New reference range for TSH?
edited by: Peter PA Smyth, UCD, Dublin
published by: Merck KGaA, Darmstadt, Germany
Georg Brabant Department of Endocrinology Christie Hospital Wilmslow Rd Manchester M20 4BX, UK Tel.: +44 1614463665 Fax: +44 1614463772 Email: [email protected]
New reference range for TSH?
Thy roid Inter na tional
Editor-in-Chief: Peter PA Smyth, UCD, Dublin
This is the title of a pub li ca tion series by Merck KGaA, Darm stadt, Germany. We are pub lish ing papers from renowned inter na tional thy roid experts in order to pass on the exten sive expe ri ence which the authors pos sess in their field to a wide range of phy si cians dealing with the diagnosis and ther apy of thy roid dis eases.
Respon sible at Merck KGaA, Darmstadt, Germany: Sigrid Butz, M.D.
Thy roid Inter na tional · 3–2008
Merck KGaA, Darmstadt, Germany, D-64271 Darm stadt ISSN 0946-5464
Cover: Manchester Town Hall
H t Thyr idology
ETA’s journal on hot and controversial topics Free access:
www.hotthyroidology.com Prof. Dr. med. Georg Brabant
Dept. of Endocrinology, Christie Hospital, University of Manchester
Following his study of medicine at the universities of Marburg, Tübingen, London, Oxford, UK he qualified from the University of Hamburg. In 1976 he finished his MD thesis in the Dept. of Gynecological Endocrinology at the University of Hamburg. Subsequently he
started a research project at the Dept. Experimental Endocrinology, University of Münster, supported by the German Research Foundation under the guidance of his long-term mentor, Prof. Nieschlag. He then moved to the Medizinische Hochschule Hannover where he underwent his formal training in Endocrinology/
Diabetes under Prof. von zur Mühlen. For his research activities on TSH secretion he was granted 1986 the Merck European von Basedow Prize. 1990–1991 he spent a sab-batical at the Free University of Bruxelles with Profs Dumont and Vassart focusing on the recently cloned TSH receptor. Back in Hannover he was appointed Professor at the Medizinische Hochschule Hannover and worked in the Dept. Clinical Endocrinology until he moved to his pres-ent position in the Dept. of Endocrinology, at the Christie Hospital, Manchester, UK. He served on the Executive Committees of the German Endocrine Society, the European Thyroid Association and served as Head of the “Sektion Schilddrüse”, the German Thyroid Association.
Measurement of serum thyrotrophin (TSH) is commonly accepted as the most sensitive test to screen for primary thyroid hormone disorders. Its log-linear relationship to free thyroxine over a wide concentration range allows detection of even minor alterations in thyroid function. It is increasingly recognized that subclini-cal forms of hyper- and hypothyroidism may carry an important risk to the patient.1 As these conditions are defined by normal free thyroxine levels but lower or higher than normal TSH concentrations, the diagnosis
Definition
It is not trivial to define a ‘normal’, ‘reference’ or ‘dis-crimination’ range in any field of endocrinology. The definition of ‘normal’ as absolute health in a popula-tion free of disease may be far too simplistic and would imply a need for correction in every situation not being normal.4 This problematic assumption of abso-lute health is avoided when defining a ‘reference’ range of a population free of thyroid disorders. Data from populations selected for any lack of thyroid disorders have to be further processed to allow the integration of confounders such as the timing of specimen collection and the environmental and physiological conditions under which the specimens were obtained. In addition,
of subclinical thyroid dysfunction entirely rest on TSH measurements and their relation to the expected range. Thus, the definition of the reference range of TSH is of critical importance for the diagnosis. Cut-off levels of 0.3–0.4 mU/l for the lower limit of TSH and 4–5 mU/l for the upper one are conventionally used, but a much lower upper limit of TSH was recently suggested based on large population studies performed both in iodine-rich and iodine-deficient regions.2, 3
technical issues such as sample preparation, storage and the analytical methods used must be considered. Finally, statistical analysis to calculate reference inter-vals from the data set is of importance.5 A recent addition to this discussion is the term ‘discrimination’ values, which is coined to determine cut-off values for medical decisions. This appears to be advantageous because it focuses not only on the sensitivity and specificity of diagnostic tests but also integrates clini-cal and epidemiologiclini-cal aspects such as prevalence and knowledge of the disease as well as the consequences of a false positive or negative diagnosis.6
Population studies
