Exp Clin Endocrinol Diabetes 2007; 115(4): 261-267
DOI: 10.1055/s-2007-973071

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

Twenty-four Hour Hormone Profiles of TSH, Free T3 and Free T4 in Hypothyroid Patients on Combined T3/T4 Therapy

P. Saravanan 1 , H. Siddique 2 , D. J. Simmons 1 , R. Greenwood 3 , C. M. Dayan 1
  • 1Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol
  • 2Department of Endocrinology, Bristol Royal Infirmary, Bristol, UK
  • 3Research and Development Support Unit, Bristol Royal Infirmary, Bristol, UK
Further Information

Publication History

received 3. 8. 05 first decision 4. 11. 05

accepted 3. 11. 06

Publication Date:
03 May 2007 (online)


The benefits of using thyroxine (T4) plus triiodothyronine (T3) in combination in thyroid hormone replacement are unproven but many individuals continue to be treated with this regime. When T3 is used alone for hypothyroidism, it results in wide fluctuations of thyroid hormone levels. However, only limited data exists on combined T3/T4 therapy. In this study, we have compared 24-hour profiles of thyroid stimulating hormone (TSH), free T4 (fT4) and free T3 (fT3) and cardiovascular parameters in 10 hypothyroid patients who had been on once daily combined T3/T4 therapy for more than 3 months with 10 patients on T4 alone. Twenty patients, who were part of a larger study, investigating the long-term benefits of combined T3/T4 therapy, were recruited into this sub-study. Over 24-hours, 12 samples were taken for thyroid hormones. Their 24-hour pulse and BP is also monitored on a separate occasion. On T4 alone, a modest 16% rise in fT4 with no change in fT3 was seen in the first 4-hours post-dose. In contrast, on combined treatment, fT3 levels showed a marked rise of 42% within the first 4-hours post-dose (T3/T4:T4=6.24: 4.63 mU/L, p<0.001). Mean exposure to fT3 calculated by area under the curve (AUC) was higher (T3/T4:T4=1148:1062, p<0.0001) on T3. Circadian rhythm of TSH was maintained on both treatments. No difference in pulse or blood pressure over the 24-hours was seen between the groups. Our data suggests that despite chronic combined T3/T4 therapy, wide peak-to-trough variation in fT3 levels persists. Although no immediate cardiovascular effects were seen, the long-term consequences for patients on combined therapy are unknown.


  • 1 Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, Endert E, van Weert HC, Wiersinga WM. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial.  J Clin Endocrinol Metab. 2005;  90 2666-2674
  • 2 Bauer DC, Ettinger B, Nevitt MC, Stone KL. Risk for fracture in women with low serum levels of thyroid-stimulating hormone.  Ann Intern Med. 2001;  134 561-568
  • 3 Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.  Endocr Rev. 2002;  23 38-89
  • 4 Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart.  Ann Intern Med. 2002a;  137 904-914
  • 5 Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of thyroid hormone on cardiac function: the relative importance of heart rate, loading conditions, and myocardial contractility in the regulation of cardiac performance in human hyperthyroidism.  J Clin Endocrinol Metab. 2002b;  87 968-974
  • 6 Blanchard KR. Dosage recommendations for combination regimen of thyroxine and 3,5,3′-triiodothyronine.  J Clin Endocrinol Metab. 2004;  89 1486-1487
  • 7 Bunevicius R, Jakubonien N, Jurkevicius R, Cernicat J, Lasas L, Prange Jr. AJ. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves' disease.  Endocrine. 2002;  18 129-133
  • 8 Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange Jr. AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism.  N Engl J Med. 1999;  340 424-429
  • 9 Busnardo B, Girelli ME, Bui F, Zanatta GP, Cimitan M. Twenty-four hour variations of triiodothyronine (T3) levels in patients who had thyroid ablation for thyroid cancer, receiving T3 as suppressive treatment.  J Endocrinol Invest. 1980;  3 353-356
  • 10 Clyde PW, Harari AE, Getka EJ, Shakir KMM. Combined Levothyroxine Plus Liothyronine Compared With Levothyroxine Alone in Primary Hypothyroidism: A Randomized Controlled Trial.  JAMA: The Journal of the American Medical Association. 2003;  290 2952-2958
  • 11 Cooper DS. Combined T4 and T3 therapy-back to the drawing board.  JAMA. 2003;  290 3002-3004
  • 12 Escobar-Morreale HF, Obregon MJ, Escobar dR, Morreale dE. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats.  J Clin Invest. 1995;  96 2828-2838
  • 13 Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone.  Ann Intern Med. 2005;  142 412-424
  • 14 Faber J, Galloe AM. Changes in bone mass during prolonged subclinical hyperthyroidism due to L-thyroxine treatment: a meta-analysis.  Eur J Endocrinol. 1994;  130 350-356
  • 15 Feek CM, Ratcliffe JG, Seth J, Gray CE, Toft AD, Irvine WJ. Patterns of plasma cortisol and ACTH concentrations in patients with Addison's disease treated with conventional corticosteroid replacement.  Clin Endocrinol (Oxf). 1981;  14 451-458
  • 16 Hennemann G, Docter R, Visser TJ, Postema PT, Krenning EP. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: proof of principle.  Thyroid. 2004;  14 271-275
  • 17 Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy.  J Clin Endocrinol Metab. 1974;  39 923-927
  • 18 Saravanan P, Chau WF, Roberts N, Vedhara K, Greenwood R, Dayan CM. Psychological well-being in patients on ‘adequate’ doses of L-thyroxine: results of a large, controlled community-based questionnaire study.  Clinical Endocrinology. 2002;  57 577-585
  • 19 Saravanan P, Dayan CM. Understanding thyroid hormone action and the effects of thyroid hormone replacement - just the beginning not the end.  Hot Thyroidology. 2004;  , October: No 1 (free access at www.hotthyroidology.com)
  • 20 Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial.  J Clin Endocrinol Metab. 2005;  90 805-812
  • 21 Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial.  J Clin Endocrinol Metab. 2003;  88 4551-4555
  • 22 Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone.  Nat Med. 2004;  10 638-642 , Epub 2004 May 16
  • 23 Scott RS, Donald RA, Espiner EA. Plasma ACTH and cortisol profiles in Addisonian patients receiving conventional substitution therapy.  Clin Endocrinol (Oxf). 1978;  9 571-576
  • 24 Sheppard MC, Holder R, Franklyn JA. Levothyroxine treatment and occurrence of fracture of the hip.  Arch Intern Med. 2002;  162 338-343
  • 25 Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, Kirsch G, Sanger E, Engel G, Hamm AO, Nauck M, Meng W. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14:1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism.  Clin Endocrinol (Oxf). 2004;  60 750-757
  • 26 Uzzan B, Campos J, Cucherat M, Nony P, Boissel JP, Perret GY. Effects on bone mass of long term treatment with thyroid hormones: a meta-analysis.  J Clin Endocrinol Metab. 1996;  81 4278-4289
  • 27 Walsh JP. Dissatisfaction with thyroxine therapy - could the patients be right?.  Curr Opin Pharmacol. 2002;  2 717-722
  • 28 Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, Dhaliwal SS, Chew GT, Bhagat MC, Cussons AJ. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism.  J Clin Endocrinol Metab. 2003;  88 4543-4550
  • 29 Walsh JP, Stuckey BG. What is the optimal treatment for hypothyroidism?.  Med J Aust. 2001;  174 141-143
  • 30 Wartofsky L.. Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: are we a step closer to the magic formula?.  Thyroid. 2004;  14 247-248
  • 31 Weeke J, Gundersen HJ. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects.  Acta Endocrinol (Copenh). 1978;  89 659-672
  • 32 Woliner K. , Combined T4/T3 Therapy: Placebo or Tomato? On line article 2003;  , (assessed at www.thyroidabout.com on 20.10.2006)

1 Financial support: Southwest National Health Service Research and Development, UK.


C. M. Dayan

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology

Dorothy Hodgkin Building

University of Bristol

Whitson St

Bristol BS1 3NY


Phone: +44/117/92 82 271

Fax: +44/117/92 84 081

Email: colin.dayan@bris.ac.uk