Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Thyroid-hormone therapy and thyroid cancer: a reassessment

Abstract

Experimental studies and clinical data have demonstrated that thyroid-cell proliferation is dependent on thyroid-stimulating hormone (TSH), thereby providing the rationale for TSH suppression as a treatment for differentiated thyroid cancer. Several reports have shown that hormone-suppressive treatment with the L-enantiomer of tetraiodothyronine (L-T4) benefits high-risk thyroid cancer patients by decreasing progression and recurrence rates, and cancer-related mortality. Evidence suggests, however, that complex regulatory mechanisms (including both TSH-dependent and TSH-independent pathways) are involved in thyroid-cell regulation. Indeed, no significant improvement has been obtained by suppressing TSH in patients with low-risk thyroid cancer. Moreover, TSH suppression implies a state of subclinical thyrotoxicosis. In low-risk patients, the goal of L-T4 treatment is therefore to obtain a TSH level in the normal range (0.5–2.5 mU/l). Only selected patients with high-risk papillary and follicular thyroid cancer require long-term TSH-suppressive doses of L-T4. In these patients, careful monitoring is necessary to avoid undesirable effects on bone and heart.

Key Points

  • Thyroid-cell proliferation is thyroid-stimulating hormone (TSH)-dependent, hence L-tetraiodothyronine (L-T4)-induced TSH suppression should be included in the treatment strategies for differentiated thyroid carcinomas

  • TSH suppression implies a state of subclinical thyrotoxicosis and becomes necessary only when there is evidence of persistent or recurrent disease; in low-risk patients, L-T4 treatment serves to return TSH level to within the normal range

  • To ensure optimal dosing, each patient must always receive the same preparation and the daily L-T4 dose should be carefully tailored

  • Adjustments of L-T4 dosage will be required under particular circumstances, for example in pregnant women, patients with significant weight gain or weight loss, those with known heart disease and older patients

  • If long-term TSH suppression is necessary because of a high-risk cancer, a cardioselective β-blocking drug can be added to reduce cardiovascular risk and to improve quality of life

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Regulation of the pituitary–thyroid axis: the role of tri-iodothyronine and tetraiodothyronine in the feedback regulation of thyroid-stimulating hormone secretion
Figure 2: Thyroid-stimulating hormone target level during treatment with L-tetraiodothyronine in high-risk and low-risk thyroid cancer patients

Similar content being viewed by others

Layal Chaker, Salman Razvi, … Robin P. Peeters

References

  1. Larsen PR et al. (2002) Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In Williams' Textbook of Endocrinology, edn 10, 331–373 (Eds Larsen PR et al.) Philadelphia: WB Saunders

    Google Scholar 

  2. Larsen PR et al. (1981) Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications. Endocr Rev 2: 87–102

    CAS  PubMed  Google Scholar 

  3. Saberi M and Utiger RD (1974) Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metab 39: 923–927

    CAS  PubMed  Google Scholar 

  4. Braverman LE et al. (1970) Conversion of thyroxine (T4) to triiodothyronine in athyreotic human subjects. J Clin Invest 49: 855–864

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Mandel SJ et al. (1993) Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 119: 492–502

    CAS  PubMed  Google Scholar 

  6. Singer PA et al. (1996) Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 156: 2165–2172

    CAS  PubMed  Google Scholar 

  7. Thyroid Carcinoma Task Force (2001) AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. Endocr Pract 7: 202–220

  8. Dunhill TP (1937) Surgery of the thyroid gland (The Lettsomian Lectures). BMJ 1: 460–461

    Google Scholar 

  9. Balme HW (1954) Metastastic carcinoma of the thyroid successfully treated with thyroxine. Lancet 266: 812–813

    CAS  PubMed  Google Scholar 

  10. Crile G Jr (1966) Endocrine dependency of papillary carcinomas of the thyroid. JAMA 195: 721–724

    PubMed  Google Scholar 

  11. Goldberg LD and Ditchek NT (1981) Thyroid carcinoma with spinal cord compression. JAMA 245: 953–954

    CAS  PubMed  Google Scholar 

  12. Mazzaferri EL and Jhiang SM (1994) Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97: 418–428

    CAS  PubMed  Google Scholar 

  13. Pujol P et al. (1996) Degree of thyrotropin suppression as a prognostic determinant in differentiated thyroid cancer. J Clin Endocrinol Metab 81: 4318–4322

    CAS  PubMed  Google Scholar 

  14. Cooper DS et al. (1998) Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid 8: 737–744

    CAS  PubMed  Google Scholar 

  15. Roger P et al. (1988) Mitogenic effects of thyrotropin and adenosine 3',5'-monophosphate in differentiated normal human thyroid cells in vitro. J Clin Endocrinol Metab 66: 1158–1165

    CAS  PubMed  Google Scholar 

  16. Nadler NJ et al. (1970) The effect of hypophysectomy on the experimental production of rat thyroid neoplasms. Cancer Res 30: 1909–1911

