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Advances in Therapy Sep 2019Hypothyroidism affects up to 5% of the general population, with a further estimated 5% being undiagnosed. Over 99% of affected patients suffer from primary... (Review)
Review
Hypothyroidism affects up to 5% of the general population, with a further estimated 5% being undiagnosed. Over 99% of affected patients suffer from primary hypothyroidism. Worldwide, environmental iodine deficiency is the most common cause of all thyroid disorders, including hypothyroidism, but in areas of iodine sufficiency, Hashimoto's disease (chronic autoimmune thyroiditis) is the most common cause of thyroid failure. Hypothyroidism is diagnosed biochemically, being overt primary hypothyroidism defined as serum thyroid-stimulating hormone (TSH) concentrations above and thyroxine concentrations below the normal reference range. Symptoms of hypothyroidism are non-specific and include mild to moderate weight gain, fatigue, poor concentration, depression, and menstrual irregularities, while the consequences of untreated or under-treated hypothyroidism include cardiovascular disease and increased mortality. Levothyroxine has long been the main tool for treating hypothyroidism and is one of the world's most widely prescribed medicines. In adults with overt hypothyroidism, levothyroxine is usually prescribed at a starting dose of 1.6 µg/kg/day, which is then titrated to achieve optimal TSH levels (0.4-4.0 mIU/L), according to the therapeutic target. We here summarise the history of levothyroxine and discuss future issues regarding the optimal treatment of hypothyroidism. Because nearly one-third of patients with treated hypothyroidism still exhibit symptoms, it is important that levothyroxine is used more appropriately to achieve maximum benefit for patients. In order to ensure this, further research should include more accurate assessments of the true prevalence of hypothyroidism in the community, optimisation of the levothyroxine substitution dose, proper duration of treatment, and identification of patients who may benefit from combination therapy with levothyroxine plus levotriiodothyronine.Funding: Merck.Plain Language Summary: Plain language summary available for this article.
Topics: Adult; Cardiovascular Diseases; Depression; Female; Humans; Hypothyroidism; Thyrotropin; Thyroxine
PubMed: 31485975
DOI: 10.1007/s12325-019-01080-8 -
International Journal of Molecular... Jun 2021Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that... (Review)
Review
Thyroid hormones are necessary for the normal functioning of physiological systems. Therefore, knowledge of any factor (whether genetic, environmental or intrinsic) that alters the levels of thyroid-stimulating hormone (TSH) and thyroid hormones is crucial. Genetic factors contribute up to 65% of interindividual variations in TSH and thyroid hormone levels, but many environmental factors can also affect thyroid function. This review discusses studies that have analyzed the impact of environmental factors on TSH and thyroid hormone levels in healthy adults. We included lifestyle factors (smoking, alcohol consumption, diet and exercise) and pollutants (chemicals and heavy metals). Many inconsistencies in the results have been observed between studies, making it difficult to draw a general conclusion about how a particular environmental factor influences TSH and thyroid hormone levels. However, lifestyle factors that showed the clearest association with TSH and thyroid hormones were smoking, body mass index (BMI) and iodine (micronutrient taken from the diet). Smoking mainly led to a decrease in TSH levels and an increase in triiodothyronine (T3) and thyroxine (T4) levels, while BMI levels were positively correlated with TSH and free T3 levels. Excess iodine led to an increase in TSH levels and a decrease in thyroid hormone levels. Among the pollutants analyzed, most studies observed a decrease in thyroid hormone levels after exposure to perchlorate. Future studies should continue to analyze the impact of environmental factors on thyroid function as they could contribute to understanding the complex background of gene-environment interactions underlying the pathology of thyroid diseases.
Topics: Animals; Biomarkers; Diet; Environment; Environmental Pollutants; Gene Expression Regulation; Gene-Environment Interaction; Genetic Background; Humans; Life Style; Thyroid Hormones; Thyrotropin
PubMed: 34204586
DOI: 10.3390/ijms22126521 -
Endokrynologia Polska 2020Thyroid hormones and thyroid-stimulating hormone (TSH) laboratory tests are commonly used worldwide, and their results have an important influence on decisions about... (Review)
Review
Thyroid hormones and thyroid-stimulating hormone (TSH) laboratory tests are commonly used worldwide, and their results have an important influence on decisions about treatment and further diagnostic processes. Any discrepancies between symptoms and laboratory results or between results of different tests should be closely investigated to avoid misdiagnosis and unnecessary treatment. Inconsistencies in hormone tests might be a result of physiological changes in hormonal balance, a disease, drug intake, or laboratory interference. Major factors that interfere with thyroid function tests are: heterophilic antibodies, macro TSH, biotin, thyroid hormones autoantibodies, anti-streptavidin, and anti-ruthenium antibodies. In this paper we discuss the influence of different factors on the procedures of hormonal immunoassays, as well as methods to minimise the risk of false results and misdiagnoses.
Topics: Diagnostic Errors; Humans; Hyperthyroidism; Immunoassay; Thyroid Function Tests; Thyrotropin; Thyroxine; Triiodothyronine
PubMed: 33378071
DOI: 10.5603/EP.a2020.0079 -
Nature Sep 2022Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor...
Thyroid hormones are vital in metabolism, growth and development. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). In patients with Graves' disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves' disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G-protein-coupled receptors with large extracellular domains.
Topics: Cell Membrane; Cryoelectron Microscopy; Graves Disease; Humans; Immunoglobulins, Thyroid-Stimulating; Phospholipids; Protein Domains; Receptors, G-Protein-Coupled; Receptors, Thyrotropin; Rotation; Thyrotropin
PubMed: 35940205
DOI: 10.1038/s41586-022-05159-1 -
The Journal of Clinical Endocrinology... Nov 2021Thyrotropin (TSH), traditionally seen as a pituitary hormone that regulates thyroid glands, has additional roles in physiology including skeletal remodeling.... (Review)
Review
Thyrotropin (TSH), traditionally seen as a pituitary hormone that regulates thyroid glands, has additional roles in physiology including skeletal remodeling. Population-based observations in people with euthyroidism or subclinical hyperthyroidism indicated a negative association between bone mass and low-normal TSH. The findings of correlative studies were supported by small intervention trials using recombinant human TSH (rhTSH) injection, and genetic and case-based evidence. Genetically modified mouse models, which disrupt the reciprocal relationship between TSH and thyroid hormone, have allowed us to examine an independent role of TSH. Since the first description of osteoporotic phenotype in haploinsufficient Tshr +/- mice with normal thyroid hormone levels, the antiosteoclastic effect of TSH has been documented in both in vitro and in vivo studies. Further studies showed that increased osteoclastogenesis in Tshr-deficient mice was mediated by tumor necrosis factor α. Low TSH not only increased osteoclastogenesis, but also decreased osteoblastogenesis in bone marrow-derived primary osteoblast cultures. However, later in vivo studies using small and intermittent doses of rhTSH showed a proanabolic effect, which suggests that its action might be dose and frequency dependent. TSHR was shown to interact with insulin-like growth factor 1 receptor, and vascular endothelial growth factor and Wnt pathway might play a role in TSH's effect on osteoblasts. The expression and direct skeletal effect of a biologically active splice variant of the TSHβ subunit (TSHβv) in bone marrow-derived macrophage and other immune cells suggest a local skeletal effect of TSHR. Further studies of how locally secreted TSHβv and systemic TSHβ interact in skeletal remodeling through the endocrine, immune, and skeletal systems will help us better understand the hyperthyroidism-induced bone disease.
Topics: Animals; Bone Diseases; Bone and Bones; Humans; Hyperthyroidism; Thyrotropin
PubMed: 34318885
DOI: 10.1210/clinem/dgab548 -
Journal of Internal Medicine Feb 2022The majority of patients with hypothyroidism feel better when levothyroxine treatment restores thyroid-stimulating hormone (TSH) concentrations to normal. Increasingly,... (Review)
Review
The majority of patients with hypothyroidism feel better when levothyroxine treatment restores thyroid-stimulating hormone (TSH) concentrations to normal. Increasingly, a significant minority of patients remain symptomatic and are dissatisfied with their treatment. Overzealous treatment of symptomatic patients with subclinical hypothyroidism may contribute to dissatisfaction among hypothyroidism patients, as potential hypothyroid symptoms in patients with minimal hypothyroidism rarely respond to treatment. Thyroid hormone prescriptions have increased by 30% in the United States in the last decade. The diagnosis of subclinical hypothyroidism should be confirmed by repeat thyroid function tests ideally obtained at least 2 months later, as 62% of elevated TSH levels may revert to normal spontaneously. Generally, treatment is not necessary unless the TSH exceeds 7.0-10 mIU/L. In double-blinded randomized controlled trials, treatment does not improve symptoms or cognitive function if the TSH is less than 10 mIU/L. While cardiovascular events may be reduced in patients under age 65 with subclinical hypothyroidism who are treated with levothyroxine, treatment may be harmful in elderly patients with subclinical hypothyroidism. TSH goals are age dependent, with a 97.5 percentile (upper limit of normal) of 3.6 mIU/L for patients under age 40, and 7.5 mIU/L for patients over age 80. In some hypothyroid patients who are dissatisfied with treatment, especially those with a polymorphism in type 2 deiodinase, combined treatment with levothyroxine and liothyronine may be preferred.
