Treatment of hypothyroidism with levothyroxine or a combination of levothyroxine plus L-triiodothyronine

Best Practice and Research: Clinical Endocrinology and Metabolism

Volumn 29, Issue 1, 2015, Pages 57-75

  Escobar Morreale, Héctor F F ^a,b   Botella Carretero, José I ^a,c   De Escobar, Gabriella Morreale ^d  

^a HOSPITAL RAMÓN Y CAJAL   (Spain)

^b UNIVERSITY OF ALCALÁ   (Spain)

^c Centro de Investigación Biomédica en Red de Cáncer CIBERONC University of Barcelona   (Spain)

^d CSIC   (Spain)

Author keywords

Combined therapy; Hypothyroidism; Levothyroxine; Liothyronine; Replacement

Indexed keywords

LEVOTHYROXINE; LIOTHYRONINE; THYROTROPIN; THYROXINE;

CLINICAL TRIAL (TOPIC); EUTHYROIDISM; FREE LIOTHYRONINE INDEX; HORMONE SUBSTITUTION; HUMAN; HYPOTHYROIDISM; MONOTHERAPY; NONHUMAN; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; THYROTROPIN BLOOD LEVEL; THYROXINE BLOOD LEVEL; COMBINATION DRUG THERAPY; TREATMENT OUTCOME;

DRUG THERAPY, COMBINATION; HORMONE REPLACEMENT THERAPY; HUMANS; HYPOTHYROIDISM; THYROXINE; TREATMENT OUTCOME; TRIIODOTHYRONINE;

EID: 84927940993     PISSN: 1521690X     EISSN: 15321908     Source Type: Journal    
DOI: 10.1016/j.beem.2014.10.004     Document Type: Review

References (70)

1. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21: 1081-125.
2. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American association of clinical endocrinologists and the American thyroid association. Endocr Pract 2012; 18: 988-1028.
3. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the American association of clinical endocrinologists and the American thyroid association. Thyroid 2012; 22: 1200-35.
4. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: An endocrine society clinical practice guideline. J Clin Endocrinol Metabolism 2012; 97: 2543-65.
5. Brenta G, Vaisman M, Sgarbi JA, et al. Clinical practice guidelines for the management of hypothyroidism. Arquivos Brasileiros de Endocrinol Metabologia 2013; 57: 265-91.
6. Leger J, Olivieri A, Donaldson M, et al. European society for paediatric endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Hormone Res Paediatr 2014; 81: 80-103.
7. Leger J, Olivieri A, Donaldson M, et al. European society for paediatric endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. J Clin Endocrinol Metabolism 2014; 99: 363-84.
8. Utiger RD. Hypothyroidism. In: De Groot LJ, editor. Endocrinology. 3rd ed. Philadelphia: W. B. Saunders Company; 1995. p. 752-68.
9. Ross DR. Treatment of hypothyroidism. In: Snyder PJ, Utiger RD, editors. Up to date in endocrinology and diabetes. Wellesley, MA: UpToDate, Inc.; 2004.
10. Pilo A, Iervasi G, Vitek F, et al. Thyroidal and peripheral production of 3,5,3'-triiodothyronine in humans by multicompartmental analysis. Am J Physiol 1990; 258: E715-26.
11. Hennessey JV, Evaul JE, Tseng YC, et al. L-Thyroxine dosage: A reevaluation of therapy with contemporary preparations. Ann Intern Med 1986; 105: 11-5.
12. Fish LH, Schwartz HL, Cavanaugh J, et al. Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans. N Engl J Med 1987; 316: 764-70.
13. Jonklaas J, Davidson B, Bhagat S, et al. Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. J Am Med Assoc 2008; 299: 769-77.
14. Carr D, McLeod DT, Parry G, et al. Fine adjustment of thyroxine replacement dosage: Comparison of the thyrotrophin releasing hormone test using a sensitive thyrotrophin assay with measurement of free thyroid hormones and clinical assessment. Clin Endocrinol (Oxf) 1988; 28: 325-33.
15. American association of clinical endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract 2002; 8: 457-69.
16. Wiersinga WM. Hypothyroidism. In: DeGroot LJ, Hennemann G, editors. Thyroid disease manager. Chicago, Ill.: The University of Chicago Pritzker School of Medicine-Endocrine Education, Inc; 2004. www.thyroidmanager.org.
17. Gow SM, Caldwell G, Toft AD, et al. Relationship between pituitary and other target organ responsiveness in hypothyroid patients receiving thyroxine replacement. J Clin Endocrinol Metabolism 1987; 64: 364-70.
18. De Groot L, Manowitz N, Chait L, et al. Differential end organ responsiveness to suboptimal thyroid hormone concentrations as assessed by short-term withdrawal of levothyroxine sodium in athyreotic patients. In: 70th annual meeting of the American thyroid association. Colorado Springs, Co; 1997. S-88.
19. Saravanan P, Chau WF, Roberts N, et al. Psychological well-being in patients on 'adequate' doses of L-thyroxine: Results of a large, controlled community-based questionary study. Clin Endocrinol (Oxf) 2002; 57: 577-85.
20. Ladenson PW. Psychological wellbeing in patients. Clin Endocrinol (Oxf) 2002; 57: 575-6.
21. Escobar-Morreale HF, Obregón MJ, Escobar del Rey F, et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. J Clin Investig 1995; 96: 2828-38.
22. Escobar-Morreale HF, Escobar del Rey F, Obregón MJ, et al. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology 1996; 137: 2490-502.
23. Escobar-Morreale HF, Obregón MJ, Hernández A, et al. Regulation of iodothyronine deiodinase activity as studied in thyroidectomized rats infused with thyroxine or triiodothyronine. Endocrinology 1997; 138: 2559-68.
24. Escobar-Morreale HF, Obregon MJ, Escobar del Rey F, et al. Tissue-specific patterns of changes in 3,5,3'-triiodo-L-thyronine concentrations in thyroidectomized rats infused with increasing doses of the hormone. Which are the regulatory mechanisms? Biochimie 1999; 81: 453-62.
25. van der Heide D, Schroder van der Elst JP. Effect of age and gender on the thyroid hormone metabolism in the rat. 10th International Thyroid Congress. The Hague, The Netherlands. 1991. p. 311.
26. Jackson IMD, Cobb WE. Why does anyone still use desiccated thyroid USP? Am J Med 1978; 64: 284-8.
27. Smith SR. Desiccated thyroid preparations. Obsolete therapy. Arch Intern Med 1984; 144: 926-7.
28. Toft AD. Thyroid hormone replacement-one hormone or two? N Engl J Med 1999; 340: 469-70.
29. Morreale de Escobar G, Obregón MJ, Escobar del Rey G. Role of thyroid hormone during early brain development. Eur J Endocrinol 2004; 151: U25-37.
30. Morreale de Escobar G, Obregón MJ, Escobar Del Rey F. Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metabolism 2004; 18: 225-48.
31. Akcay T, Turan S, Guran T, et al. T4 plus T3 treatment in children with hypothyroidism and inappropriately elevated thyroid-stimulating hormone despite euthyroidism on T4 treatment. Hormone Res Paediatr 2010; 73: 108-14.
32. Strich D, Naugolny L, Gillis D. Persistent hyperthyrotropinemia in congenital hypothyroidism: Successful combination treatment with levothyroxine and liothyronine. J Pediatr Endocrinol Metabolism 2011; 24: 347-50.
33. Peter F, Muzsnai A. Combined l-thyroxine and l-triiodothyronine replacement therapy in congenital hypothyroidism. Orvosi Hetil 2013; 154: 738-44.
34. Schroder van der Elst JP, van der Heide D. Effects of 5,5'-diphenylhydantoin on thyroxine and 3,5,3'-triiodothyronine concentrations in several tissues of the rat. Endocrinology 1990; 126: 186-91.
35. Schroder van der Elst JP, van der Heide D. Thyroxine, 3,5,3'-triiodothyronine, and 3,3',5'-triiodothyronine concentrations in several tissues of the rat: Effects of amiodarone and desethylamiodarone on thyroid hormone metabolism. Endocrinology 1990; 127: 1656-64.
36. Schroder van der Elst JP, van der Heide D, Kohrle J. In vivo effects of flavonoid EMD 21388 on thyroid hormone secretion and metabolism in rats. Am J Physiol 1991; 261: E227-32.
37. Schroder van der Elst JP, van der Heide D. Effects of streptozocin-induced diabetes and food restriction on quantities and source of T4 and T3 in rat tissues. Diabetes 1992; 41: 147-52.
38. Surks MI, Schadlow AR, Oppenheimer JH. A new radioimmunoassay for plasma L-triiodothyronine: Measurements in thyroid disease and in patients maintained on hormonal replacement. J Clin Investig 1972; 51: 3104-13.
39. Rees-Jones RW, Larsen PR. Triiodothyronine and thyroxine content of desiccated thyroid tablets. Metabolism 1977; 26: 1213-8.
40. Taylor S. Thyroid extract. Lancet 1961; 1: 332-3.
41. Taylor S, Kapur M, Adie R. Combined thyroxine and triiodothyronine for thyroid replacement therapy. Br Med J 1970; 1: 270-1.
42. Smith RN, Taylor SA, Massey JC. Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br Med J 1970; 4: 145-8.
43. Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340: 424-9.
44. Kaplan MM, Sarne DH, Schneider AB. In search of the impossible dream? Thyroid hormone replacement therapy that treats all symptoms in all hypothyroid patients. J Clin Endocrinol Metabolism 2003; 88: 4540-2.
45. Bunevicius R, Prange Jr. AJ. Mental improvement after replacement therapy with thyroxine plus triiodothyronine: Relationship to cause of hypothyroidism. Int J Neuropsychopharmacol 2000; 3: 167-74.
46. Bunevicius R, Jakubonien N, Jurkevicius R, et al. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves' disease. Endocrine 2002; 18: 129-33.
47. Walsh JP, Shiels L, Lim EM, et al. 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 Metabolism 2003; 88: 4543-50.
48. Sawka AM, Gerstein HC, Marriot MJ, et al. Does a combination regimen of thyroxine (T4) and 3,5,30-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metabolism 2003; 88: 4551-5.
49. Clyde PW, Harari AE, Getka EJ, et al. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: A randomized controlled trial. J Am Med Assoc 2003; 290: 2952-8.
50. Saravanan P, Simmons DJ, Greenwood R, et al. 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 Metabolism 2005; 90: 805-12.
51. Rodriguez T, Lavis VR, Meininger JC, et al. Substitution of liothyronine at a 1: 5 ratio for a portion of levothyroxine: Effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract 2005; 11: 223-33.
52. Fadeyev VV, Morgunova TB, Sytch JP, et al. TSH and thyroid hormones concentrations in patients with hypothyroidism receiving replacement therapy with L-thyroxine alone or in combination with L-triiodothyronine. Horm (Athens) 2005; 4: 101-7.
53. Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, et al. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: A randomized controlled trial. Endocr Res 2009; 34: 80-9.
54. Nygaard B, Jensen EW, Kvetny J, et al. Effect of combination therapy with thyroxine (T4) and 3,5,3'-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol 2009; 161: 895-902.
55. Fadeyev VV, Morgunova TB, Melnichenko GA, et al. Combined therapy with L-thyroxine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Horm (Athens) 2010; 9: 245-52.
56. Schmidt U, Nygaard B, Jensen EW, et al. Peripheral markers of thyroid function: The effect of T4 monotherapy vs T4/T3 combination therapy in hypothyroid subjects in a randomized crossover study. Endocr Connect 2013; 2: 55-60.
57. Cooper DS. Combined T4 and T3 therapy-back to the drawing board. J Am Med Assoc 2003; 290: 3002-4.
58. Escobar-Morreale HF, Botella-Carretero JI, Escobar del Rey F, et al. REVIEW: Treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J Clin Endocrinol Metabolism 2005; 90: 4946-54.
59. Wiersinga WM, Duntas L, Fadeyev V, et al. 2012 ETA guidelines: The Use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J 2012; 1: 55-71.
60. Biondi B, Wartofsky L. Combination treatment with T4 and T3: Toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metabolism 2012; 97: 2256-71.
61. Wartofsky L. Combination L-T3 and L-T4 therapy for hypothyroidism. Curr Opin Endocrinol Diabetes, & Obes 2013; 20: 460-6.
62. Cassio A, Cacciari E, Cicognani A, et al. Treatment for congenital hypothyroidism: Thyroxine alone or thyroxine plus triiodothyronine? Pediatrics 2003; 111: 1055-60.
63. Siegmund W, Spieker K, Weike AI, et al. 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: 750-7.
64. Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, et al. Thyroid hormone replacement therapy in primary hypothyroidism: A randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med 2005; 142: 412-24.
65. Appelhof BC, Fliers E, Wekking EM, et al. Combined therapy with levothyroxine and liothyronine in two ratio's compared with levothyroxine monotherapy in primary hypothyroidism; a double blind, randomized controlled clinical trial. J Clin Endocrinol Metabolism 2005; 90: 2666-74.
66. Regalbuto C, Maiorana R, Alagona C, et al. Effects of either LT4 monotherapy or LT4/LT3 combined therapy in patients totally thyroidectomized for thyroid cancer. Thyroid 2007; 17: 323-31.
67. Panicker V, Saravanan P, Vaidya B, et al. Common variation in the DIO2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin Endocrinol Metabolism 2009; 94: 1623-9.
68. Appelhof BC, Peeters RP, Wiersinga WM, et al. Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine/3,5,3'-triiodothyronine therapy. J Clin Endocrinol Metabolism 2005; 90: 6296-9.
69. Hennemann G, Docter R, Visser TJ, et al. Thyroxine plus low-dose, slow-release triiodothyronine replacement in hypothyroidism: Proof of principle. Thyroid 2004; 14: 271-5.
70. Wartofsky L. Combined levotriiodothyronine and levothyroxine therapy for hypothyroidism: Are we a step closer to the magic formula? Thyroid 2004; 14: 247-8.