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      Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients

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          Abstract

          Context

          Levothyroxine monotherapy is the treatment of choice for hypothyroid patients because peripheral T4 to T3 conversion is believed to account for the overall tissue requirement for thyroid hormones. However, there are indirect evidences that this may not be the case in all patients.

          Objective

          To evaluate in a large series of athyreotic patients whether levothyroxine monotherapy can normalize serum thyroid hormones and thyroid-pituitary feedback.

          Design

          Retrospective study.

          Setting

          Academic hospital.

          Patients

          1,811 athyreotic patients with normal TSH levels under levothyroxine monotherapy and 3,875 euthyroid controls.

          Measurements

          TSH, FT4 and FT3 concentrations by immunoassays.

          Results

          FT4 levels were significantly higher and FT3 levels were significantly lower (p<0.001 in both cases) in levothyroxine-treated athyreotic patients than in matched euthyroid controls. Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls. A wide range of FT3/FT4 ratios indicated a major heterogeneity in the peripheral T3 production capacity in different individuals. The correlation between thyroid hormones and serum TSH levels indicated an abnormal feedback mechanism in levothyroxine-treated patients.

          Conclusions

          Athyreotic patients have a highly heterogeneous T3 production capacity from orally administered levothyroxine. More than 20% of these patients, despite normal TSH levels, do not maintain FT3 or FT4 values in the reference range, reflecting the inadequacy of peripheral deiodination to compensate for the absent T3 secretion. The long-term effects of chronic tissue exposure to abnormal T3/T4 ratio are unknown but a sensitive marker of target organ response to thyroid hormones (serum TSH) suggests that this condition causes an abnormal pituitary response. A more physiological treatment than levothyroxine monotherapy may be required in some hypothyroid patients.

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          Most cited references 34

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          Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

          The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.
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            Psychological well-being in patients on 'adequate' doses of l-thyroxine: results of a large, controlled community-based questionnaire study.

            Over 1% of the UK population is receiving thyroid hormone replacement with l-thyroxine (T4). However, many patients complain of persistent lethargy and related symptoms on T4 even with normal TSH levels. To date there has been no large study to determine whether this is related to thyroxine replacement or coincidental psychological morbidity. We have therefore attempted to address this issue using a large, community-based study. Computerized prescribing records of five general practices were used to identify 961 patients who had been on thyroxine for a minimum of 4 months from a population of 63 000 (1.5%), along with age- and sex-matched controls. All 1922 individuals were sent a two-page questionnaire, made up of the short form of the General Health Questionnaire (GHQ-12), designed to detect minor psychiatric disorders in the community, and a 12-question 'thyroid symptom questionnaire' (TSQ) in the same format. A covering letter explained that we were interested in 'how patients felt on medication' and made no direct reference to thyroxine. Scores from the GHQ and TSQ were marked for each individual using the GHQ and Likert scoring methods. Patients' latest TSH measurements were obtained from laboratory records. Comparisons were then made on scores for the total GHQ-12, TSQ and individual questions between patients (P) and control (C) groups. Separate analyses were made comparing the patients with a normal TSH (nP) and the control group. Five hundred and ninety-seven (62%) of the patients (P) and 551 (57%) of the controls (C) responded and fully completed at least one of the two questionnaire. Three hundred and ninety-seven responding patients (nP) had a TSH estimation performed in the previous 12 months with the last result being in the local laboratory normal range for TSH (0.1-5.5 or 0.2-6.0 mU/l, according to the assay method used). The responding P, nP and C populations were well matched for age (59.96, 59.73, 59.35 years) and sex (85%, 83%, 87% female). The number of individuals scoring 3 or more on the GHQ-12 (indicating 'caseness') was 21% higher in P than C [185/572 (32.3%) vs. 137/535 (25.6%), P = 0.014] and 26% higher in nP than C [131/381 (34.4%) vs. 137/535 (25.6%), P < 0.005]. Stronger differences were seen with the TSQ scores [C = 187/535 (35.0%), P = 273/583 (46.8%), P < 0.001, P vs. C; and nP = 189/381 (48.6%), P < 0.001, nP vs. C]. Differences existed in chronic drug use and chronic disease prevalence between the control and patient groups, but the differences in GHQ and TSQ scores between the groups remained significant even after correction for these factors as well as age and sex in multiple regression analysis. This community-based study is the first evidence to indicate that patients on thyroxine replacement even with a normal TSH display significant impairment in psychological well-being compared to controls of similar age and sex. In view of the large numbers of people on thyroxine replacement, we believe that these differences, although not large, could contribute to significant psychological morbidity in a substantial number of individuals.
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              Selenium, the thyroid, and the endocrine system.

              Recent identification of new selenocysteine-containing proteins has revealed relationships between the two trace elements selenium (Se) and iodine and the hormone network. Several selenoproteins participate in the protection of thyrocytes from damage by H(2)O(2) produced for thyroid hormone biosynthesis. Iodothyronine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. The Se content in endocrine tissues (thyroid, adrenals, pituitary, testes, ovary) is higher than in many other organs. Nutritional Se depletion results in retention, whereas Se repletion is followed by a rapid accumulation of Se in endocrine tissues, reproductive organs, and the brain. Selenoproteins such as thioredoxin reductases constitute the link between the Se metabolism and the regulation of transcription by redox sensitive ligand-modulated nuclear hormone receptors. Hormones and growth factors regulate the expression of selenoproteins and, conversely, Se supply modulates hormone actions. Selenoproteins are involved in bone metabolism as well as functions of the endocrine pancreas and adrenal glands. Furthermore, spermatogenesis depends on adequate Se supply, whereas Se excess may impair ovarian function. Comparative analysis of the genomes of several life forms reveals that higher mammals contain a limited number of identical genes encoding newly detected selenocysteine-containing proteins.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                1 August 2011
                : 6
                : 8
                Affiliations
                [1]Endocrine Unit, Department of Clinical and Molecular Biomedicine, University of Catania Medical School, Garibaldi-Nesima Hospital, Catania, Italy
                Cardiff University, United Kingdom
                Author notes

                Conceived and designed the experiments: DG AL RV. Performed the experiments: DG AL RV. Analyzed the data: DG AL RV. Wrote the paper: DG RV. Critical revision of the article for important intellectual content: DG FF AL RV. Collection and assembly of data: DG AL FF RLM GP.

                Article
                PONE-D-11-04673
                10.1371/journal.pone.0022552
                3148220
                21829633
                4f1ca6c5-cb98-4043-b8c5-c4495e7f78a9
                Gullo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 7
                Categories
                Research Article
                Medicine
                Anatomy and Physiology
                Endocrine System
                Endocrine Physiology
                Hormones
                Thyroid
                Drugs and Devices
                Drug Research and Development
                Endocrinology
                Endocrine Physiology
                Hormones
                Thyroid
                Thyroid
                Hypothyroidism

                Uncategorized

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