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

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T(4)) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T(4)/tri-iodothyronine (T(3)) combination therapy over T(4) 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 T(4) (FT(4)) to free T(3) (FT(3)) concentrations. Development of a sustained-release T(3) preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT(4)-FT(3) 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 T(4)/T(3) combination therapy than on T(4) monotherapy.