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Do we need still more trials on T₄ and T₃ combination therapy in hypothyroidism?

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands

(Correspondence should be addressed to W M Wiersinga; Email: w.m.wiersinga{at}amc.uva.nl)

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T₄) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T₄/tri-iodothyronine (T₃) combination therapy over T₄ monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T₄ (FT₄) to free T₃ (FT₃) concentrations. Development of a sustained-release T₃ preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT₄–FT₃ ratio's throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T₄/T₃ combination therapy than on T₄ monotherapy.