients.

Objective: Initial high-dose sodium levothyroxine (Na-LT 4 ) (10-15 μg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT 4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT 4 on serum thyroid hormone levels., Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT 4 ) levels. Time taken to achieve target hormone levels was compared within groups., Results: Initial mean Na-LT 4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 μg/kg/day. Serum fT 4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT 4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT 4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016)., Conclusion: Not all patients diagnosed with CH require high-dose Na-LT 4 . Initial dose of Na-LT 4 may be selected on the basis of pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Objective: The pharmacological additional information for many medications includes warnings stating that the blood sugar control may be worsened by the intake of certain drugs. However a quantification of the effects is missing. This may result in confusion for patients as well as for their physicians. The aim of this study was to assess a potential association between medication (beta blockers, thiazides, levothyroxine) and HbA 1c in people without diabetes., Methods: In this cross-sectional study we analysed data from 2 921 people (7 699 visits) without diabetes (age 46.6 y; 69.1% women; BMI 27.6±6.4 kg/m²; HbA 1c 5.2%) who had at least one HbA 1c determination and a complete documentation of their drug intake. An oral glucose tolerance test was not performed. The participants were divided in 8 groups (no regular drug intake, levothyroxine alone, beta blockers alone, thiazides alone, combination 2 of 3, combination of all 3). Patients with known distorting influences of the HbA 1c were excluded., Results: People with no regular drug intake had an HbA 1c of 5.4% [35.8 mmol/mol]. The HbA 1c of the group that took all 3 drugs in combination was 5.6% [38.2 mmol/mol]. A multiple linear mixed model showed an increase in HbA 1c for thiazides (β=0.0558, p=0.025) and a decrease for combination of levothyroxine and thiazide (β=-0.0765, p=0.010)., Conclusion: Thiazides and the combination of levothyroxine and thiazides were associated with slight changes in HbA 1c . In this study there was no association between the intake of beta blockers and HbA 1c. At least for people without diabetes these effects seem to be of minor importance., Competing Interests: J Roth received a research support from Tosoh Bioscience in 2014. The other authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Levothyroxine is a widely prescribed medication for the treatment of an underactive thyroid. The relationship between levothyroxine use and cancer risk is largely underdetermined. To investigate the magnitude of the possible association between levothyroxine use and cancer risk, this retrospective case-control study was conducted using Taiwan's Health and Welfare Data Science Center database. Cases were defined as all patients who were aged ≥20 years and had a first-time diagnosis for cancer at any site for the period between 2001 and 2011. Multivariable conditional logistic regression models were used to calculate an adjusted odds ratio (AOR) to reduce potential confounding factors. A total of 601 733 cases and 2 406 932 controls were included in the current study. Levothyroxine users showed a 50% higher risk of cancer at any site (AOR: 1.50, 95% CI: 1.46-1.54; P < .0001) compared with non-users. Significant increased risks were also observed for brain cancer (AOR: 1.90, 95% CI: 1.48-2.44; P < .0001), skin cancer (AOR: 1.42, 95% CI: 1.17-1.72; P < .0001), pancreatic cancer (AOR: 1.27, 95% CI: 1.01-1.60; P = .03), and female breast cancer (AOR: 1.24, 95% CI: 1.15-1.33; P < .0001). Our study results showed that levothyroxine use was significantly associated with an increased risk of cancer, particularly brain, skin, pancreatic, and female breast cancers. Levothyroxine remains a highly effective therapy for hypothyroidism; therefore, physicians should carefully consider levothyroxine therapy and monitor patients' condition to avoid negative outcomes. Additional studies are needed to confirm these findings and to evaluate the potential biological mechanisms., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD)., Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH., Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age., Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age., Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+)., Competing Interests: SM reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. RP reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. DS reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. NR reported receiving grants from the Swiss National Science Foundation and the Velux Foundation during the conduct of the study. KP reported receiving grants from Netherlands Organisation for Health Research and Development (ZonMw) and the European Union FP7-HEALTH-2011 programme during the conduct of the study. T-HC reported receiving grants from the Swiss National Science Foundation during the conduct of the study. JG reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. 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., (Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.)

