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Thyroid Disorders Section Heading Section sub Short-term Withdrawal of Levothyroxine, Induced Increase of Thyroid-stimulating Hormone and an Increased Ratio of Triiodothyronine to Thyroxine Martin Carlwe, 1 Thomas Schaffer 1 and Stefan Sjöberg 1,2 1. Department of Medicine, Halland County Hospital, Halmstad; 2. Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm Abstract Objective: Treatment with levothyroxine in primary hypothyroid patients does not always provide complete regression of associated symptoms despite normalised thyroid-stimulating hormone (TSH) levels. Several sources report ratios of triiodothyronine (T3) to thyroxine (T4) are diminished in hypothyroid patients following a daily levothyroxine regimen. It is known that TSH increases de-iodination of T4 to T3. We hypothesise that a rise in TSH levels caused by a temporary withdrawal of oral levothyroxine will be followed by an increased conversion of T4 to T3. Methods: Thirteen patients treated with monotherapy of levothyroxine were included in our pilot study. Treatment was temporarily discontinued for 1 week in which TSH, free T3 (fT3) and free T4 (fT4) were monitored. TSH and fT3 to fT4 ratios were compared with baseline values. Results: Statistically significant elevations in TSH and fT3 plasma levels relative to fT4 were demonstrated in all patients after withdrawal of levothyroxine. Conclusion: Both TSH and fT3 to fT4 ratios rose following temporary discontinuation of levothyroxine. The effect on symptoms and quality of life is not evaluated in this pilot study. Our results warrant further investigation into whether or not longer dosing intervals would demonstrate commensurate hormone elevations that better reflects the hormonal ratios in healthy subjects and if this also has an effect on quality of life scores. Keywords Hypothyroidism, chronic autoimmune thyroiditis, levothyroxine, monotherapy, combination therapy, T3/T4-ratio in plasma Disclosure: The authors have no conflicts of interest to declare. Acknowledgements: The authors thank Mr Tom Lundahl of the Department of Clinical Chemistry, Halland County Hospital who carried out the biochemical analysis. Professor Ulf Strömberg and Mr Anders Holmén of the Department of Clinical Research Center, Halland County Hospital, who performed the statistical analysis. We also wish to thank Dr Max Berry, Department of Vascular and Interventional Radiology, University of Alabama, Birmingham for critical reading and valuable feedback on the manuscript. Received: 20 December 2012 Accepted: 14 February 2013 Citation: European Endocrinology, 2013;9(1):37–9 Correspondence: Martin Carlwe, Department of Medicine, Halland County Hospital, Halmstad, SE-30185, Sweden. E: Hypothyroidism is a ubiquitous condition. According to the National Board of Health and Welfare, thyroid-hormone replacement was prescribed to approximately 370,000 individuals in Sweden during 2010. Eighty-three per cent were women, representing more than 6 % of the female population. 1 Autoimmune thyroiditis is the most predominant cause, but it may also be a consequence of previous radioiodine therapy or thyroidectomy. Hoarse voice, dry skin and muscle cramps are common symptoms. Intensified fatigue, coldness, tendency to constipation or depressive symptoms will often force the patient to a physician. Increased thyroid-stimulating hormone (TSH) – indicating a primary hypothyroid insufficiency – may contribute to the diagnosis of hypothyroidism. However, a weak association is reported between a higher TSH and a number of symptoms. 2 A hypothyroid patient is commonly treated with levothyroxine and the dose adjusted until TSH is normalised. 3 Despite treatment resulting in normalised serum TSH Saravanan et al. have reported that patients show a permanent impairment in psychological wellbeing compared with healthy subjects. 4 A coupling to the lower triiodothyronine (T3) to thyroxine (T4) ratio noted in levothyroxine-treated patients compared with healthy subjects 5–8 has been proposed to be a contributing cause. Thus, combined T3 and T4 treatment have been tried to improve patient’s wellbeing. However, a recent meta-analysis of 1,200 patients demonstrated ambiguous results when searching for clear correlation. 9 © To u ch MEd ica l MEdia 2013 Another study using higher T3 supplementation supported the notion that an increased T3 level may be associated with a better wellbeing. 10 The conversion from T4 to T3 is regulated by deiodinase and the activity is elevated in the hypothyroid state as supported by in vitro studies in which thyroid cells incubated with TSH demonstrated increased deiodinase and messenger RNA (mRNA) activity. 11,12 Our study’s aim was to determine if withdrawal of oral levothyroxine would elevate TSH and free T3 (fT3) to free T4 (fT4) ratios due to an increased conversion of fT4 to fT3. Bearing in mind the limited number of patients studied it was not intended to evaluate changes in symptoms. Materials and Methods Patients with primary hypothyroidism, 18–70 years of age, regularly controlled at our out-patient clinic, the Medical Department at Halland County Hospital, Sweden, were registered. The 71 patients who had treatment with levothyroxine alone without dose adjustments during the last three months, with normalised fT4 levels and normal or subnormal TSH were sent a written invitation. Patients with a symptomatic cardiac disease undergoing treatment with drugs that might have affected the levels of thyroid hormone in the last three months were excluded (iodine-containing X-ray contrast and antidepressants). In addition, pregnant and nursing women were also excluded. A total of 13 patients, after written consent was received, were included in our study. 37