Skip to main content

Advertisement

SpringerLink
Log in

The emergence of levothyroxine as a treatment for hypothyroidism

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Objective

To describe the historical refinements, understanding of physiology and clinical outcomes observed with thyroid hormone replacement strategies.

Methods

A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review. Additional references were identified in the course of review of the literature identified.

Results

Physicians have intervened in cases of thyroid dysfunction for more than two millennia. Ingestion of animal thyroid derived preparations has been long described but only scientifically documented for the last 130 years. Refinements in hormone preparation, pharmaceutical production and regulation continue to this day. The literature provides documentation of physiologic, pathologic and clinical outcomes which have been reported and continuously updated. Recommendations for effective and safe use of these hormones for reversal of patho-physiology associated with hypothyroidism and the relief of symptoms of hypothyroidism has documented a progressive refinement in our understanding of thyroid hormone use. Studies of thyroid hormone metabolism, action and pharmacokinetics have allowed evermore focused recommendations for use in clinical practice. Levothyroxine mono-therapy has emerged as the therapy of choice of all recent major guidelines.

Conclusions

The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. E.C. Kendall, The isolation in crystalline form of the compound containing iodin, which occurs in the thyroid: its chemical nature and physiologic activity. J. Am. Med. Assoc. 64, 2042–2043 (1915)

    Article  CAS  Google Scholar 

  2. C.R. Harington, G. Barger, Chemistry of thyroxine: constitution and synthesis of thyroxine. Biochem. J. 21(1), 169–183 (1927)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. C.R. Harington, Chemistry of thyroxine: constitution and synthesis of desiodo-thyroxine. Biochem. J. 20(2), 300–313 (1926)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. B. Biondi, L. Wartofsky, Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J. Clin. Endocrinol. Metab. 97(7), 2256–2271 (2012). doi:10.1210/jc.2011-3399

    Article  CAS  PubMed  Google Scholar 

  5. J. Gross, R. Pitt-Rivers, The identification of 3:5:3′-L-triiodothyronine in human plasma. Lancet 1(6705), 439–441 (1952). doi:S0140-6736(52)91952-1

    Article  CAS  PubMed  Google Scholar 

  6. J. Gross, R. Pitt-Rivers, 3:5:3′ -triiodothyronine. 1. Isolation from thyroid gland and synthesis. Biochem. J. 53(4), 645–650 (1953)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. J. Roche, S. Lissitzky, R. Michel, The metabolism of triiodothyronin and its biosynthesis as a thyroid hormone. C. R. Seances Soc. Biol. Fil. 146(19-20), 1474–1477 (1952)

    CAS  PubMed  Google Scholar 

  8. L.E. Braverman, S.H. Ingbar, K. Sterling, Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. J. Clin. Invest 49, 855–864 (1970)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. A.C. Bianco, D. Salvatore, B. Gereben, M.J. Berry, P.R. Larsen, Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr. Rev. 23(1), 38–89 (2002)

    Article  CAS  PubMed  Google Scholar 

  10. J. Jonklaas, B. Davidson, S. Bhagat, S. SJ, : Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA 299(7), 769–777 (2008)

    Article  CAS  PubMed  Google Scholar 

  11. A. Pilo, G. Iervasi, F. Vitek, M. Ferdeghini, F. Cazzuola, R. Bianchi, Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J. Physiol. 258(4 Pt 1), E715–726 (1990)

    CAS  PubMed  Google Scholar 

  12. S. Snyder, R.E. Listecki, Bioidentical thyroid replacement therapy in practice: Delivering a physiologic T4:T3 ratio for improved patient outcomes with the Listecki-Snyder protocol. Int. J. Pharm. Compd. 16(5), 376–380 (2012)

    PubMed  Google Scholar 

  13. S. Slater, The discovery of thyroid replacement therapy. Part 3: a complete transformation. J. R. Soc. Med. 104(3), 100–106 (2011). doi:10.1258/jrsm.2010.10k052

    Article  PubMed  PubMed Central  Google Scholar 

  14. F. Semon, In discussion of ‘A typical case of myxedema’. In: Drewitt, F.D. (ed.) Proceedings of the Clinical Society of London, London, GB 1883, Vol. ii, pp. 1072–1074. BMJ

  15. C.T. Sawin, The invention of thyroid therapy in the late nineteenth century. Endocrinol. 11(1), 1–3 (2001)

    Article  Google Scholar 

  16. Report on myxoedema. In, vol. Suppl 1. Transactions of the clinical society of London, (1888)

  17. R. Bettencourt, S. J-A, Un cas de myxoedeme traite par la greffe hypodermique du corps thyroide d’um mouton. La. Sem. Med. 1884(10), 294 (1890)

    Google Scholar 

  18. R. Bettencourt, J.-A. Serrano, Un cas de myxoedeme (cachexie pachydermique) traite par la greffe hypodermique du corps thyroide d’um mouton. In: l’Association Francaise puor l’Advancement des Sciences, Limoges 1890, pp. 683–690 (1891)

  19. A.M. Bettencourt-Rodrigues. Communicacoes scientificas. In: C.b. Sawin (ed.) Lisbon Society of Medical Sciences. J. Soc. Sci. Med. Lisboa, Lisbon, p. 114 (1890)

    Google Scholar 

  20. G.R. Murray, Note on the treatment of Myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. British Medical Association. (BMJ, Bournemouth), p. 796 (1891)

    Google Scholar 

  21. G.R. Murray, Remarks on the treatment of myxedema with thyroid juice, with notes on four cases. In: 60th Annual Meeting of the British Medical Association 1892, pp. 449–451. BMJ

  22. S. Slater, The discovery of thyroid replacement therapy. Part 2: the critical 19th century. J. R. Soc. Med. 104(2), 59–63 (2011). doi:10.1258/jrsm.2010.10k051

    Article  PubMed  PubMed Central  Google Scholar 

  23. H.W.G. Mackenzie, A case of myxedema treated with great benefit by feeding with fresh thyroid glands. BMJ 1892(ii), 940–941 (1892)

    Article  Google Scholar 

  24. G.R. Murray, The life-history of the first case of myxedema treated by thyroid extract. BMJ 1920(i), 359–360 (1920)

    Article  Google Scholar 

  25. E.L. Fox, A case of myxoedema treated by taking extract of thyroid by mouth. Br. Med. J. 2, 941 (1892)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. H.W.G. Mackenzie, A case of myxoedema treated with great benefit by feeding with fresh thyroid glands. Br. Med. J. 2 (1892)

  27. B. Bramwell, The thyroid treatment of myxoedema and sporatic cretinism, with notes of twenty-three cases of myxoedema and five cases of sporadic cretinism, treated by thyroid extract. Edinburgh Hosp. Rep. 1895(3), 116–249 (1895)

    Google Scholar 

  28. H.A. Selenkow, M.S. Wool, A. New, Synthetic thyroid hormone combination for clinical therapy. Ann. Intern. Med. 67(1), 90–99 (1967)

    Article  CAS  Google Scholar 

  29. G.J. Canaris, J.F. Steiner, E.C. Ridgway, Do traditional symptoms of hypothyroidism correlate with biochemical disease? J. Gen. Intern. Med. 12(9), 544–550 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. G.J. Canaris, N.R. Manowitz, G.H. Mayor, E.C. Ridgway, The colorado thyroid disease prevalence study. Arch. Intern. Med. 160(4), 526–534 (2000)

    Article  CAS  PubMed  Google Scholar 

  31. A. Carle, I.B. Pedersen, N. Knudsen, H. Perrild, L. Ovesen, P. Laurberg, Hypothyroid symptoms and the likelihood of overt thyroid failure: a population-based case-control study. Eur. J. Endocrinol. 171(5), 593–602 (2014). doi:10.1530/EJE-14-0481

    Article  CAS  PubMed  Google Scholar 

  32. S. Taylor, M. Kapur, R. Adie, Combined thyroxine and triiodothyronine for thyroid replacement therapy. Br. Med. J. 2(5704), 270–271 (1970)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. R.F. Farquharson, A.H. Squires, Inhibition of secretrion of thyroid gland by continued ingestion of thyroid substance. Tr. Am. Phys. 56, 87–97 (1941)

    CAS  Google Scholar 

  34. M.A. Greer, The effect on endogenous thyroid activity of feeding desiccated thyroid to normal human subjects. N. Engl. J. Med. 244(11), 385–390 (1951). doi:10.1056/NEJM195103152441101

    Article  CAS  PubMed  Google Scholar 

  35. L.E. Braverman, S.H. Ingbar, Anomalous effects of certain preparations of desiccated thyroid on serum protein-bound iodine. N. Engl. J. Med. 270, 439–442 (1964). doi:10.1056/NEJM196402272700903

    Article  CAS  PubMed  Google Scholar 

  36. E.A. Novak, J.M. Holthaus, R.O. Ogborn, Clinical study of levo-thyroxine and aged desiccated thyroid in euthyroid subjects. Am. J. Med. Sci. 247, 336–343 (1964)

    Article  CAS  PubMed  Google Scholar 

  37. P. Starr, Hormone content of desiccated thyroid. JAMA 205(5), 313–314 (1968)

    Article  CAS  PubMed  Google Scholar 

  38. A.G. Macgregor, Why does anybody use thyroid B.P.?. Lancet 1(7172), 329–332 (1961)

    Article  CAS  PubMed  Google Scholar 

  39. P.B. Fowler, Thyroid extract. Br. Med. J. 2(6144), 1089 (1978)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. M.I. Surks, A.R. Schadlow, J.H. Oppenheimer, A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement. J. Clin. Invest. 51(12), 3104–3113 (1972). doi:10.1172/JCI107137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. J. Chalmers, G. Dickson, J. Elks, et al. The synthesis of thyroxine and related substances. Part V. A synthesis of L-thyroxine from l-tyrosine. J. Chem. Soc. 3424–3422 (1949)

  42. Drugbank: DrugBank: Levothyroxine. http://www.drugbank.ca/drugs/DB00451 (2016). Accessed 21 Jun 2005

  43. B.A. Sachs, L. Wolfman, G. Murthy, Lipid and clinical response to a new thyroid hormone combination. Am. J. Med. Sci. 256(4), 232–238 (1968)

    Article  CAS  PubMed  Google Scholar 

  44. R.N. Smith, S.A. Taylor, J.C. Massey, Controlled clinical trial of combined triiodothyronine and thyroxine in the treatment of hypothyroidism. Br. Med. J. 4(5728), 145–148 (1970)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. I.M. Jackson, W.E. Cobb, Why does anyone still use desiccated thyroid USP? Am. J. Med. 64(2), 284–288 (1978)

    Article  CAS  PubMed  Google Scholar 

  46. R. Penny, S.D. Frasier, Elevated serum concentrations of triiodothyronine in hypothyroid patients. Values for patients receiving USP thyroid. Am. J. Dis. Child 134(1), 16–18 (1980)

    Article  CAS  PubMed  Google Scholar 

  47. M.S. LeBoff, M.M. Kaplan, J.E. Silva, P.R. Larsen, Bioavailability of thyroid hormones from oral replacement preparations. Metabolism. 31(9), 900–905 (1982)

    Article  CAS  PubMed  Google Scholar 

  48. A. Lev-Ran, Part-of-the-day hypertriiodothyroninemia caused by desiccated thyroid. JAMA 250(20), 2790–2791 (1983)

    Article  CAS  PubMed  Google Scholar 

  49. S.R. Smith, Desiccated thyroid preparations. Obsolete therapy. Arch. Intern. Med. 144(5), 926–927 (1984)

    Article  CAS  PubMed  Google Scholar 

  50. C.T. Sawin, A. Geller, J.M. Hershman, W. Castelli, P. Bacharach, The aging thyroid. The use of thyroid hormone in older persons. JAMA 261(18), 2653–2655 (1989)

    Article  CAS  PubMed  Google Scholar 

  51. K. Petersen, C. Bengtsson, L. Lapidus, G. Lindstedt, E. Nystrom, Morbidity, Mortality and quality of life for patients treated with levothyroxine. Arch. Intern. Med. 150(10), 2077–2081 (1990)

    Article  CAS  PubMed  Google Scholar 

  52. G. Mercuro, M.G. Panzuto, A. Bina, M. Leo, R. Cabula, L. Petrini, F. Pigliaru, S. Mariotti, Cardiac function, physical exercise capacity, and quality of life during long-term thyrotropin-suppressive therapy with levothyroxine: effect of individual dose tailoring. J. Clin. Endocrinol. Metab. 85(1), 159–164 (2000)

    Article  CAS  PubMed  Google Scholar 

  53. J.V. Hennessey, K.D. Burman, L. Wartofsky, The equivalency of two L-Thyroxine preparations. Ann. Intern. Med. 102, 770–773 (1985)

    Article  CAS  PubMed  Google Scholar 

  54. J.M. Stock, M.I. Surks, J.H. Oppenheimer, Replacement dosage of L-thyroxine in hypothyroidism. A re-evaluation. N. Engl. J. Med. 290(10), 529–533 (1974). doi:10.1056/NEJM197403072901001

    Article  CAS  PubMed  Google Scholar 

  55. M. Maeda, N. Kuzuya, Y. Masuyama, Y. Imai, H. Ikeda, Changes in serum triiodothyronine, thyroxine, and thyrotropin during treatment with thyroxine in severe primary hypothyroidism. J. Clin. Endocrinol. Metab. 43(1), 10–17 (1976). doi:10.1210/jcem-43-1-10

    Article  CAS  PubMed  Google Scholar 

  56. R.L. Rosenbaum, U.S. Barzel, Levothyroxine replacement dose for primary hypothyroidism decreases with age. Ann. Intern. Med. 96(1), 53–55 (1982)

    Article  CAS  PubMed  Google Scholar 

  57. C.T. Sawin, T. Herman, M.E. Molitch, M.H. London, S.M. Kramer, Aging and the thyroid. Decreased requirement for thyroid hormone in older hypothyroid patients. Am. J. Med. 75(2), 206–209 (1983)

    Article  CAS  PubMed  Google Scholar 

  58. I.E. Brajkovich, K. Mashiter, G.F. Joplin, J. Cassar, Serum T4, T3, and TSH levels in primary hypothyroidism during replacement therapy with thyroxine. Metabolism 32(8), 745–747 (1983). doi:0026-0495(83)90101-4

    Article  CAS  PubMed  Google Scholar 

  59. F.B. Davis, R.S. LaMantia, S.W. Spaulding, R.E. Wehmann, P.J. Davis, Estimation of a physiologic replacement dose of levothyroxine in elderly patients with hypothyroidism. Arch. Intern. Med. 144(9), 1752–1754 (1984)

    Article  CAS  PubMed  Google Scholar 

  60. J.V. Hennessey, J.E. Evaul, Y.-C. Tseng, K.D. Burman, L. Wartofsky, L-thyroxine dosage: A reevaluation of therapy with contemporary preparations. Ann. Intern. Med. 105, 11–15 (1986)

    Article  CAS  PubMed  Google Scholar 

  61. L.H. Fish, H.L. Schwartz, J. Cavanaugh, M.W. Steffes, J.P. Bantle, J.H. Oppenheimer, Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. N. Engl. J. Med. 316, 764–770 (1987)

    Article  CAS  PubMed  Google Scholar 

  62. J.V. Hennessey, L. Wartofsky, Thyroxine preparations. Ann. Intern. Med. 101(1), 140 (1984)

    Article  Google Scholar 

  63. C.T. Sawin, M.I. Surks, M. London, R. Chingleput, P.R. Larsen, Oral thyroxine: variation in biologic action and tablet content. Ann. Intern. Med. 100, 641–645 (1984)

    Article  CAS  PubMed  Google Scholar 

  64. J.R. Garber, R.H. Cobin, H. Gharib, J.V. Hennessey, I. Klein, J.I. Mechanick, R. Pessah-Pollack, P.A. Singer, K.A. Woeber, Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 22(12), 1200–1235 (2012). doi:10.1089/thy.2012.0205

    Article  CAS  PubMed  Google Scholar 

  65. J. Jonklaas, A.C. Bianco, A.J. Bauer, K.D. Burman, A.R. Cappola, F.S. Celi, D.S. Cooper, B. Kim, R. Peeters, M.S. Rosenthal, A. Sawka, Guidelines for the treatment of hypothyroidism. Thyroid (2014). doi:10.1089/thy.2014.0028

  66. J.V. Hennessey, Levothyroxine a new drug? Since when? How could that be?. Thyroid 13(3), 279–282 (2003)

    Article  PubMed  Google Scholar 

  67. J.V. Hennessey, Historical and current perspective in the use of thyroid extracts for the treatment of hypothyroidism. Endocr. Pract. 21(10), 1161–1170 (2015). doi:10.4158/EP14477.RA

    Article  PubMed  Google Scholar 

  68. D.A. Escalante, N. Arem, R. Arem, Assessment of interchangeability of two brands of levothyroxine preparations with a third-generation TSH Assay. Am. J. Med. 98, 374–378 (1995)

    Article  CAS  PubMed  Google Scholar 

  69. R.W. Rees-Jones, A.R. Rolla, P.R. Larsen, Hormonal content of thyroid replacement preparations. JAMA 243(6), 549–550 (1980)

    Article  CAS  PubMed  Google Scholar 

  70. B.J. Dong, V.R. Young, B. Rapoport, The nonequivalence of levothyroxine products. Drug Intell. Clin. Pharm. 20, 77–78 (1986)

    CAS  PubMed  Google Scholar 

  71. S.S. Stoffer, W.E. Szpunar, Potency of current levothyroxine preparations evaluated by high-performance liquid chromatography. Henry Ford Med. J 36(1), 64–65 (1988)

    CAS  Google Scholar 

  72. J.M. Jacobsen, A. Ramos-Gabatin, R.L. Young, S.G. Watkins, M.L. Brown, Nonequality of brand name thyroxine products. JAMA 243(8), 733 (1980)

    Article  Google Scholar 

  73. A. Ramos-Gabatin, J.M. Jacobson, R.L. Young, In vivo comparison of Levothyroxine preparations. JAMA 247(2), 203–205 (1982)

    Article  CAS  PubMed  Google Scholar 

  74. N. Lowy, Regulatory Issues regarding slow release T3, extracts, and compunded T4/T3. Paper presented at the Treatment of Hypothyroidism; Exploring the Possibilities, Westin City Center, Washington DC, 25 April 2013

  75. Docket Number 97N-0314, Prescription drug products; levothyroxine sodium. Fed. Regist. 62(157), 43535–43538 (1997)

    Google Scholar 

  76. Guidance for industry: Levothyroxine sodium tablets- In vivo pharmacokinetic and bioavailability studies and invitro dissolution testing. U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 1–8 (2000)

  77. Guidance for Industry: Levothyroxine Sodium Products Enforcement of August 14, 2001; Compliance Date and Submission of New Applications.: In: U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). pp. 1–6. (2001)

  78. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products- General Considerations (Draft Guidance). (2002)

  79. V.A. Blakesley, W. Awni, C. Locke, T. Ludden, G.R. Granneman, L.E. Braverman, Are bioequivalalence studies of levothyroxine sodium formulations in euthyroid volunteers reliable?. Thyroid 14(3), 191–200 (2004)

    Article  CAS  PubMed  Google Scholar 

  80. Tiche Softgel. http://www.thyroidcollection.net/cont/download.asp?u=21 (2016)

  81. C. Virili, P. Trimboli, F. Romanelli, M. Centanni, Liquid and softgel levothyroxine use in clinical practice: state of the art. Endocrine (2016). doi:10.1007/s12020-016-1035-1

  82. D. Pabla, F. Akhlaghi, H. Zia, A comparative pH-dissolution profile study of selected commercial levothyroxine products using inductively coupled plasma mass spectrometry. Eur. J. Pharm. Biopharm. 72(1), 105–110 (2009). doi:10.1016/j.ejpb.2008.10.008

    Article  CAS  PubMed  Google Scholar 

  83. M.G. Santaguida, C. Virili, S.C. Del Duca, M. Cellini, I. Gatto, N. Brusca, C. De Vito, L. Gargano, M. Centanni, Thyroxine softgel capsule in patients with gastric-related T4 malabsorption. Endocrine 49(1), 51–57 (2015). doi:10.1007/s12020-014-0476-7

    Article  CAS  PubMed  Google Scholar 

  84. R. Vita, S. Benvenga, Tablet levothyroxine (L-T4) malabsorption induced by proton pump inhibitor; a problem that was solved by switching to L-T4 in soft gel capsule. Endocr. Pract. 20(3), e38–41 (2014). doi:10.4158/EP13316.CR

    Article  PubMed  Google Scholar 

  85. P.J. Kim, I. Sachmechi, Levothyroxine malabsorption induced by diabetic gastroparesis exacerbated during pregnancies: effect of intramuscular levothyroxine injections and levothyroxine soft gel capsules. AACE Clin. Case Rep. 1, e73–e78 (2015)

    Article  Google Scholar 

  86. R. Vita, G. Saraceno, F. Trimarchi, S. Benvenga, A novel formulation of L-thyroxine (L-T4) reduces the problem of L-T4 malabsorption by coffee observed with traditional tablet formulations. Endocrine 43(1), 154–160 (2013). doi:10.1007/s12020-012-9772-2

    Article  CAS  PubMed  Google Scholar 

  87. T.M. Grant, T. Zhu, C. Brandquist, N.S. Teuscher, M.J. Lamson, Randomized, open-label, single-dose, two-way crossover study to determine the relative bioavailability of a reformulated levothyroxine tablet compared with the commercial tablet (levoxyl(R)) in healthy volunteers. Clin. Pharmacol. Ther. 85(Suppliment 1), S95 (2009). PIII-85

    Google Scholar 

  88. P. Colucci, P. D’Angelo, G. Mautone, C. Scarsi, M.P. Ducharme, Pharmacokinetic equivalence of a levothyroxine sodium soft capsule manufactured using the new food and drug administration potency guidelines in healthy volunteers under fasting conditions. Ther Drug Monit 33(3), 355–361 (2011). doi:10.1097/FTD.0b013e318217b69f

    Article  CAS  PubMed  Google Scholar 

  89. J.V. Hennessey, The FDA revises requirements for levothyroxine products. Thyroid 18(5), 487–490 (2008)

    Article  PubMed  Google Scholar 

  90. J.V. Hennessey, A.O. Malabanan, B.R. Haugen, E.G. Levy, Adverse event reporting in patients treated with levothyroxine: results of the pharmacovigilance task force survey of the american thyroid association, american association of clinical endocrinologists, and the endocrine society. Endocr. Pract. 16(3), 357–370 (2010)

    Article  PubMed  Google Scholar 

  91. D.S. Ross, G.H. Daniels, D. Gouveia, The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid function test in an out-patient endocrine clinic. J. Clin. Endocrinol. Metab 71(3), 764–769 (1990)

    Article  CAS  PubMed  Google Scholar 

  92. L. Somwaru, A.M. Arnold, N. Joshi, L.P. Fried, A.R. Cappola, High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women Aged 65 and Over. J. Clin. Endocrinol. Metab. 94(4), 1342–1345 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. J.J. Diez, Hypothyroidism in patients older than 55 years: an analysis of the etiology and assessment of the effectiveness of therapy. J. Gerontol. A Biol. Sci. Med. Sci. 57(5), M315–320 (2002)

    Article  PubMed  Google Scholar 

  94. J.G. Hollowell, N.W. Staehling, W.D. Flanders, W.H. Hannon, E.W. Gunter, C.A. Spencer, Serum TSH, T4, and Thyroid Antibodies in the United States Population(1988 to 1994): National Health and Nutrition Survey (NHANES III). J. Clin. Endocrinol. Metab. 87, 489–499 (2002)

    Article  CAS  PubMed  Google Scholar 

  95. J.V. Parle, J.A. Franklyn, K.W. Cross, S.R. Jones, M.C. Sheppard, Thyroxine prescription in the community: serun thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br. J. Gen. Pract. 43(368), 107–109 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  96. R.W. Flynn, S.R. Bonellie, R.T. Jung, T.M. MacDonald, A.D. Morris, G.P. Leese, Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J. Clin. Endocrinol. Metab. 95(1), 186–193 (2010). doi:10.1210/jc.2009-1625

    Article  CAS  PubMed  Google Scholar 

  97. J.S. Mammen, J. McGready, R. Oxman, C.W. Chia, P.W. Ladenson, E.M. Simonsick, Thyroid hormone therapy and risk of thyrotoxicosis in community-resident older adults: findings from the baltimore longitudinal study of aging. Thyroid 25(9), 979–986 (2015). doi:10.1089/thy.2015.0180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. D.J. Lips, M.T. van Reisen, V. Voigt, W. Venekamp, Diagnosis and treatment of levothyroxine pseudomalabsorption. Neth. J. Med. 62(4), 114–118 (2004)

    CAS  PubMed  Google Scholar 

  99. R.M. Bagattoli, M. Vaisman, J.S. Lima, L.S. Ward, Estudo de Adesao ao Tratamento do Hipotiroidismo. Arq. Braz. Endocrinol. Metab. 44(2), 483–487 (2000)

    Google Scholar 

  100. F. Vaisman, C.M. Coeli, L.S. Ward, H. Graf, G. Carvalho, R. Montenegro Jr., M. Vaisman, How good is the levothyroxine replacement in primary hypothyroidism patients in Brazil? Data of a multicentre study. J. Endocrinol. Invest. 36(7), 485–488 (2013). doi:10.3275/8810

    CAS  PubMed  Google Scholar 

  101. A.S. Kesselheim, N.K. Choudhry, J. Avorn, Burden of changes in generic pill appearance. Ann. Intern. Med. 161(11), 840 (2014). doi:10.7326/L14-5028-3

    Article  PubMed  Google Scholar 

  102. J.K. Lee, K.A. Grace, A.J. Taylor, Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. JAMA 296(21), 2563–2571 (2006). doi:10.1001/jama.296.21.joc60162

    Article  CAS  PubMed  Google Scholar 

  103. K.W. Wenzel, Optimization of levothyroxine treatment. Dosage dependence on the existing parenchymal mass, age, body weight and fasting intake. Dtsch. Med. Wochenschr. 111(36), 1356–1362 (1986). doi:10.1055/s-2008-1068634

    Article  CAS  PubMed  Google Scholar 

  104. M.J. Lamson, C.L. Pamplin, R.L. Rolleri, I. Klein, Quantitation of a substantial reduction in levothyroxine absorption by food. Thyroid 14, 876 (2004)

    Google Scholar 

  105. 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(10), 3905–3912 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. C.L. Perez, F.S. Araki, H. Graf, G.A. de Carvalho, Serum thyrotropin levels following levothyroxine administration at breakfast. Thyroid 23(7), 779–784 (2013). doi:10.1089/thy.2012.0435

    Article  CAS  PubMed  Google Scholar 

  107. S.A. Irving, T. Vadiveloo, G.P. Leese, Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS). Clin. Endocrinol. (Oxf) 82(1), 136–141 (2015). doi:10.1111/cen.12559

    Article  CAS  Google Scholar 

  108. A. Stagnaro-Green, M. Abalovich, E. Alexander, F. Azizi, J. Mestman, R. Negro, A. Nixon, E.N. Pearce, O.P. Soldin, S. Sullivan, W. Wiersinga, Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21(10), 1081–1125 (2011). doi:10.1089/thy.2011.0087

    Article  PubMed  PubMed Central  Google Scholar 

  109. C. Virili, G. Bassotti, M.G. Santaguida, R. Iuorio, S.C. Del Duca, V. Mercuri, A. Picarelli, P. Gargiulo, L. Gargano, M. Centanni, Atypical celiac disease as cause of increased need for thyroxine: a systematic study. J. Clin. Endocrinol. Metab. 97(3), E419–422 (2012). doi:10.1210/jc.2011-1851

    Article  CAS  PubMed  Google Scholar 

  110. M. Munoz-Torres, M. Varsavsky, G. Alonso, Lactose intolerance revealed by severe resistance to treatment with levothyroxine. Thyroid 16(11), 1171–1173 (2006). doi:10.1089/thy.2006.16.1171

    Article  CAS  PubMed  Google Scholar 

  111. M. Cellini, M.G. Santaguida, I. Gatto, C. Virili, S.C. Del Duca, N. Brusca, S. Capriello, L. Gargano, M. Centanni, Systematic appraisal of lactose intolerance as cause of increased need for oral thyroxine. J. Clin. Endocrinol. Metab. 99(8), E1454–1458 (2014). doi:10.1210/jc.2014-1217

    Article  CAS  PubMed  Google Scholar 

  112. M. Asik, F. Gunes, E. Binnetoglu, M. Eroglu, N. Bozkurt, H. Sen, E. Akbal, C. Bakar, Y. Beyazit, K. Ukinc, Decrease in TSH levels after lactose restriction in Hashimoto’s thyroiditis patients with lactose intolerance. Endocrine 46(2), 279–284 (2014). doi:10.1007/s12020-013-0065-1

    Article  CAS  PubMed  Google Scholar 

  113. S. Checchi, A. Montanaro, L. Pasqui, C. Ciuoli, V. De Palo, M.C. Chiappetta, F. Pacini, L-thyroxine requirement in patients with autoimmune hypothyroidism and parietal cell antibodies. J. Clin. Endocrinol. Metab. 93(2), 465–469 (2008). doi:10.1210/jc.2007-1544

    Article  CAS  PubMed  Google Scholar 

  114. 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. 354(17), 1787–1795 (2006)

    Article  CAS  PubMed  Google Scholar 

  115. V. Fonseca, M. Thomas, A. Katrak, P. Sweny, J.F. Moorhead, Can urinary thyroid hormone loss cause hypothyroidism? Lancet 338(8765), 475–476 (1991). doi:0140-6736(91)90546-2

    Article  CAS  PubMed  Google Scholar 

  116. S. Benvenga, R. Vita, F. Di Bari, P. Fallahi, A. Antonelli, Do not forget nephrotic syndrome as a cause of increased requirement of levothyroxine replacement therapy. Eur. Thyroid J. 4(2), 138–142 (2015). doi:10.1159/000381310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. J.M. Carswell, J.H. Gordon, E. Popovsky, A. Hale, R.S. Brown, Generic and brand name L-thyroxine are not bioequivalent for children with severe congenital hypothyroidism. J. Clin. Endocrinol. Metab. (2013)

  118. C.J. Worell, Sandoz Introduces Levothyroxine Sodium Tablets, USP, A Bioequivalent Alternative Product to Synthroid and Levoxyl. In. Sandoz, a Novartis Company, Advertisement to Physicians, (2004)

  119. AACE, ATA, TES: Joint position Statement on the use and interchangeability of Thyroxine Products. www.thyoid.org/professionals/advocacy/04_12_08_thyroxine.html (2005). Accessed 3 Feb 2005

  120. H.M. Robertson, A.K. Narayanaswamy, O. Pereira, S.A. Copland, R. Herriot, A.W. McKinlay, J.S. Bevan, P. Abraham, Factors contributing to high levothyroxine doses in primary hypothyroidism: an interventional audit of a large community database. Thyroid 24(12), 1765–1771 (2014). doi:10.1089/thy.2013.0661

    Article  CAS  PubMed  Google Scholar 

  121. H.T. Stelfox, S.B. Ahmed, J. Fiskio, D.W. Bates, An Evaluation of the adequacy of outpatient monitoring of thyroid replacement therapy. J. Eval. Clin. Pract. 10(4), 525–530 (2004)

    Article  PubMed  Google Scholar 

  122. J. Jonklaas, Sex and age differences in levothyroxine dosage requirement. Endocr. Pract. 16(1), 71–79 (2010)

    Article  PubMed  Google Scholar 

  123. A.A. Ismail, P.L. Walker, J.H. Barth, K.C. Lewandowski, R. Jones, W.A. Burr, Wrong biochemistry results: two case reports and observational study in 5310 patients on potentially misleading thyroid-stimulating hormone and gonadotropin immunoassay results. Clin. Chem. 48(11), 2023–2029 (2002)

    CAS  PubMed  Google Scholar 

  124. W.M. Wiersinga, L. Duntas, V. Fadeyev, B. Nygaard, M.P. Vanderpump, 2012 ETA guidelines: the use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur. Thyroid J. 1(2), 55–71 (2012). doi:10.1159/000339444

    Article  PubMed  PubMed Central  Google Scholar 

  125. G. Brenta, M. Vaisman, J.A. Sgarbi, L.M. Bergoglio, N.C. Andrada, P.P. Bravo, A.M. Orlandi, H. Graf, Clinical practice guidelines for the management of hypothyroidism. Arq. Bras. Endocrinol. Metabol. 57(4), 265–291 (2013). doi:S0004-27302013000400003

    Article  PubMed  Google Scholar 

  126. E.M. Lichten, Synthetic thyroxine vs dessicated thyroid. JAMA 291(12), 1445 (2004). doi:10.1001/jama.291.12.1445-a

    CAS  PubMed  Google Scholar 

  127. P.S. Jellinger, Acquired hypothyroidism after switching from thyroid USP to levothyroxine. Clin. Cornerstone 7(Suppl 2), S22–24 (2005). doi:S1098-3597(05)80055-9

    Article  PubMed  Google Scholar 

  128. T.D. Hoang, C.H. Olsen, V.Q. Mai, P.W. Clyde, M.K. Shakir, Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J. Clin. Endocrinol. Metab. 98(5), 1982–1990 (2013). doi:10.1210/jc.2012-4107

    Article  CAS  PubMed  Google Scholar 

  129. P. Saravanan, W.-F. Chau, N. Roberts, K. Vedhara, R. Greenwood, C.M. Dayan, Psychological well-being in patients on “adequate” doses of L-thyroxine: results of a large, controlled community-based questionaire study. Clin. Endocrinol. 57, 577–585 (2002)

    Article  CAS  Google Scholar 

  130. ,R. Bunevicius, G. Kazanavicius, R. Zalinkevicius, A.J. Prange, Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N. Engl. J. Med 340, 424–429 (1999)

    Article  CAS  PubMed  Google Scholar 

  131. W. Siegmund, K. Spieker, A.I. Weike, T. Giessmann, C. Modess, T. Dabers, G. Kirsch, E. Sanger, G. Engel, A.O. Hamm, M. Nauck, W. Meng, 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) 60(6), 750–757 (2004). doi:10.1111/j.1365-2265.2004.02050.x

    Article  CAS  Google Scholar 

  132. H.F. Escobar-Morreale, J.I. Botella-Carretero, F. Escobar Del Ray, G. Morreale De Escobar, Review: treatment of hypothyroidism with combinations of levothyroxine plus liothyronine. J. Clin. Endocrinol. Metab. 90(8), 4946–4954 (2005)

    Article  CAS  PubMed  Google Scholar 

  133. S. Grozinsky-Glasberg, A. Fraser, E. Nahshoni, A. Weizman, L. Leibovici, Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J. Clin. Endocrinol. Metab. 91(7), 2592–2599 (2006)

    Article  CAS  PubMed  Google Scholar 

  134. C. Ma, J. Xie, X. Huang, G. Wang, Y. Wang, X. Wang, S. Zuo, Thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. Nucl. Med. Commun. 30(8), 586–593 (2009). doi:10.1097/MNM.0b013e32832c79e0

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosures

The author has acted as a scientific consultant on regulatory affairs for Abbvie Inc. in 2016. The Author is an immediate past member of the Board of Directors of the American Thyroid Association. The opinions expressed are the personal opinions of the author and do not represent any official position of the American Thyroid Association.

Author information

Authors and Affiliations

  1. Harvard Medical School, Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Gryzmish 619, Boston, 02215, MA, USA

    James V. Hennessey

Authors
  1. James V. Hennessey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James V. Hennessey.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hennessey, J.V. The emergence of levothyroxine as a treatment for hypothyroidism. Endocrine 55, 6–18 (2017). https://doi.org/10.1007/s12020-016-1199-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-1199-8

Keywords

Search

Navigation