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      Thyroid Hormone Replacement Therapy

      Hormone Research in Paediatrics

      S. Karger AG

      Hypothyroidism, Thyroxine, Thyrotropin, Replacement therapy, Triiodothyronine, Euthyroidism

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          Abstract

          Thyroid hormone replacement has been used for more than 100 years in the treatment of hypothyroidism, and there is no doubt about its overall efficacy. Desiccated thyroid contains both thyroxine (T<sub>4</sub>) and triiodothyronine (T<sub>3</sub>); serum T<sub>3</sub> frequently rises to supranormal values in the absorption phase, associated with palpitations. Liothyronine (T<sub>3</sub>) has the same drawback and requires twice-daily administration in view of its short half-life. Synthetic levothyroxine (L-T<sub>4</sub>) has many advantages: in view of its long half-life, once-daily administration suffices, the occasional missing of a tablet causes no harm, and the extrathyroidal conversion of T<sub>4</sub> into T<sub>3</sub> (normally providing 80% of the daily T<sub>3</sub> production rate) remains fully operative, which may have some protective value during illness. Consequently, L-T<sub>4</sub> is nowadays preferred, and its long-term use is not associated with excess mortality. The mean T<sub>4</sub> dose required to normalize serum thyroid stimulating hormone (TSH) is 1.6 µg/kg per day, giving rise to serum free T<sub>4</sub> (fT<sub>4</sub>) concentrations that are slightly elevated or in the upper half of the normal reference range. The higher fT<sub>4</sub> values are probably due to the need to generate from T<sub>4</sub> the 20% of the daily T<sub>3</sub> production rate that otherwise is derived from the thyroid gland itself. The daily maintenance dose of T<sub>4</sub> varies widely between 75 and 250 µg. Assessment of the appropriate T<sub>4</sub> dose is by assay of TSH and fT<sub>4</sub>, preferably in a blood sample taken before ingestion of the subsequent T<sub>4</sub> tablet. Dose adjustments can be necessary in pregnancy and when medications are used that are known to interfere with the absorption or metabolism of T<sub>4</sub>. A new equilibrium is reached after approximately 6 weeks, implying that laboratory tests should not be done earlier. With a stable maintenance dose, an annual check-up usually suffices. Accumulated experience with L-T<sub>4</sub> replacement has identified some areas of concern. First, the bioequivalence sometimes differs among generics and brand names. Second, many patients on T<sub>4</sub> replacement have a subnormal TSH. TSH values of ≤0.1 mU/l carry a risk of development of atrial fibrillation and are associated with bone loss although not with a higher fracture rate. It is thus advisable not to allow TSH to fall below – arbitrarily – 0.2 mU/l. Third, recent animal experiments indicate that only the combination of T<sub>4</sub> and T<sub>3</sub> replacement, and not T<sub>4</sub> alone, ensures euthyroidism in all tissues of thyroidectomized rats. It is indeed the experience of many physicians that there exists a small subset of hypothyroid patients who, despite biochemical euthyroidism, continue to complain of tiredness, lack of energy, discrete cognitive disorders and mood disturbances. As organs vary in the extent to which their T<sub>3</sub> content is derived from serum T<sub>3</sub> or locally produced T<sub>3</sub> from T<sub>4</sub>, these complaints may have a biologic substrate; for example, brain T<sub>3</sub> content is largely determined by local deiodinase type II activity. Against this background it is of interest that a number of psychometric scores improved significantly in hypothyroid patients upon substitution of 50 µg of their T<sub>4</sub> replacement dose by 12.5 µg T<sub>3</sub>. Confirmatory studies on this issue are urgently awaited. It could well be that a slow-release preparation containing both T<sub>4</sub> and T<sub>3</sub> might improve the quality of life, compared with T<sub>4</sub> replacement alone, in some hypothyroid patients.

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          Most cited references 10

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          Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.

          Patients with hypothyroidism are usually treated with thyroxine (levothyroxine) only, although both thyroxine and triiodothyronine are secreted by the normal thyroid gland. Whether thyroid secretion of triiodothyronine is physiologically important is unknown. We compared the effects of thyroxine alone with those of thyroxine plus triiodothyronine (liothyronine) in 33 patients with hypothyroidism. Each patient was studied for two five-week periods. During one period, the patient received his or her usual dose of thyroxine. During the other, the patient received a regimen in which 50 microg of the usual dose of thyroxine was replaced by 12.5 microg of triiodothyronine. The order in which each patient received the two treatments was randomized. Biochemical, physiologic, and psychological tests were performed at the end of each treatment period. The patients had lower serum free and total thyroxine concentrations and higher serum total triiodothyronine concentrations after treatment with thyroxine plus triiodothyronine than after thyroxine alone, whereas the serum thyrotropin concentrations were similar after both treatments. Among 17 scores on tests of cognitive performance and assessments of mood, 6 were better or closer to normal after treatment with thyroxine plus triiodothyronine. Similarly, among 15 visual-analogue scales used to indicate mood and physical status, the results for 10 were significantly better after treatment with thyroxine plus triiodothyronine. The pulse rate and serum sex hormone-binding globulin concentrations were slightly higher after treatment with thyroxine plus triiodothyronine, but blood pressure, serum lipid concentrations, and the results of neurophysiologic tests were similar after the two treatments. In patients with hypothyroidism, partial substitution of triiodothyronine for thyroxine may improve mood and neuropsychological function; this finding suggests a specific effect of the triiodothyronine normally secreted by the thyroid gland.
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            Increased need for thyroxine in women with hypothyroidism during estrogen therapy.

             B Arafah (2001)
            Women with hypothyroidism that is being treated with thyroxine often need higher doses when they are pregnant. Whether this need can be attributed solely to estrogen-induced increases in serum thyroxine-binding globulin or whether other factors are involved is not known. In 11 postmenopausal women with normal thyroid function and 25 postmenopausal women with hypothyroidism treated with thyroxine, I assessed thyroid function before they started estrogen therapy and every 6 weeks for 48 weeks thereafter. The women with hypothyroidism included 18 women receiving thyroxine-replacement therapy and 7 women receiving thyrotropin-suppressive thyroxine therapy. On each occasion, serum thyroxine, free thyroxine, thyrotropin, and thyroxine-binding globulin were measured. In the women with normal thyroid function, the serum free thyroxine and thyrotropin concentrations did not change, whereas at 12 weeks the mean (+/-SD) serum thyroxine concentration had increased from 8.0+/-0.9 microg per deciliter (103+/-12 nmol per liter) to 10.4+/-1.5 microg per deciliter (134+/-19 nmol per liter, P<0.001) and the serum thyroxine-binding globulin concentration had increased from 20.3+/-3.5 mg per liter to 31.3+/-3.2 mg per liter, P<0.001). The women with hypothyroidism had similar increases in serum thyroxine and thyroxine-binding globulin concentrations during estrogen therapy, but their serum free thyroxine concentration decreased from 1.7+/-0.4 ng per deciliter (22+/-5 pmol per liter) to 1.4+/-0.3 ng per deciliter (18+/-4 pmol per liter, P<0.001) and their serum thyrotropin concentration increased from 0.9+/-1.1 to 3.2+/-3.1 microU per milliliter (P<0.001). The serum thyrotropin concentrations increased to more than 7 microU per milliliter in 7 of the 18 women in the thyroxine-replacement group and to more than 1 microU per milliliter in 3 of the 7 women in the thyrotropin-suppression group. In women with hypothyroidism treated with thyroxine, estrogen therapy may increase the need for thyroxine.
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              Thyroxine therapy.

               A Toft (1994)
              The availability of sensitive thyrotropin assays allows effective biochemical monitoring of both replacement and suppressive therapy with thyroxine. Whatever target organ is examined, there is tissue thyrotoxicosis if the serum thyrotropin concentration is low, even if the serum triiodothyronine and thyroxine concentrations are normal. Although suppression of thyrotropin secretion is recommended in the treatment of patients with thyroid carcinoma, the aim of thyroxine-replacement therapy in patients with primary hypothyroidism should be to maintain the serum thyrotropin concentration in the normal range. The most convincing argument for the treatment of subclinical hypothyroidism is progression to overt hypothyroidism at a rate of 5 to 20 percent per year.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                978-3-8055-7369-6
                978-3-318-00810-4
                1663-2818
                1663-2826
                2001
                January 2002
                17 November 2004
                : 56
                : Suppl 1
                : 74-81
                Affiliations
                Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam, The Netherlands
                Article
                48140 Horm Res 2001;56(suppl 1):74–81
                10.1159/000048140
                11786691
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 3, References: 41, Pages: 8
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