    CAS  PubMed  Google Scholar 

  17. Ichikawa Y et al. (1976) Presence of TSH receptor in thyroid neoplasms. J Clin Endocrinol Metab 42: 395–398

    CAS  PubMed  Google Scholar 

  18. Carayon P et al. (1980) Human thyroid cancer: membrane thyrotropin binding and adenylate cyclase activity. J Clin Endocrinol Metab 51: 915–920

    CAS  PubMed  Google Scholar 

  19. Clark OH et al. (1983) Characterization of the thyrotropin receptor–adenylate cyclase system in neoplastic human thyroid tissue. J Clin Endocrinol Metab 57: 140–147

    CAS  PubMed  Google Scholar 

  20. Tanaka K et al. (1997). Relationship between prognostic score and thyrotropin receptor (TSH-R) in papillary thyroid carcinoma: immunohistochemical detection of TSH-R. Br J Cancer 76: 594–599

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Lazar V et al. (1999) Expression of the Na+/I-symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab 84: 3228–3234

    CAS  PubMed  Google Scholar 

  22. Filetti S et al. (1999) Sodium/iodide symporter a key transport system in thyroid cancer cell metabolism. Eur J Endocrinol 141: 443–457

    CAS  PubMed  Google Scholar 

  23. Filetti S et al. (1988) The role of thyroid-stimulating antibodies of Graves' disease in differentiated thyroid cancer. N Engl J Med 318: 753–759

    CAS  PubMed  Google Scholar 

  24. Belfiore A et al. (2001) Graves' disease, thyroid nodules and thyroid cancer. Clin Endocrinol (Oxf) 55: 711–718

    CAS  Google Scholar 

  25. Westermark K et al. (1983) Epidermal growth factor modulates thyroid growth and function in culture. Endocrinology 112: 1680–1686

    CAS  PubMed  Google Scholar 

  26. Wynford-Thomas D (1993) Molecular basis of epithelial tumorigenesis: the thyroid model. Crit Rev Oncol 4: 1–23

    CAS  Google Scholar 

  27. Fagin JA (2004) How thyroid tumors start and why it matters: kinase mutants as targets for solid cancer pharmacotherapy. J Endocrinol 183: 249–256

    CAS  PubMed  Google Scholar 

  28. Russo D et al. (1995) Activating mutations of the TSH receptor in differentiated thyroid carcinomas. Oncogene 11: 1907–1911

    CAS  PubMed  Google Scholar 

  29. Spambalg D et al. (1996) Structural studies of the thyrotropin receptor and Gs alpha in human thyroid cancer: low prevalence of mutation predicts infrequent involvement in malignant transformation. J Clin Endocrinol Metab 81: 3898–3901

    CAS  PubMed  Google Scholar 

  30. Challeton C et al. (1995) Pattern of ras and gsp oncogene mutations in radiation-associated human thyroid tumors. Oncogene 11: 601–603

    CAS  PubMed  Google Scholar 

  31. Nicoloff JT and Spencer CA (1992) Non-thyrotropin-dependent thyroid secretion. J Clin Endocrinol Metab 75: 343

    CAS  PubMed  Google Scholar 

  32. Burmeister LA et al. (1992) Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 75: 344–350

    CAS  PubMed  Google Scholar 

  33. Demers LM and Spencer CA (2003) Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13: 33–44

    Google Scholar 

  34. Surks M et al. (2004) Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291: 228–238

    CAS  PubMed  Google Scholar 

  35. Hollowell JG et al. (2002) Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87: 489–499

    CAS  PubMed  Google Scholar 

  36. Bjoro T et al. (2000) Prevalence of thyroid disease, thyroid dysfunction, and thyroid peroxidase antibodies in a large unselected population. Eur J Endocrinol 143: 639–637

    CAS  PubMed  Google Scholar 

  37. Parle JV et al. (2001) Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 358: 861–865

    CAS  PubMed  Google Scholar 

  38. Biondi B et al. (2005) Subclinical hyperthyroidism: clinical features and treatment options. Eur J Endocrinol 152: 1–9

    CAS  PubMed  Google Scholar 

  39. Spencer CA et al. (1986) Thyrotropin secretion in thyrotoxic and thyroxine treated patients: assessment by a sensitive immunoenzymometric assay. J Clin Endocrinol Metab 63: 349–355

    CAS  PubMed  Google Scholar 

  40. Cailleux AF et al. (2000) Is diagnostic iodine-131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 85: 175–178

    CAS  PubMed  Google Scholar 

  41. Pacini F et al. (2001) Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. J Clin Endocrinol Metab 86: 5686–5690

    CAS  PubMed  Google Scholar 

  42. American Thyroid Association; Endocrine Society; American Association of Clinical Endocrinologists (2004) Joint statement on the U.S. Food and Drug Administration's decision regarding bioequivalence of levothyroxine sodium. Thyroid 14: 486

  43. Hays MT (1991) Localization of human thyroxine absorption. Thyroid 1: 242–248

    Google Scholar 

  44. Ladenson PW (2003) Problems in the management of hypothyroidism. In Diseases of the Thyroid, edn 2, 161–176 (Ed. Braverman LE) Totowa: Humana Press

    Google Scholar 

  45. Arafah BM (2001) Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 344: 1743–1749

    CAS  PubMed  Google Scholar 

  46. Howanitz PJ et al. (1982) Incidence and mechanism of spurious increase in serum thyrotropin. Clin Chem 28: 427–431

    CAS  PubMed  Google Scholar 

  47. Sherman SI et al. (1997) Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine. J Clin Endocrinol Metab 82: 2153–2158

    CAS  PubMed  Google Scholar 

  48. Mechelany C et al. (1991) TRIAC (3,5,3'-triiodothyroacetic acid ) has parallel effects at pituitary and peripheral tissue levels in thyroid cancer patients treated with L-thyroxine. Clin Endocrinol 35: 123–128

    CAS  Google Scholar 

  49. Goldman JM et al. (1980) Influence of triiodothyronine withdrawal time on 131I uptake post-thyroidectomy for thyroid cancer. J Clin Endocrinol Metab 50: 734–739

    CAS  PubMed  Google Scholar 

  50. Bunevicius R et al. (1999) Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 340: 424–429

    CAS  PubMed  Google Scholar 

  51. Sawka AM et al. (2003) 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 88: 4551–4555

    CAS  PubMed  Google Scholar 

  52. Walsh JP et al. (2003) 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 88: 4543–4550

    CAS  PubMed  Google Scholar 

  53. Clyde PW et al. (2003) Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism. A randomized controlled trial. JAMA 290: 2952–2958

    CAS  PubMed  Google Scholar 

  54. Henneman G et al. (2004) Thyroxine plus low-dose, slow release triiodothyronine replacement in hypothyroidism: proof of principle. Thyroid 14: 271–275

    Google Scholar 

  55. Saravan P et al. (2005) Partial substitution of thyroxine (T4) with triiodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab 90: 805–812

    Google Scholar 

  56. Appelhof BC et al. (2005) 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 90: 2666–2674

    CAS  PubMed  Google Scholar 

  57. Escobar-Morreale HF et al. (2005) Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med 142: 412–424

    CAS  PubMed  Google Scholar 

  58. Santini F et al. (2005) Lean body mass is a major determinant of levothyroxine dosage in the treatment of thyroid diseases. J Clin Endocrinol Metab 90: 124–127

    CAS  PubMed  Google Scholar 

  59. Sawin CT et al. (1989) The aging thyroid. The use of thyroid hormone in older person. JAMA 261: 2653–2655

    CAS  PubMed  Google Scholar 

  60. Alexander EK et al. (2004) Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 351: 241–249

    CAS  PubMed  Google Scholar 

  61. Andersen S et al. (2002) Narrow individual variations in serum T4 and T3 in normal subjects: a clue to understanding of subclinical thyroid disease. J Clin Endocrinol Metab 87: 1068–1072

    CAS  PubMed  Google Scholar 

  62. Sheppard MC et al. (2002) Levothyroxine treatment and occurrence of fracture of the hip. Arch Intern Med 162: 338–343

    CAS  PubMed  Google Scholar 

  63. Bauer DC et al. (2001) Risk for fracture in women with low serum levels of thyroid-stimulating hormone. Ann Intern Med 134: 561–568

    CAS  PubMed  Google Scholar 

  64. Marcocci C et al. (1994) Carefully monitored levothyroxine therapy is not associated with bone loss in premenopausal women. J Clin Endocrinol Metab 78: 818–823

    CAS  PubMed  Google Scholar 

  65. Biondi B et al. (1993) Cardiac effects of long-term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab 77: 334–338

    CAS  PubMed  Google Scholar 

  66. Sawin CT et al. (1994) Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 331: 1249–1252

    CAS  PubMed  Google Scholar 

  67. Biondi B et al. (2002) Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med 137: 904–914

    PubMed  Google Scholar 

  68. Biondi B et al. (1994) Control of adrenergic overactivity by β-blockade improves quality of life in patients receiving long term suppressive therapy with levothyroxine. J Clin Endocrinol Metab 78: 1028–1033

    CAS  PubMed  Google Scholar 

  69. Fazio S et al. (1992) Evaluation by noninvasive methods of the effects of acute loss of thyroid hormone on the heart. Angiology 43: 287–293

    CAS  PubMed  Google Scholar 

  70. Bengel FM et al. (2000) Effect of thyroid hormones on cardiac function, geometry, and oxidative metabolism assessed noninvasively by positron emission tomography and magnetic resonance imaging. J Clin Endocrinol Metab 85: 1822–1827

    CAS  PubMed  Google Scholar 

  71. Biondi B et al. (2003) Cardiovascular safety of acute recombinant human thyrotropin administration to patients monitored for differentiated thyroid cancer. J Clin Endocrinol Metab 88: 211–214

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernadette Biondi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Biondi, B., Filetti, S. & Schlumberger, M. Thyroid-hormone therapy and thyroid cancer: a reassessment. Nat Rev Endocrinol 1, 32–40 (2005). https://doi.org/10.1038/ncpendmet0020

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0020

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing