Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism

Journal name:
Nature Reviews Endocrinology
Year published:
Published online


Impaired psychological well-being, depression or anxiety are observed in 5–10% of hypothyroid patients receiving levothyroxine, despite normal TSH levels. Such complaints might hypothetically be related to increased free T4 and decreased free T3 serum concentrations, which result in the abnormally low free T4:free T3 ratios observed in 30% of patients on levothyroxine. Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone. Levothyroxine plus liothyronine combination therapy is gaining in popularity; although the evidence suggests it is generally not superior to levothyroxine monotherapy, in some of the 14 published trials this combination was definitely preferred by patients and associated with improved metabolic profiles. Disappointing results with combination therapy could be related to use of inappropriate levothyroxine and liothyronine doses, resulting in abnormal serum free T4:free T3 ratios. Alternatively, its potential benefit might be confined to patients with specific genetic polymorphisms in thyroid hormone transporters and deiodinases that affect the intracellular levels of T3 available for binding to T3 receptors. Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered.

At a glance


  1. Correlation between serum TSH and free thyroid hormone levels in 3,875 euthyroid controls and 1,811 athyreotic patients receiving levothyroxine monotherapy.
    Figure 1: Correlation between serum TSH and free thyroid hormone levels in 3,875 euthyroid controls and 1,811 athyreotic patients receiving levothyroxine monotherapy.

    Abbreviation: NS, not significant. © Gullo, D. et al. PLoS ONE 6, e22552 (2011).53 Published under a CC-BY licence.

  2. Thyroid hormone production and metabolism.
    Figure 2: Thyroid hormone production and metabolism.

    a | In healthy individuals, 100% of T4 production is thyroidal; by contrast, only 20% of T3 production is thyroidal, with the remaining 80% derived from extrathyroidal conversion of T4 into T3, mediated by DIO1 and DIO2. The amount of intracellular T3 available for binding to nuclear TRs is further modulated by thyroid hormone transporters (such as MCT8) in the plasma membrane, and DIO3-mediated conversion of T3 into inactive T2. Wide variation exists between target tissues in the expression and activity of thyroid hormone transporters and deiodinases, and in the relative contributions of locally generated and plasma-derived T3 to receptor-bound T3. b | In hypothyroid patients on levothyroxine replacement therapy, increased extrathyroidal T3 production compensates for the lack of thyroidal T3 secretion. However, serum free T4 levels above the upper limit of normal and serum free T3 levels below the lower limit of normal are observed in 7% and 15% of levothyroxine-treated patients, respectively, indicating limited peripheral T3 production capacity. Nonphysiological changes in nuclear T3 receptor occupancy in target tissues might also be aggravated by polymorphisms in thyroid hormone transporters and deiodinases. Abbreviations: DIO, iodothyronine deiodinase; TR, thyroid hormone receptor.


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  1. Department of Endocrinology & Metabolism, Academic Medical Centre, Room F5-165, Meibergdreef 9, Amsterdam 1105AZ, Netherlands.

    • Wilmar M. Wiersinga

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  • Wilmar M. Wiersinga

    Dr Wilmar M. Wiersinga is Professor of Endocrinology at the University of Amsterdam, Netherlands, and was Chief of the Division of Endocrinology & Metabolism at the Academic Medical Centre in Amsterdam during 1996 2007. His main research topics are autoimmune thyroid disease (especially Graves ophthalmopathy), nonthyroidal illness syndrome, and amiodarone. In the past he has served as President of the European Thyroid Association, and currently he is editor-in-chief of the European Thyroid Journal.

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