Impaired Metabolism of Selenomethionine in Graves' Disease: A Biokinetics Study of Soft Gel Capsule Formulation.

Patients with Graves' disease are known to have low selenium (Se) status, Se supplementation resulting in clinical and biochemical improvement. Selenomethionine (SeMet) in a new soft gel capsule formulation was used in a pilot study in 6 patients with acute Graves' disease and low selenium levels (61.3±12.9 µg/l) before and in 4/6 patients 3 months after combined treatment with methimazole and SeMet 200 µg/day (113.3±46.3 µg/l), as well as in 6 euthyroid controls (82±11.8 µg/l). The biokinetics were studied following ingestion of 200 µg SeMet (single dose) soft gel capsule, Se serum concentrations being measured at various time points within 24 h. Se levels rose variably in all patients and controls. While levels peaked in all subjects following 8 h of intake, the increase was somewhat slower in acute hyperthyroidism as compared to 3 months later when these patients had been rendered euthyroid, this possibly due to derangement of Se storage capacity by SEPP or increased requirements in the acute phase of the disease, leading to depletion of the trace element. The compound was shown to be bioavailable and safe and patients treated for 3 months exhibited higher Se levels at the different time points. These findings are of major importance for sufferers of GD since they indicate that early Se supplementation, with its beneficial antioxidant impact on inflammatory activity, could slow, or possibly even forestall, the clinical progression of the disease.

Toxic chemicals and thyroid function: hard facts and lateral thinking.

Increasing quantities of evidence-based data incriminate a large number of environmental pollutants for toxic effects on the thyroid. Among the many chemical contaminants, halogenated organochlorines and pesticides variably affect the hypothalamic-pituitary-thyroid axis and disrupt thyroid function. PCBs and their metabolites and PBDEs bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Meanwhile, at the molecular level, PCB congeners may activate phosphorylation of Akt, p-Akt, and forkhead box O3a (FoxO3a) protein resulting in inhibition of the natrium/iodide symporter. Given therefore the growing concern developing around these multiple toxic chemicals today invading numerous environments and their long-term deleterious effects not only on the thyroid but also on general health, we strongly advocate their strict regulation and, moreover, their gradual reduction. A good degree of "lateral thinking", we feel, will lead to a use of chemicals that will enhance life while concurrently carefully protecting the environment.

Nutrition and thyroid disease.

PURPOSE OF REVIEW: The aim of this review was to determine, based on the most recent findings, the involvement of trace elements and vitamins critical for thyroid function and combating thyroid disease. RECENT FINDINGS: Nutritional guidance is pivotal to reducing the risk of thyroid disease and to managing it when it arises, this meaning the prescription of diets rich in such micronutrients as iodine, selenium, iron, zinc, and vitamins B12, D3, and A. Most of the above micronutrients are good antioxidants, building up an anti-inflammatory profile, reducing thyroid autoantibodies and body fat, and improving thyroid function. Diets are increasingly being prescribed, especially for those suffering from Hashimoto's thyroiditis. Notable among prescribed diets is the Mediterranean diet. Rich in critical elements, it benefits patients at the immune endocrine and biomolecular levels. SUMMARY: Importantly, it is likely that widespread adherence to the Mediterranean diet, together with a reduction of meat consumption and potential elimination of gluten and lactose may improve inflammation and have an impact on public health while possibly diminishing thyroiditis symptoms. It is hoped that this review can direct policymakers towards undertaking cost-effective interventions to minimize deficiency of essential minerals and vitamins and thus protect both general and thyroid health.

The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities.

This review addresses the role of the essential trace element, selenium, in type-2 diabetes mellitus (T2DM) and its metabolic co-morbidities, i.e., metabolic syndrome, obesity and non-alcoholic fatty liver disease. We refer to the dietary requirements of selenium and the key physiological roles of selenoproteins. We explore the dysregulated fuel metabolism in T2DM and its co-morbidities, emphasizing the relevance of inflammation and oxidative stress. We describe the epidemiology of observational and experimental studies of selenium in diabetes and related conditions, explaining that the interaction between selenium status and glucose control is not limited to hyperglycemia but extends to hypoglycemia. We propose that the association between high plasma/serum selenium and T2DM/fasting plasma glucose observed in many cross-sectional studies may rely on the upregulation of hepatic selenoprotein-P biosynthesis in conditions of hyperglycemia and insulin resistance. While animal studies have revealed potential molecular mechanisms underlying adverse effects of severe selenium/selenoprotein excess and deficiency in the pathogenesis of insulin resistance and ß-cell dysfunction, their translational significance is rather limited. Importantly, dietary selenium supplementation does not appear to be a major causal factor for the development of T2DM in humans though we cannot currently exclude a small contribution of selenium on top of other risk factors, in particular if it is ingested at high (supranutritional) doses. Elevated selenium biomarkers that are often measured in T2DM patients are more likely to be a consequence, rather than a cause, of diabetes.

On the Centennial of Vitamin D-Vitamin D, Inflammation, and Autoimmune Thyroiditis: A Web of Links and Implications.

The 100th anniversary of the discovery of vitamin D3 (VitD3) coincides with significant recent advances in understanding its mechanism of action along with accumulating knowledge concerning its genomic and nongenomic activities. A close relationship between VitD3 and the immune system, including both types of immunity, innate and adaptive, has been newly identified, while low levels of VitD3 have been implicated in the development of autoimmune thyroiditis (AIT). Active 1,25(OH)2 D3 is generated in immune cells via 1-α-hydroxylase, subsequently interacting with the VitD3 receptor to promote transcriptional and epigenomic responses in the same or adjacent cells. Despite considerable progress in deciphering the role of VitD3 in autoimmunity, its exact pathogenetic involvement remains to be elucidated. Finally, in the era of coronavirus disease 2019 (COVID-19), brief mention is made of the possible links between VitD3 deficiency and risks for severe COVID-19 disease. This review aims to commemorate the centennial of the discovery of VitD3 by updating our understanding of this important nutrient and by drawing up a framework of guidance for VitD3 supplementation, while emphasizing the necessity for personalized treatment in patients with autoimmune thyroid disease. A tailored approach based on the specific mechanisms underlying VitD3 deficiency in different diseases is recommended.

Metabolic, Oxidative and Psychological Stress as Mediators of the Effect of COVID-19 on Male Infertility: A Literature Review.

Over 300 million patients with coronavirus disease 2019 (COVID-19) have been reported worldwide since the outbreak of the pandemic in Wuhan, Hubei Province, China. COVID-19 is induced by the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The effect of SARS-CoV-2 infection on the male reproductive system is unclear. The aim of this review is to assess the effect of SARS-CoV-2 infection on male fertility and the impact of possible mediators, such as metabolic, oxidative and psychological stress. SARS-CoV-2 infection aggravates metabolic stress and directly or indirectly affects male fertility by reducing seminal health. In addition, SARS-CoV-2 infection leads to excessive production of reactive oxygen species (ROS) and increased psychological distress. These data suggest that SARS-CoV-2 infection reduces male fertility, possibly by means of metabolic, oxidative and psychological stress. Therefore, among other consequences, the possibility of COVID-19-induced male infertility should not be neglected.

New insights into subclinical hypothyroidism and cardiovascular risk.

Subclinical hypothyroidism (SH) is a frequent condition affecting millions of people around the world. Defined by increased thyrotropin-stimulating hormone (TSH) and accompanied by normal thyroid hormone levels, SH reflects a mild tissue hypothyroidism that has been associated with metabolic derangements and-although this issue is still contentious-possibly with increased cardiovascular risk. Depending on the degree of TSH elevation, SH has accordingly been associated with hyperlipidemia, arterial hypertension, and cardiovascular disease (CVD), as well as, increasingly, newly emerging CVD risk factors such as serum C-reactive protein and retinol binding protein 4 levels. There have also been reports of abnormalities in glucose metabolism and of hemostatic parameters, mainly underscored by the increased activity of factor VII. This review discusses the results of the latest studies on the various parameters affected by SH while highlighting the need for timely treatment with levothyroxine.

The interface between thyroid and diabetes mellitus.

Thyroid disease and type 1 but also type 2 diabetes mellitus (DM) are strongly associated, and this has important clinical implications for insulin sensitivity and treatment requirements. The pathophysiological basis of this association has only recently been better elucidated. It rests on a complex interaction of common signalling pathways and, in the case of type 1 diabetes and autoimmune thyroid disease, on a linked genetic susceptibility. The pathophysiological mechanisms underlying this linked regulation are increasingly being unravelled. They are exemplified in the regulation of 5' adenosine monophosphate-activated protein kinase (AMPK), a central target not only for the modulation of insulin sensitivity but also for the feedback of thyroid hormones on appetite and energy expenditure. The present review will discuss these concepts and their consequences for the clinical care of patients with DM and thyroid disorders. Moreover, it makes reference to the added effect of metformin in suppressing TSH.

Aging and the hypothalamic-pituitary-thyroid axis.

The world's population is increasingly aging, this noted particularly in the Western world where there are ever greater numbers of centenarians and those over 85 years. Given the immense importance of the thyroid gland for optimal health and the fact that morphological and functional changes in the hypothalamic-pituitary-thyroid (HPT) axis take place as a natural adaptation to the aging process, a clear distinction must be made in older individuals between these and the onset of disease. However, this is problematic since, frequently, subtle differences exist between them, making diagnosis a challenging task, especially as concerns subclinical disease. The newly emerging interdisciplinary field of geroscience offers the prospect of being used as a platform to investigate the effect of disrupted HPT function on functional capacity and cognitive ability among the aged, as well as the risk or onset of age-associated diseases, thus enhancing healthspan and lifespan. Because optimal functioning of the thyroid gland is a prerequisite for longevity as well as for mental and physical wellbeing, this review summarizes the recent scientific data regarding HPT and aging while discussing alternative and personalized treatment approaches to maintaining a healthy thyroid as a means to ensuring a long, active, and healthy life.

COVID-19 and Thyroid Diseases: A Bidirectional Impact.

CONTEXT: COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has become the most lethal and rapidly moving pandemic since the Spanish influenza of 1918-1920, is associated with thyroid diseases. METHODS: References were identified through searches of PubMed and MEDLINE for articles published from Jan 1, 2019 to February 19, 2021 by use of the MeSH terms "hypothyroidism", "hyperthyroidism", "thyroiditis", "thyroid cancer", "thyroid disease", in combination with the terms "coronavirus" and "COVID-19". Articles resulting from these searches and references cited in those articles were reviewed. RESULTS: Though preexisting autoimmune thyroid disease appears unlikely to render patients more vulnerable to COVID-19, some reports have documented relapse of Graves' disease (GD) or newly diagnosed GD about 1 month following SARS-CoV-2 infection. Investigations are ongoing to investigate molecular pathways permitting the virus to trigger GD or cause subacute thyroiditis (SAT). While COVID-19 is associated with non-thyroidal illness, it is not clear whether it also increases the risk of developing autoimmune hypothyroidism. The possibility that thyroid dysfunction may also increase susceptibility for COVID-19 infection deserves further investigation. Recent data illustrate the importance of thyroid hormone in protecting the lungs from injury, including that associated with COVID-19. CONCLUSION: The interaction between the thyroid gland and COVID-19 is complex and bidirectional. COVID-19 infection is associated with triggering of GD and SAT, and possibly hypothyroidism. Until more is understood regarding the impact of coronavirus on the thyroid gland, it seems advisable to monitor patients with COVID-19 for new thyroid disease or progression of preexisting thyroid disease.

Selenium and at-risk pregnancy: challenges and controversies.

Selenium (Se), an essential trace element, is inserted as selenocysteine into an array of functional proteins and forms the core of various enzymes that play a cardinal role in antioxidant defense mechanisms, in redox regulation, and in thyroid hormone metabolism. Variations in plasma Se are due to nutritional habits, geographic and ethnic differences, and probably to genetic polymorphisms, the latter still to be conclusively established. Se concentrations were reported to be low in women of reproductive age in the UK, decreasing further during pregnancy, this resulting in low plasma and placental antioxidant enzyme activities. Since low serum Se levels have been found in women with preeclampsia, it has been hypothesized that low maternal Se status during early gestation may be an indicator of preterm birth. Moreover, it is documented that Se administration during pregnancy tendentially reduced the markers of thyroid autoimmunity and the incidence of maternal hypothyroidism in the postpartum period. Importantly, low Se levels in pregnant women affect fetal growth and augment the risk of delivering a small-for-gestational age infant by reducing placental antioxidant defense, while low Se in the third trimester is thought to indicate increased demands by the placenta, an issue which requires further confirmation. There is evidently a need for double-blind, placebo-controlled studies to better determine the efficacy and safety of Se supplementation in pregnancy at high risk for complications, and for measurement of Se levels or of selenoprotein P, the most reliable parameter of Se status, particularly in selenopenic regions.

50 years of the ETA: "the selenium connection".

The recent celebration of the 50 years of the ETA closely coincided with that of the 200 years since the discovery and description of selenium, an essential trace element for normal thyroid gland function and thus an adjuvant in the treatment of thyroid diseases. The aim of this commentary is to briefly outline the half centennial of the ETA while also signaling important moments in the history of selenium, developments in its availability round the world, details of its connection with thyroid function and, finally, its current and projected modes of application.

Evidence for a manifold role of selenium in infertility.

This review aimed to assess the evidence from observational and interventional studies in humans and animals regarding the role of selenium (Se) in male and female infertility. As oxidative stress can seriously impair male, and possibly also female, reproductive functions, it can be speculated that the antioxidant properties of Se could constitute one of the pathways by which this element is involved in fertility. Specifically, there are strong indications that Se influences the growth, maturation, and replication of oocytes, though the precise mechanisms have not as yet been fully elucidated. Given that it is not clear at present which tissue sample (blood, serum, seminal plasma, sperm, or follicular fluid) renders the most accurate picture of Se concentration in terms of its role in reproduction, the data are still insufficient to recommend routine assessment of Se status in men and women seeking fertility. Nevertheless, the existing evidence, despite being of limited quantity and somewhat low quality, suggests that Se supplementation (< 200 µg/d) is possibly beneficial in men through its improvement of sperm motility. Well-designed, randomized control studies are needed to reveal the seemingly diverse protective/positive role of Se supplementation in men and women seeking fertility treatment.

