We are certainly aware that there are differences in the effects of L-thyroxine and liothyronine. In fact, several studies by our group have shown that the addition of liothyronine to L-thyroxine is essential to ensure euthyroidism in plasma and all tissues of thyroidectomized rats (1-3). However, thyroid hormone physiology is quite different in humans. This might help explain why, contrary to the expectations raised by our previous animal data, our study in hypothyroid patients and most similar studies conducted to date failed to demonstrate any objective advantage of combined L-thyroxine plus liothyronine replacement therapy over standard treatment with L-thyroxine alone. In addition, it should be noted that we evaluated clinical and biochemical variables pertaining to most body organs and systems, including the heart.

We agree that it would also have been appropriate to measure markers of skeletal muscle function in our study, although Dr. Eisinger points out the difficulties inherent in such an evaluation. However, we are not entirely convinced that doing so would have allowed us to determine why our patients preferred combined L-thyroxine and liothyronine replacement therapy.

On one hand, our study includes a detailed evaluation of cardiac muscle function, which failed to reveal any benefit of combined L-thyroxine plus liothyronine replacement therapy over L-thyroxine alone. On the other, the fact that muscle function may take months to improve after initiation of L-thyroxine therapy (as Dr. Eisinger correctly points out) makes it unlikely that our patients preferred combination therapy because of an improvement of skeletal muscle function, especially since this treatment was given for only 8 weeks in our study. Therefore, we do not share Dr. Eisinger's conclusions, especially when, to the best of our knowledge, there is no consensus, or even clinical guidelines, about the "usual caution, low dosages, and appropriate adjustment" for liothyronine therapy in hypothyroid patients when "L-thyroxine does not yield satisfying clinical improvement." Moreover, the pharmacokinetic profile of oral liothyronine, together with the excessive amount contained in most commercially available preparations, makes its routine use and adjustment particularly difficult.

For these reasons, and especially considering the possibility of severe adverse events when adding even small doses of liothyronine to L-thyroxine (4), we insist that L-thyroxine alone should remain the drug of choice for treatment of hypothyroidism in humans, until clear advantages of combination therapy are demonstrated scientifically.