Clinical hypothyroidism affects one in 300 people in the United States, with a higher prevalence among female and older patients. Symptoms range from minimal to life-threatening (myxedema coma); more common symptoms include cold intolerance, fatigue, weight gain, dry skin, constipation, and voice changes. The signs and symptoms that suggest thyroid dysfunction are nonspecific and nondiagnostic, especially early in disease presentation; therefore, a diagnosis is based on blood levels of thyroid-stimulating hormone and free thyroxine. There is no evidence that population screening is beneficial. Symptom relief and normalized thyroid-stimulating hormone levels are achieved with levothyroxine replacement therapy, started at 1.5 to 1.8 mcg per kg per day. Adding triiodothyronine is not recommended, even in patients with persistent symptoms and normal levels of thyroid-stimulating hormone. Patients older than 60 years or with known or suspected ischemic heart disease should start at a lower dosage of levothyroxine (12.5 to 50 mcg per day). Women with hypothyroidism who become pregnant should increase their weekly dosage by 30% up to nine doses per week (i.e., take one extra dose twice per week), followed by monthly evaluation and management. Patients with persistent symptoms after adequate levothyroxine dosing should be reassessed for other causes or the need for referral. Early recognition of myxedema coma and appropriate treatment is essential. Most patients with subclinical hypothyroidism do not benefit from treatment unless the thyroid-stimulating hormone level is greater than 10 mIU per L or the thyroid peroxidase antibody is elevated.

Background: The use of prescribed medications during pregnancy is a challenge and an underestimated source of treatment burden. Levothyroxine (LT4) for the treatment of overt and subclinical hypothyroidism is extensively prescribed during pregnancy. To this end, we aimed to explore the patients' perceived benefits and risks, knowledge, beliefs, attitudes, and related burden of LT4 therapy during pregnancy. Methods: In this cross-sectional study, we surveyed pregnant women who were treated with LT4 during pregnancy from January 1, 2019, to December 31, 2019, in a tertiary academic medical center of the United States. The anonymous online survey included questions to gather demographic data and multiple-choice questions regarding the benefits and risks, knowledge, beliefs, attitudes, and burden related to LT4 use during pregnancy. Results: Sixty-four pregnant women (mean age 31.5 years) completed the study survey (response rate: 96%): 62% were diagnosed with hypothyroidism more than 12 months before pregnancy, 16% less than or about 12 months before pregnancy, and 22% during pregnancy. We found that one-third of pregnant women using LT4 had a feeling of uneasiness/anxiety due to their hypothyroidism diagnosis. About half of the respondents (45%) reported that they did not receive an explanation by their clinician regarding the maternal/fetal risks of uncontrolled hypothyroidism or the benefits of adequate control. Finally, two in three patients expressed various concerns of LT4-related treatment burden. Conclusions: Our findings support the need for increased effective communication and tailored counseling to address fears, anxiety, and uncertainties about the benefits and risks of LT4 use in pregnancy. For patients with clear benefits from LT4 treatment in pregnancy, it could help to overcome their concerns, promote adherence, and decrease adverse maternal/fetal outcomes. For patients with no clear benefits established, clinicians need to be aware of LT4-related treatment burden in pregnancy and implement patient-centered approaches in their clinical practices.

Levothyroxine (L-T4) treatment of overt hypothyroidism can be more challenging in elderly compared to young patients. The elderly population is growing, and increasing incidence and prevalence of hypothyroidism with age are observed globally. Elderly people have more comorbidities compared to young patients, complicating correct diagnosis and management of hypothyroidism. Most importantly, cardiovascular complications compromise the usual start dosage and upward titration of L-T4 due to higher risk of decompensating cardiac ischemia and -function. It therefore takes more effort and care from the clinician, and the maintenance dose may have to be lower in order to avoid a cardiac incidence. On the other hand, L-T4 has a beneficial effect on cardiac function by increasing performance. The clinical challenge should not prevent treating with L-T4 should the patient develop e.g., cardiac ischemia. The endocrinologist is obliged to collaborate with the cardiologist on prophylactic cardiac measures by invasive cardiac surgery or medical therapy against cardiac ischemic angina. This usually allows subsequent successful treatment. Management of mild (subclinical) hypothyroidism is even more complex. Prevalent comorbidities in the elderly complicate correct diagnosis, since many concomitant morbidities can result in non-thyroidal illness, resembling mild hypothyroidism both clinically and biochemically. The diagnosis is further complicated as methods for measuring thyroid function (thyrotropin and thyroxine) vary immensely according to methodology and background population. It is thus imperative to ensure a correct diagnosis by etiology (e.g., autoimmunity) before deciding to treat. Even then, there is controversy regarding whether or not treatment of such mild forms of hypothyroidism in elderly will improve mortality, morbidity, and quality of life. This should be studied in large cohorts of patients in long-term placebo-controlled trials with clinically relevant outcomes. Other cases of hypothyroidism, e.g., medications, iodine overload or hypothalamus-pituitary-hypothyroidism, each pose specific challenges to management of hypothyroidism; these cases are also more frequent in the elderly. Finally, adherence to treatment is generally challenging. This is also the case in elderly patients, which may necessitate measuring thyroid hormones at individually tailored intervals, which is important to avoid over-treatment with increased risk of cardiac morbidity and mortality, osteoporosis, cognitive dysfunction, and muscle deficiency., 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 © 2021 Effraimidis, Watt and Feldt-Rasmussen.)

Background: Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. Methods: The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Results: Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 μg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. Discussion: This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.

Background: Levothyroxine (LT4) as a medication is used by up to 5.3% of the adult population. For optimal efficacy, the traditional tablet formulation (LT4tab) requires that patients avoid concomitant ingestion with food, drinks, and certain medications, as well as excellent patient compliance. Some comorbidities influence bioavailability of LT4 and may mandate repeated dose adjustments. Summary: New LT4 formulations (soft gel [LT4soft] and liquid [LT4liq]) containing predissolved LT4 are claimed to improve bioavailability, presumably by facilitating absorption. Thus, these formulations may well be more suitable than LT4tab for patients whose daily requirements are subjected to variations in bioavailability. Here, we review the evidence and indications for use of new LT4 formulations and highlight areas of uncertainty that are worthy of further investigation. While bioequivalence is established for LT4soft and LT4liq administered to healthy volunteers compared with LT4tab in pharmacokinetic (PK) studies, therapeutic equivalence of the new formulations seems to be different in several clinical settings. Some evidence suggests that new formulations of LT4 may mitigate against the strict requirements relating to concomitant ingestion with food, drinks, and certain medications, which apply to traditional LT4 tablets. The principal indication is in selected patients with disease fluctuations and intermittent therapies with interfering medications, where the need for frequent dose adjustments and office visits may be diminished. Whether the use of LT4soft or LT4liq in patients with impaired gastric acid secretion results in better control of hypothyroidism than LT4tab remains unclear. Conclusions: The evidence in favor of using LT4soft and LT4liq in clinical practice over LT4tab is weak, and the underlying putative PK mechanisms unclear. Additional studies to investigate these potential benefits, define the cost-effectiveness, and understand the PK mechanisms involved with new LT4 formulations are needed.

Objective: To conduct a systematic review of the association of levothyroxine treatment with pregnancy outcomes in euthyroid women who are thyroid autoantibody positive. Methods: Medline, Excerpta Medica (EMBASE), Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Wanfang data and VIP database were searched from inception until Jan. 28, 2020. All published randomized controlled trials assessing the association of levothyroxine treatment with pregnancy outcomes in euthyroid women with thyroid autoantibody-positive were included. STATA 11.0 and RevMan 5.3 softwares were used to perform this Meta-analysis. Results: A total of 6 studies met the inclusion criteria, with 2 188 women randomized. Meta-analysis showed that there was no significantly association between miscarriage ( OR =0.85, 95% CI : 0.65-1.11, P =0.234) and preterm birth ( OR =0.79, 95% CI : 0.54-1.16, P =0.224) with levothyroxine treatment. Conclusions: Levothyroxine therapy could not reduce the risk of miscarriage and preterm birth in euthyroid women with thyroid autoantibody-positive. Therefore, levothyroxine should be used with caution for these pregnant women.

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil-based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3-19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9-6.2), 49.6 ng/mL (14.4-302.0), and 226.3 ng ⋅ h/mL (70.5-861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine-CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring., (© 2020 International League Against Epilepsy.)

Background: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2 (-/-) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-β ( THRB ) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 ( SECISBP2 ), and THRB were fully sequenced. Results: Eighteen hypothyroid patients (nine of each sex, 3-59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8 ± 2.4 pM; RR: 9-20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03-0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 μg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3-15.3 and 2.5 ± 1.4, RR: 7.5-8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.

Drugs are being prescribed with more frequency and in higher quantities. A serious adverse drug event from prescribed medications constitutes 2.4% to 16.2% of all hospital admissions. Many of the adverse drug events present intraorally or periorally in isolation or as a clinical symptom of a systemic effect. Clinical recognition and treatment of adverse drug events are important to increase patient adherence, manage drug therapy, or detect early signs of potentially serious outcomes. Oral manifestations of commonly prescribed medications include gingival enlargement, oral hyperpigmentation, oral hypersensitivity reaction, medication-related osteonecrosis, xerostomia, and other oral or perioral conditions. To prevent dose-dependent adverse drug reactions, physicians should prescribe medications judiciously using the lowest effective dose with minimal duration. Alternatively, for oral hypersensitivity reactions that are not dose dependent, quick recognition of clinical symptoms associated with time-dependent drug onset can allow for immediate discontinuation of the medication without discontinuation of other medications. Physicians can manage oral adverse drug events in the office through oral hygiene instructions for gingival enlargement, medication discontinuation for oral pigmentation, and prescription of higher fluoride toothpastes for xerostomia.

Objective: To evaluate the causes behind the association between hypothyroidism and the risk of preeclampsia., Methods: Checking of individual hospital and birth records from 149 levothyroxine users among 2,508 women in the preeclampsia case-control study (2002-2016)., Results: There were significant association between levothyroxine medication and preeclampsia (OR 1.48, 95 th CI 1.06-2.07; p ≤ 0.022). The presence of comorbid diseases was associated with a significantly higher risk for the development of preeclampsia in women using levothyroxine., Conclusion: Levothyroxine use during pregnancy was associated with 1.5-times higher risk for preeclampsia, but it is also linked to the other comorbid risk factors.

Topical hormone therapy with natural or synthetic ligands of nuclear hormone receptors such as glucocorticoids, vitamin D analogues and retinoids has a long and highly successful tradition in dermatology. Yet the dermatological potential of thyroid hormone receptor (TR) agonists has been widely ignored, despite abundant clinical, cell and molecular biology, mouse in vivo, and human skin and hair follicle organ culture data documenting a role of TR-mediated signalling in skin physiology and pathology. Here, we review this evidence, with emphasis on wound healing and hair growth, and specifically highlight the therapeutic potential of repurposing topical L-thyroxine (T4) for selected applications in future dermatological therapy. We underscore the known systemic safety and efficacy profile of T4 in clinical medicine, and the well-documented impact of thyroid hormones on, for example, human epidermal and hair follicle physiology, hair follicle epithelial stem cells and pigmentation, keratin expression, mitochondrial energy metabolism and wound healing. On this background, we argue that short-term topical T4 treatment deserves careful further preclinical and clinical exploration for repurposing as a low-cost, effective and widely available dermatotherapeutic, namely in the management of skin ulcers and telogen effluvium, and that its predictable adverse effects are well-manageable., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Conflicting results has been reported regard osteoporosis and fractures in patients with Differentiated Thyroid Cancer (DTC). Our objective was to evaluate the long-term effects of TSH suppression therapy with Levothyroxine (LT4) on trabecular bone score (TBS) and bone mineral density (BMD) in females with DTC after thyroidectomy., Methods: About 145 women with resected DTC and receiving long-term TSH therapy, were stratified according to the degree of TSH suppression. Mean duration of follow-up was 12.3 ± 6.1 years. BMD and TBS, were assessed using dual-energy X-ray absorptiometry (DXA) and TBS iNsight (Med-Imaps), at baseline (1-3 months after surgery) and at the final study visit., Results: In patients stratified by duration of TSH suppression therapy (Group I, 5-10 years; Group II, >10 years), slight increases from baseline TSH levels were observed. Significant decreases in LS-BMD and FN-BMD were seen in patients after >10 years. TBS values were lower in Groups I (1.289 ± 0.122) and II (1.259 ± 0.129) compared with baseline values (P = .0001, both groups). Regarding the degree of TSH suppression, TBS was significantly reduced in those with TSH < 0.1 µU/mL (P = .0086), and not in patients with TSH suppression of 0.1.-0.5 or >0.5 µU/mL., Conclusions: We found deterioration of trabecular structure in patients with DTC and TSH suppression therapy below 0.1 µU/mL and after 5-10 years of follow-up. Significant changes in BMD according to TSH levels were not observed. Trabecular Bone Score is a useful technique for identifying thyroid cancer patients with risk of bone deterioration., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)