Several large population studies representing areas of historically high and low iodine intake, such as the USA and Germany, evaluated TSH reference ranges in the general population. The American NHANES III survey designed to give national normative estimates of the health and nutritional status of the US civilian represented a population of 13,344 subjects (> 12 years of age). Subjects were excluded if they had known thyroid disease, goitres, were on thyroid medication, or were pregnant females. Also excluded were patients using sex steroids, lithium, or those positive for thyroid antibodies.2 Another large American investigation, the Hanford study, included even a normal thyroid ultra-sound.7 The SHIP study selected a reference popula-tion of 1488 persons without sonographical signs of a goitre or of inhomogeneous thyroid pattern, nodules or hypoechogenicity from a large population cohort from the north-east of Germany and used the same exclusion criteria as the NHANES III survey.3 Another
much smaller German study is remarkable for using the stringent criteria of the National Academy of Clinical Biochemistry (NACB) along with thyroid ultrasound to select 453 out of 870 subjects.8 Finally, two different large Danish studies with exclusion criteria of previ-ous thyroid disease, positive TPO antibodies and with normal thyroid ultrasound defined a TSH reference range as 0.40–3.6 mU/l and an upper normal limit of TSH as 4.5 mU/l, respectively.9,10 All data revealed an approximately log normal distribution of TSH which was right skewed. Whereas all studies agreed on a lower TSH threshold between 0.2 and 0.4 mU/l, the tailing of higher TSH levels which defines an upper TSH cut-off around the generally used 4.0–5.0 mU/l started a broad discussion on the upper threshold of the TSH normal range. If a Gaussian distribution is assumed, the upper TSH threshold would be expected to be 2.5–3 mU/l, which is much closer to the results of the SHIP study,3 averaging the upper TSH levels at 2.1 mU/l (Figure 1).
Figure 1. The percentage frequency distribution of serum thyrotrophin (TSH) in various concentration intervals
between 0 and 10.0 mU/l (adapted from Hollowell et al.2 and Völzke et al.3).
40 30 20 50 10 TSH (mU/l) Frequency distribution (%) 0.2 0.3 1.0 3.0 10.0
Conventional reference range
Median 1.4 mU/l Median 0.9 mU/l
It was argued that the tailing of the TSH levels may be due to hidden thyroid pathology, namely autoimmune thyroid disease. This was supported by recent data
An important new feature was provided by a very recent evaluation of the NHANES III data where subjects with no indication of any thyroid disease, including negative antithyroid antibodies, were stratified by age, which revealed an independent major impact of age.12 In this US population, TSH clearly increased with increasing age, suggesting that a lower cut-off of TSH may lead to a mal-classification of patients. The data fit well to previous studies in a different regional area. In 1993, in a large group of centenarians in Italy, Mariotti et al. reported that serum TSH levels were significantly higher than in younger subjects, indicating a prima-ry decrease in thyroid function with compensatoprima-ry increase in TSH.13 However, this was not a universal finding.14 The differences may not only be explained by
from the NHANES III study where the lowest incidence for thyroid antibodies was found in the proposed core normal TSH range (up to 2.0 mU/l).11
exogenous factors like alterations in nutritional iodine supply (discussed below), but may also rest on disease-specific changes such as hidden thyroid autonomy. With the known problems in sleep with increasing age, alterations in the sleep pattern may impact on TSH levels. Acute studies in young volunteers revealed that sleep withdrawal increases TSH levels, whereas more sleep during the night following complete sleep with-drawal substantially decreases the previous increase in TSH secretion.15 These mechanisms may well play an important role when studying hospital inpatients. In an own survey on the distribution of TSH concentrations in hospitalized patients without known thyroid disease, TSH serum levels were clearly at variance with the age dependent increase reported from population studies.
Role of thyroid antibodies on serum TSH levels
Role of age on serum TSH levels
Figure 2. Scattergraph of serum thyrotrophin (TSH) values in hospitalized patients without known thyroid pathology.
1 10 0.1 Age (years) TSH (mU/l) n = 3857 (TSH 0 1 6) 10 0 20 30 40 50 60 70 80
The wide scatter shown in Figure 2 further illustrates the difficulties in evaluating a population not free of disease.
Important influences on the thyroid occur not only at the end but also during the very early phase of life. We know that serum TSH levels in neonates are much higher than later in life. This has been addressed in sev-eral very large recent studies, showing a dramatic shift of TSH levels within the first 24–48 hours and a further adaptation to adult levels in the period thereafter.16 Figure 3 illustrates the shift in the TSH distribution curves in this early postpartum period.
Following that period, data are scarce, but a recent large Indian study confirms that TSH levels later in life are comparable with TSH serum levels in the adult.17
Another period where TSH levels have to be adapted is pregnancy. We do know that high levels of human chorionic gonadotrophin (hCG) may alter thyroid func-tion and can contribute to pregnancy-related problems such as hyperemesis gravidarum.18 It is expected that in the first trimester of pregnancy, the frequency of suppressed TSH levels may thus be increased. Cotzias et al., in a very careful study, delineated recently these subtle changes in normal pregnancies and established reference ranges not only for TSH but also for free thyroid hormones.19 These data were supported in a very large Indian study of more than 500 pregnancies, which included not only biochemical testing, including the thyroid antibody status, but also ultrasound evalu-ation of the thyroid.20 The relative changes of TSH are depicted in Figure 4 using only the subpopulation of healthy women in pregnancy without any signs of autoimmune thyroid disease or morphological changes of the thyroid evaluated by ultrasound.
Figure 3. The shift in serum thyrotrophin (TSH) 5 % frequency distribution at various time intervals postpartum
(adapted from Lott et al.16).
140
100
60
20
TSH serum concentration (mU/l)
Frequency 1 6 11 16 21 26 31 36 41 46 51 0–24 hours 24–48 hours 48–72 hours 72–96 hours > 96 hours postpartum
Analytical variations in the measurement of TSH are generally low, but it must be considered that due to the glycosylation status of TSH, immunoactivity of the hor-mone does not necessarily match its bioactivity. This is best known from patients with hypothalamic–pituitary hypothyroidism, which is frequently associated with apparently normal immunoreactive TSH levels.21,22
Individuals have individual set points for TSH. In a group of apparently healthy subjects, measured at monthly intervals, the intra-individual variation was only half that of the group.25 These variations most likely reflect genetic influences on the hypothalamo– pituitary set point, which may translate into subtle changes of thyroid function and impact on energy homeostasis reflected in body mass index.26 This varia-tion in set point applies also to subclinical hypothy-roidism. Recent data on subclinical hypothyroidism
Glycosylation-induced heterogeneity of TSH may also lead to problems in the standardization of its measure-ment, which may explain differences of around 30–40 % in TSH values due to assay technology.23 Among other reasons, this led the NACB laboratory guidelines to include laboratory-specific rigorous internal and exter-nal quality controls for TSH measurement.24
from Laurberg and colleagues support the notion that serum fT4 and fT3 has to differ by more than 15 % and TSH concentrations have to be at least 40 % different from a previous test to suggest any difference with 90 % confidence.27 Measuring a cohort of patients with subclinical hypothyroidism in monthly intervals over 1 year revealed a disturbing influence of the inter-visit interval and of the procedures by which thyroid hor-mone levels are measured.28 This indicates that not only methodological but also patient-specific confounders
Methodological considerations
Patient-specific factors
Figure 4. Serum thyrotrophin (TSH) reference ranges during normal pregnancy. Percentiles (2.5–97.5 %) shown by coloured
lines (adapted from Cotzias et al.19). 8 97.5 percentile 2.5 percentile 50 percentile 6 4 2 Gestational week TSH (mU/l) 10 20 30 40
are relevant to explain the spontaneous normalization observed by others.29,30
Patient-specific factors may further consist of known physiological confounders such as acute sleep with-drawal, acute stress or high physical activity, which may impact on TSH levels.31 The latter may stimulate TSH as much as fourfold.32 Disease-specific alterations exemplified in non-thyroidal illness are associated with suppressed TSH secretion and a decrease in serum tri-iodothyronine levels, but may result in an increase of the serum TSH level above 4 mU/l during the recovery
period.33 Nutritional factors and drugs may acutely or chronically affect TSH secretion. Although the effects of iodine supply are regarded to be small, experimental evidence in healthy subjects clearly demonstrates that short-term alterations in iodide availability may change TSH considerably, with a doubling of TSH levels 3 weeks after iodine treatment.34 Finally, a number of non-thyroidal drugs such as metoclopramide, somatostatin analogues, dopamine, glucocorticoids or sulpiride may affect TSH secretion, whereas the increase in thyroxine-binding globulin by oestrogens induces a much slower and smaller rise in TSH over days to weeks.24
The economic relevance of any change in upper TSH cut-offs for the diagnosis of subclinical hypothyroidism has recently been addressed by Fatourechi et al.35 These authors calculated the number of subjects labelled with a diagnosis of subclinical thyroid dysfunction at the Mayo Clinic when the conventional cut-off for nor-mal TSH of 5.0 mU/l was lowered to 3.0 mU/l. With more than 10,000 additional patients thus classified as being diagnosed with subclinical hypothyroidism, there would be a shift in the relative frequency of patients with functional thyroid disorders from 4.6 % to 20 % of all patients seen at the institution. A similar calculation
In a very thorough review, Biondi and Cooper recently evaluated the clinical and long-term impact of both conditions1. These data clearly support an increased health risk of subclinical hyperthyroidism predomi-nantly based on the risks to develop arrhythmias (Table 1).
In subclinical hypothyroidism, the risk is much less clearly defined. Particularly, there are no evidence-based data available to support a difference in risk pro-files when TSH is below or above the discussed old TSH cut-off of 5 mU/l vs the new lower threshold of 3 mU/l. This applies particularly to negative effects reported
performed by Surks et al. on the NHANES data supports this conclusion and suggests that 4 million Americans have to be additionally regarded as thyroid patients when the upper threshold of TSH is lowered from 5 to 3 mU/l.36
These figures illustrate the importance of a clear defi-nition of reference or discrimination ranges to avoid over- or under-treatment and firm data on the pathophysiology and the benefit of any treatment in these conditions.
on left ventricular diastolic function, on plasma lip-ids, on arteriosclerosis risk factors and neurological symptoms, and even treatment of a TSH level between 5 and 10 mU/l and normal free thyroid hormone levels is queried by many groups. In contrast, the need for close monitoring of the thyroid function in patients with sub-clinical hypothyroidism, especially with autoimmune thyroid disease, is generally accepted.
An important aspect in the debate is the observation from large studies that treatment with thyroxine may produce exogenous subclinical or even overt hyper-thyroidism in a significant proportion of patients. Up
Impact of alteration of TSH reference range
to one-third of patients on thyroxine therapy develop abnormally low TSH values. Over-replacement of thy-roxine is the most common cause of suppressed TSH in population studies and, surprisingly, was not readily corrected under routine clinical conditions.
Thus, the potential benefits of correcting subclinical hypothyroidism have to be balanced against the fact that we are still not delivering optimal treatment to those who unequivocally need it. The clinical impact of subclinical forms of thyroid dysfunction, however, highlights the importance of a discrimination range of TSH that integrates TSH reference levels and the clini-cal needs of patients for an optimal long-term cliniclini-cal outcome.
In summary, mild forms of thyrotoxicosis with firmed serum TSH levels of <0.3 mU/l should be con-sidered as a potentially relevant clinical condition which needs consideration for treatment. Concerning the upper end of the TSH reference range, the clinical data available currently do not justify a lowering of the threshold from 4–5 mU/l. This approach, based on the scarce intervention data, avoids generating a large group of new thyroid ‘patients’. It neglects, however, the convincing evidence from population studies for the use of a lower TSH threshold in the range between 2 and 3 mU/l in younger subjects. Therefore, a limited controlled trial of thyroxine treatment may be helpful in patients with TSH levels in the critical range between 3 and 5 mU/l and symptoms fitting to an underactive thyroid, especially when thyroid specific antibodies are detectable.
Table 1. Risk factors associated with subclinical
hyperthyroidism
• Cardiovascular effects
– increased heart rate, increased risk for atrial arrhythmias
– increased left ventricular mass, reduced exercise capacity
• Potential effects on mood and cognitive functions • Can cause reduced bone mineral density and exo genous thyroxine may accelerate bone turnover in post-menopausal patients
• Large prospective randomized trials are lacking
Table 2. Risk factors associated with subclinical
hypothyroidism
• Impaired left ventricular diastolic function
• Results concerning systolic function at rest are not consistent
– effects reversible with treatment
• Increase in systemic vascular resistance and arterial stiffness/endothelial function • Conflicting results about lipid pattern and
‘non-traditional’ cardiovascular risk factors • Impaired muscle metabolism and impaired
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11. Spencer CA, Hollowell JG, Kazarosyan M, Braverman LE. National Health and Nutrition
Examination Survey III thyroid-stimulating hor-mone (TSH)-thyroperoxidase antibody relation-ships demonstrate that TSH upper reference limits may be skewed by occult thyroid dysfunction. J Clin Endocrinol Metab 2007;92:4236–40.
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29. Diez JJ, Iglesias P, Burman KD. Spontaneous normalization of thyrotropin concentrations in patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2005;90:4124–7.
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31. Brabant G, Beck-Peccoz P, Jarzab B, et al. Is there a need to redefine the upper normal limit of TSH? Eur J Endocrinol 2006;154:633–7.
32. Buxton OM, Frank SA, L'Hermite-Balériaux M, Leproult R, Turek FW, Van Cauter E. Roles of inten-sity and duration of nocturnal exercise in causing phase delays of human circadian rhythms. Am J Physiol Endocrinol Metab 1997;273:536–42. 33. Adriaanse R, Romijn JA, Brabant G, Endert E,
Wiersinga WM. Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:1313–7.
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No 2-2008 American Thyroid Association: Highlights of the 78th Annual Meeting (Stephen W Spaulding, Peter PA Smyth)
No 1-2008 Report of the 32th Annual Meeting of the European Thyroid Association (GJ Kahaly, P.P.A. Smyth)
No 4-2007 The Thyroid and Twins (Pia Skov Hansen, Thomas Heiberg Brix, Laszlo Hegedüs)
No 3-2007 Clinical Aspects of Thyroid Disorders in the Elderly (Valentin Fadeyev)
No 2-2007 Report of the 31th Annual Meeting of the European Thyroid Association (John H Lazarus, Peter PA Smyth)
No 1-2007 The story of the ThyroMobil (F. Delange, C.J. Eastman, U. Hostalek, S. Butz, P.P.A. Smyth)
No 3-2006 Thyroid Peroxidase – Enzyme and Antigen (Barbara Czarnocka)
No 2-2006 Genetics of benign and malignant thyroid tumours (Dagmar Führer)
No 1-2006 Highlights of the 13th ITC
(Sheue-yann Cheng, Peter PA Smyth)
No 4-2005 Thyroid Eye Disease:
Current Concepts and the EUGOGO Perspective (Gerasimos E Krassas, Wilmar M Wiersinga)
No 3-2005 Clinical Expression of Mutations in the TSH Receptor: TSH-R Disorders
(Davide Calebiro, Luca Persani, Paolo Beck-Peccoz)
No 2-2005 Transient Hypothyroxinaemia and Preterm Infant Brain Development
(Robert Hume, Fiona LR Williams, Theo J Visser)
No 1-2005 The Spectrum of Autoimmunity in Thyroid Disease (Anthony P. Weetman)
No 5-2004 Postpartum Thyroiditis: An Update (Kuvera E. Premawardhana, John H. Lazarus)
No 4-2004 Report of the 29th Annual Meeting of the European Thyroid Association (G. Hennemann)
No 3-2004 Autoimmune Thyroiditis And Pregnancy (Alex F. Muller, Arie Berghout)
No 2-2004 Report of the 75th Annual Meeting of the American Thyroid Association (G. Hennemann)
No 1-2004 Thyroid and Lipids: a Reappraisal (Leonidas H. Duntas)
No 5-2003 Use of Recombinant TSH in Thyroid Disease: An Evidence-Based Review (Sara Tolaney M.D., Paul W. Ladenson M.D.)
No 4-2003 New Insights for Using Serum Thyroglobulin (Tg) Measurement for Managing Patients with Differentiated Thyroid Carcinomas (C.A. Spencer)
No 3-2003 The Significance of Thyroid Antibody Measurement in Clinical Practice (A. Pinchera, M. Marinò, E. Fiore)
Former Editions of Thyroid International
No 2-2003 Etiology, diagnosis and treatment of Graves’ disease (A.P. Weetman)
No 1-2003 Report of the 74th Annual Meeting of the American Thyroid Association (G. Hennemann)
No 6-2002 Report of the 28th Annual Meeting of the European Thyroid Association (G. Hennemann)
No 5-20 02 Iodine Deficiency in Europe anno 2002 (François M. Delange, MD, PhD)
No 4-20 02 Thyroid Imaging in Nuclear Medicine (Dik J. Kwekkeboom, Eric P. Krenning)
No 3-20 02 Congenital Hypothyroidism (Delbert A. Fisher)
No 2-20 02 The Use of Fine Needle Aspiration Biopsy (FNAB) in Thyroid Disease (Antonino Belfiore)
No 1-20 02 Report of the 73rd Annual Meeting of the American Thyroid Association (G. Hennemann)
No 6-2001 Report of the 27th Annual Meeting of the European Thyroid Association (G. Hennemann)
No 5-2001 Subclinical Hyperthyroidism (E.N. Pearce, L.E. Braverman)
No 4-2001 Thyroid hormone treatment – how and when? (A.D. Toft)
No 3-2001 Resistance to thyroid hormone (O. Bakker, W.M. Wiersinga)
No 1/2-20 0 1 Report of the 12th International Thyroid Congress (G. Hennemann)
No 5-2000 Percutaneous ethanol injection therapy for thyroid diseases (Enio Martino)
No 4-2000 Inheritable forms of thyroid carcinoma (Martin Schlumberger)
No 3-2000 Multinodular goitre (Peter Laurberg)
No 2-2000 Drug effects on thyroid function (Jan R. Stockigt)
No 1-2000 Thyroid disease, menstrual function and fertility (Gerasimos E. Krassas)
No 6-1999 Report of the 27th Annual Meeting of the American Thyroid Association (G. Hennemann)
No 5-1999 Report of the 26th Annual Meeting of the European Thyroid Association (G. Hennemann)
No 4-1999 Report of the 8th Biannual Meeting of the Latin American Thyroid Society (LATS) (Geraldo Medeiros-Neto)
No 3-1999 Subclinical Hypothyroidism (Demetrios A. Koutras)
No 2-1999 Radioactive iodine treatment for benign thyroid disease (L. Hegedüs)
No 1-1999 Report of the 26th Annual Meeting of the European Thyroid Association (G. Hennemann)
No 6-1998 Thyroid and Bone
(P. L. A. van Daele, H. A. P. Pols)
secretly steals life.
Taking the offensive against hypothyroidism. With Euthyrox.
• multiple dosage strengths for precise dose titration
• galenic formulation with reliable unit conformity
• first levothyroxine preparation with a European and FDA approval
Other registered tradenames: Eutirox, Supratirox
Active substance: Levothyroxine sodium. Prescription only medicine. Composition: Each tablet (round with cross score) of Euthyrox 25/50/75/100/125/150/175/200 µg contains 25/50/75/100/125/150/175/200 µg of levothyro xi ne sodium.
Other ingredients: Corn starch, croscarmellose sodium, gelatin, lactose monohydrate, magnesium stearate. Indications: Euthyrox 25 - 200 µg: Euthyroid goitre, prophylaxis of relapse goitre after goitre resection, hypothyroidism,
suppression therapy in thyroid cancer. Additional indication for Euthyrox 25 - 100 µg: Concomitant therapy in antithyroid drug therapy of hyperthyroidism after having achieved a euthyroid function. Additional indication for Euthyrox 100/150/200 µg: Thyroid suppression test. Contraindications: Intolerance to the active substance or any of the excipients. Untreated adrenocortical insufficiency, untreated pituitary insufficiency, untreated hyperthyroidism. Do not
initiate therapy in acute myocardial infarction, acute myocarditis, acute pancarditis. Adverse reactions: Adverse reactions are not to be expected under adequate therapy. In (individual) intolerance of the chosen dosage or overdosage
(particularly if the dose is increased too quickly at the start of treatment): tachycardia, palpitations, cardiac arrhythmias, angina pectoris, headache, muscle weakness and cramps, sensation of heat, fever, vomiting, menstrual disorders, pseudotumor cerebri, tremor, restlessness, insomnia, hyperhidrosis, weight loss, and diarrhoea. In such cases reduce the daily dosage or interrupt treatment for several days. Allergic reactions may occur in the case of hypersensitivity. Other notes: Treatment with thyroid hormones should be continued consistently during pregnancy in particular. The thyroid hormone quantity secreted into breast milk during lactation is not sufficient to cause development of hyperthyroid ism
or suppression of TSH secretion in the infant. During pregnancy contraindicated as concomitant treatment to antithyroid drug therapy. Exclude or treat coronary insufficiency, angina pectoris, arteriosclerosis, hypertension, pi tu i tary or adrenocortical insufficiency, and thyroid autonomy before initiating therapy with thyroid hormones. Prevent drug-induced hyperthyroidism in coronary insufficiency, heart failure, and achycardiac arrhythmias. Clarify cause of secondary hypothyroidism before initiating replacement therapy. In compensated adrenocortical insufficiency start adequate replacement therapy where necessary. When hypothyroid, postmenopausal women at increased risk of developing oste-oporosis are treated, their thyroid function should be checked more frequently in order to prevent supraphysiologic levothyroxine blood levels. Do not use in: patients with galactose intolerance, lactase deficiency or glucose-galactos-emalabsorption. Presentation and pack sizes: depending on the local registration state. For more detailed information please refer to the data sheet or package leaflet. Issued: October 2001. Merck KGaA, D-64271 Darmstadt, Germany.