Topics: Aged; Aged, 80 and over; Humans; Hypothyroidism; Thyroid Hormones; Thyrotropin; Thyroxine
PubMed: 34766382
DOI: 10.1111/joim.13410 -
Best Practice & Research. Clinical... Mar 2017Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects.... (Review)
Review
Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects. Affected individuals have elevated serum TSH in the absence of goiter, with the severity ranging from nongoitrous isolated hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Conceptually, defects leading to RTSH impair both aspects of TSH-mediated action, namely thyroid hormone synthesis and gland growth. These include inactivating mutations in the genes encoding the TSH receptor and the PAX8 transcription factor. A common third cause has been genetically mapped to a locus on chromosome 15, but the underlying pathophysiology has not yet been elucidated. This review provides a succinct overview of currently defined causes of nonsyndromic RTSH, their differential diagnoses (autoimmune; partial iodine organification defects; syndromic forms of RTSH) and implications for the clinical approach to patients with RTSH.
Topics: Congenital Hypothyroidism; Drug Resistance; Humans; Mutation; Receptors, Thyrotropin; Syndrome; Thyroid Dysgenesis; Thyroid Hormones; Thyrotropin
PubMed: 28648507
DOI: 10.1016/j.beem.2017.03.004 -
Annual Review of Medicine Jan 2024Levothyroxine (LT4) is effective for most patients with hypothyroidism. However, a minority of the patients remain symptomatic despite the normalization of serum... (Review)
Review
Levothyroxine (LT4) is effective for most patients with hypothyroidism. However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels. Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone. Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3. For these patients, new slow-release LT3 formulations that provide stable serum T3 levels are being tested. In addition, progress in regenerative technology has led to the development of human thyroid organoids that restore euthyroidism after being transplanted into hypothyroid mice. Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved. This is seen, for example, in patients with metabolic (dysfunction)-associated fatty liver disease, for whom liver-selective T3-like molecules have been utilized successfully in clinical trials.
Topics: Humans; Mice; Animals; Thyroxine; Quality of Life; Thyrotropin; Hypothyroidism; Triiodothyronine
PubMed: 37738506
DOI: 10.1146/annurev-med-060622-101007 -
Thyroid : Official Journal of the... Mar 2014Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic... (Review)
Review
Serum thyrotropin (TSH) is considered the single most sensitive and specific measure of thyroid function in the general population owing to its negative logarithmic association with free triiodothyronine and free thyroxine concentrations. It is therefore often the test of choice for screening, diagnosis, and monitoring of primary hypothyroidism. Serum TSH concentrations can be analyzed quantitatively using third-generation immunoassays, whereas its bioactivity can be measured by TSH activity assays in cell culture. Theoretically, if serum TSH concentrations are directly related to TSH activity, the two tests should yield comparable results. However, on occasion, the results are discordant, with serum concentrations being higher than TSH biological activity. This review focuses on the dissociation between the clinical state and serum TSH concentrations and addresses clinically important aspects of TSH analysis.
Topics: Humans; Hypothyroidism; Immunoassay; Protein Isoforms; Thyroid Function Tests; Thyrotropin
PubMed: 24073798
DOI: 10.1089/thy.2013.0119 -
Medical Sciences (Basel, Switzerland) Apr 2022The effect of thyroid function on semen parameters has been studied in pathological conditions in small studies. With this research work, we aimed to study thyroid...
The effect of thyroid function on semen parameters has been studied in pathological conditions in small studies. With this research work, we aimed to study thyroid hormone effects on semen parameters in 130 men who were evaluated for couple subfertility. Our study was cross-sectional. We noted semen volume, sperm concentration, total sperm count, testosterone levels and thyrotropin (TSH) levels. The analysis included ordinary least squares regression (OLS-R), quantile regression (QR) and segmented line regression (SR). Using OLS-R, a weak negative correlation was found between the logTSH levels and semen volume (r = -0.16, r = 0.03, = 0.05). In Q-R, each incremental unit increase in logTSH decreased the mean semen volume between -0.78 ± 0.44 and -1.33 ± 0.34 mL (40-60th response quantile) and between -1.19 ± 0.71 and -0.61 ± 0.31 mL (70-90th response quantile) ( = 0.049). With SR, a biphasic relationship of sperm concentration with TSH was noted (positive turning to negative, peaking at TSH = 1.22 μIU/mL). Thus, a weak negative association between the TSH levels and semen volume was noted, showing a trough within the usual normal range for TSH. Moreover, a biphasic relationship between the sperm concentration and TSH was also noted, peaking at approximately mid-normal TSH levels. Based on our results, TSH explained slightly less than 3% of the variation in semen volume and 7% of the sperm concentration (thus, other factors, which were not studied here, have a more important effect on it).
Topics: Cross-Sectional Studies; Humans; Male; Semen; Sperm Count; Testosterone; Thyrotropin
PubMed: 35466230
DOI: 10.3390/medsci10020022