The 'rings of fire' and thyroid cancer.

Several studies have revealed an increased incidence of thyroid cancer in volcanic areas around the world. Hawaii and the Philippines on the rim of the Pacific Ocean, where the greatest number of volcanoes are located at convergent plate boundaries, are among the regions with the highest incidence of thyroid carcinoma worldwide. Iceland is another region also rich in volcanoes in which the highest incidence of thyroid cancer in Europe is found. The common denominator of these regions is their numerous volcanoes and the fact that several constituents of volcanic lava have been postulated as being involved in the pathogenesis of thyroid cancer. This article aims at presenting pertinent data that could link a volcanic environment to thyroid cancer.

Levothyroxine Dose Adjustment to Optimise Therapy Throughout a Patient's Lifetime.

Levothyroxine is the standard therapy for patients with hypothyroidism, a condition that affects up to 5% of people worldwide. While levothyroxine therapy has substantially improved the lives of millions of hypothyroid patients since its introduction in 1949, the complexity of maintaining biochemical and clinical euthyroidism in patients undergoing treatment with levothyroxine cannot be underestimated. Initial dosing of levothyroxine can vary greatly and may be based on the amount of residual thyroid function retained by the patient, the body weight or lean body mass of the patient, and thyroid-stimulating hormone levels. As levothyroxine is usually administered over a patient's lifetime, physiological changes throughout life will affect the dose of levothyroxine required to maintain euthyroidism. Furthermore, dose adjustments may need to be made in patients with concomitant medical conditions, in patients taking certain medications, as well as in elderly patients. Patients who have undergone any weight or hormonal changes may require dose adjustments, and the majority of pregnant women require increased doses of levothyroxine. Optimal treatment of hypothyroidism requires a partnership between patient and physician. The physician is tasked with vigilant appraisal of the patient's status based on a thorough clinical and laboratory assessment and appropriate adjustment of their levothyroxine therapy. The patient in turn is tasked with medication adherence and reporting of symptomatology and any changes in their medical situation. The goal is consistent maintenance of euthyroidism, without the patient experiencing the adverse events and negative health consequences of under- or overtreatment.Funding Merck.Plain Language Summary Plain language summary available for this article.

MANAGEMENT OF ENDOCRINE DISEASE: The role of rhTSH in the management of differentiated thyroid cancer: pros and cons.

The use of recombinant human thyrotropin (rhTSH) testing in the diagnosis and therapy of differentiated thyroid cancer (DTC) has been adopted over the last two decades as an alternative to the classical thyroid hormone withdrawal avoiding the threat of hypothyroidism. Serum thyroglobulin (Tg) measurement is crucial for monitoring DTC patients over time. Until about a decade ago, optimal sensitivity of Tg assays for the detection of smaller disease foci required Tg measurement after thyrotropin (TSH) stimulation, carried out following thyroid hormone withdrawal or rhTSH administration. In very recent years, significant improvements in assay technology have resulted in highly sensitive Tg (hsTg) assays, sufficiently sensitive to obviate the need for rhTSH stimulation in most DTC patients. The aim of this paper is to review and discuss, via a 'pros and cons' approach, the current clinical role of rhTSH to stimulate radioiodine (RAI) uptake for treatment and/or imaging purposes and to increase the clinical sensitivity of Tg measurement for monitoring DTC patients when high-sensitive Tg assays are available.

Correction to: Thyroid hormone therapy: past, present, and future.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Diagnosis and treatment of hypothyroidism in the elderly.

The global population is aging with millions of people today living into their 90 s. Thyroid disease, particularly hypothyroidism, is widespread among all age groups, and it is expected to steadily increase as the population gets older. Clinical diagnosis of hypothyroidism is challenging, as the TSH reference range needs to be evaluated according to age, while evaluation of TSH levels must also take into account body weight and other variants such as polypharmacy, comorbidities, and general health condition. Since thyroid hormone has a potent regulatory effect on cholesterol metabolism, the possibility of thyroid dysfunction should be considered in cases of unexplained dyslipidemia. Once hypothyroidism has been confirmed, treatment requires caution, frequent cardiovascular monitoring, and individualized (precision) medicine. Treatment of subclinical hypothyroidism (SCH) in the elderly should be undertaken with care, guided by age and the degree of SCH: a TSH higher than 10 mU/l seems a reasonable threshold, though it should be regularly re-evaluated, while the LT4 dose needs to be tailored, taking into account the patient's health condition and the potential presence of dyslipidemia as well as other metabolic derangements.

European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium.

BACKGROUND: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions. SUMMARY: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions. CONCLUSIONS: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes.