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Effect of timing of levothyroxine administration on the treatment of hypothyroidism: a three-period crossover randomized study

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Hypothyroidism is a common clinical problem that is successfully treated with hormone substitutes in the form of levothyroxine (LT4). LT4 is a drug with a narrow therapeutic index and is usually administered by strict rules, standardly at least half an hour before breakfast. The aim of this study was to investigate a possible effect of different timings of administration on thyroid function status and lipid profile.


The study included patients with the diagnosis of primary hypothyroidism, which were using a stable dose of levothyroxine. They were randomized into three different groups regarding the timing of LT4 administration in a crossover fashion. Each timing regimen lasted for at least 8 weeks; timing regimen A—half an hour before breakfast; timing regimen B—an hour before the main meal of the day; timing regimen C—at bedtime (minimally 2 h after dinner). The hormones (TSH, fT3, fT4) and lipid profile (triglycerides, HDL-, LDL-, and total cholesterol) were measured before the study, at the beginning of every timing regimen and at the end of the study.


Altogether, 84 patients finished the study. Different timings of LT4 administration were non-inferior in comparison to the standard one and between each other. Median differences in TSH level between baseline and timing regimens were: baseline vs. A = −0.017 95% C.I. (−0.400–0.192); baseline vs. B = −0.325 95% C.I. (−0.562–0.023); baseline vs. C = −0.260 95% C.I. (−0.475–0.000). There were no statistically significant differences in either TSH, fT4, or fT3 when compared between all three timing regimens of LT4 administration and the baseline. There were no statistically significant differences in any of the lipid profile parameters (triglycerides, HDL-, LDL-, and total cholesterol) when compared between all three timing regimens of LT4 administration and the baseline.


The three investigated timing regimens of LT4 administration were equally efficient and offer additional options regarding the treatment individualization.

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Free triiodothyronin


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  1. Y. Aoki, R.M. Belin, R. Clickner, R. Jeffries, L. Phillips, K.R. Mahaffey, Serum, TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002). Thyroid 17, 1211–1223 (2007)

    Article  Google Scholar 

  2. M. Devdhar, Y. Ousman, K. Burman, Hypothyroidism. Endocrinol. Metab. Clin. North. Am. 36, 595–615 (2007)

    Article  CAS  Google Scholar 

  3. C.V. Rizos, M.S. Elisaf, E.N. Liberopoulos, Effects of thyroid dysfunction on lipid profile. Open Cardiovasc. Med. J. 5, 76–84 (2011)

    Article  CAS  Google Scholar 

  4. B. Biondi, I. Klein, Hypothyroidism as a risk factor for cardiovascular disease. Endocrine 24, 1–13 (2004)

    Article  CAS  Google Scholar 

  5. L. Liwanpo, J.M. Hershman, Conditions and drugs interfering with thyroxine absorption. Best. Pract. Res. Clin. Endocrinol. Metab. 23, 781–792 (2009)

    Article  CAS  Google Scholar 

  6. S.J. Mandel, G.A. Brent, P.R. Larsen, Levothyroxine therapy in patients with thyroid disease. Ann. Intern. Med. 119, 492–502 (1993)

    Article  CAS  Google Scholar 

  7. M. Skelin, T. Lucijanić, D. Amidžić Klarić, A. Rešić, M. Bakula, A. Liberati-Čizmek, H. Gharib, D. Rahelić, Factors affecting gastrointestinal absorption of levothyroxine: a review. Clin. Ther. 39, 378–403 (2017)

    Article  CAS  Google Scholar 

  8. Agency for Medicinal Products and Medical Devices. (2015) Euthyrox 100 mg tablets Accessed 10 January 2017.

  9. A.J. Claxton, J. Cramer, C.A. Pierce, A systematic review of the associations between dose regimens and medication compliance. Clin. Ther. 23, 1296–1310 (2001)

    Article  CAS  Google Scholar 

  10. N. Bolk, T.J. Visser, A. Kalsbeek, R.T. Van Domburg, A. Berghout, Effects of evening vs morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients. Clin. Endocrinol. (Oxf.). 66, 43–48 (2007)

    CAS  PubMed  Google Scholar 

  11. T.G. Bach-Huynh, B. Nayak, J. Loh, S. Soldin, J. Jonklaas, Timing of levothyroxine administration affects serum thyrotropin concentration. J. Clin. Endocrinol. Metab. 94, 3905–3912 (2009)

    Article  CAS  Google Scholar 

  12. S. Ala, O. Akha, Z. Kashi, H. Asgari, A. Bahar, N. Sasanpour, Dose administration time from before breakfast to before dinner affect thyroid hormone levels? Casp. J. Intern. Med. 6, 134–140 (2015)

    Google Scholar 

  13. M. Centanni, L. Gargano, G. Canettieri, N. Viceconti, A. Franchi, G. Delle Fave, B. Annibale, Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N. Engl. J. Med. 17, 1787–1795 (2006)

    Article  Google Scholar 

  14. J.G. Moore, E.Jr Englert, Circadian rhythm of gastric acid secretion in man. Nature 226, 1261–1262 (1970)

    Article  CAS  Google Scholar 

  15. S. Benvenga, L. Bartolone, S. Squadrito, F. Lo Giudice, F. Trimarchi, Delayed intestinal absorption of levothyroxine. Thyroid 5, 249–253 (1995)

    Article  CAS  Google Scholar 

  16. R. Vita, P. Fallahi, A. Antonelli, S. Benvenga, The administration of L-thyroxine as soft gel capsule or liquid solution. Expert. Opin. Drug. Deliv. 11, 1103–1111 (2006)

    Article  Google Scholar 

  17. G. Ianiro, F. Mangiola, T.A. Di Rienzo, S. Bibbò, F. Franceschi, A.V. Greco, A. Gasbarrini, Levothyroxine absorption in health and disease, and new therapeutic perspectives. Eur. Rev. Med. Pharmacol. Sci. 18, 451–456 (2014)

    CAS  PubMed  Google Scholar 

  18. A.M. Formenti, G. Mazziotti, R. Giubbini, A. Giustina, Treatment of hypothyroidism: all that glitters is gold? Endocrine 52, 411–413 (2016)

    Article  CAS  Google Scholar 

  19. R. Rajput, S. Chatterjee, M. Rajput, Can levothyroxine be taken as evening dose? Comparative evaluation of morning versus evening dose of levothyroxine in treatment of hypothyroidism. J. Thyroid Res. 2011, 505239 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. P. Trimboli, C. Virili, M. Centanni, L. Giovanella, Thyroxine treatment with softgel capsule formulation: usefulness in hypothyroid patients without malabsorption. Front. Endocrinol. (Lausanne). 9, 118 (2018)

    Article  Google Scholar 

  21. E. Lahner, C. Virili, M.G. Santaguida, B. Annibale, M. Centanni, Helicobacter pylori infection and drugs malabsorption. World J. Gastroenterol. 20, 10331–10337 (2014)

    Article  CAS  Google Scholar 

  22. M. Cellini, M.G. Santaguida, C. Virili, S. Capriello, N. Brusca, L. Gargano, M. Centanni, Hashimoto’s thyroiditis and autoimmune gastritis. Front. Endocrinol. (Lausanne). 8, 92 (2017)

    Article  Google Scholar 

  23. I. Sachmechi, D.M. Reich, M. Aninyei, F. Wibowo, G. Gupta, P.J. Kim, Effect of proton pump inhibitors on serum thyroid-stimulating hormone level in euthyroid patients treated with levothyroxine for hypothyroidism. Endocr. Pract. 13, 345–349 (2007)

    Article  Google Scholar 

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This study did not receive any external funding.

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All authors contributed to preparation of this manuscript.

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Correspondence to Marko Skelin.

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Conflict of interest

DR has served as principal investigator or co-investigator in clinical trials of AstraZeneca, Eli Lilly, MSD, Novo Nordisk, Sanofi Aventis, Solvay, and Trophos. He has received honoraria for speaking or advisory board engagements and consulting fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Lifescan–Johnson & Johnson, Novartis, Novo Nordisk, MSD, Merck Sharp & Dohme, Pfizer, Pliva, Roche, Salvus, Sanofi Aventis, and Takeda. MS has recevied honoraria for lectures from Roche. Other co-authors have no conflict of interest. TL has served as principal investigator or co-investigator in clinical trials of Bayer HealthCare AG, Sanofi Aventis, Institut de Recherches Internationales Servier, Zavante Therapeutics, and Novo Nordisk. He has received honoraria for speaking engagements from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, MSD.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Skelin, M., Lucijanić, T., Liberati-Čizmek, AM. et al. Effect of timing of levothyroxine administration on the treatment of hypothyroidism: a three-period crossover randomized study. Endocrine 62, 432–439 (2018).

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