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Combination thyroxine and triiodothyronine therapy
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Levothyroxine has long been the treatment of choice in the management of hypothyroidism. Guidelines published by the American Association of Clinical Endocrinologists, the American Thyroid Association and the Endocrine Society recommend levothyroxine and suggest against combination thyroxine and triiodothyronine in the routine management of hypothyroidism.
Nevertheless, using levothyroxine alone is somewhat of a compromise. The normal human thyroid produces about 100 mcg of T4 per day. However, it is T3, not T4, that is the “active” thyroid hormone. About 80% of T3 is produced through peripheral 5’-deiodination of T4. The other 20% (only about 6 mcg) is secreted directly from the thyroid gland.
Over the past decade there has been renewed interest in adding T3 to T4. Many hypothyroid patients do not feel optimal on T4 therapy alone. A study published in The New England Journal of Medicine in 1999, suggested that partial substitution of T4 with T3 improved mood and neuropsychological function. A criticism was that many subjects were rendered hyperthyroid with low thyroid-stimulating hormone. This study was also not designed to evaluate the long-term management of hypothyroidism.
Most other studies of combination T3/T4 therapy have been negative or equivocal. A meta-analysis in 2006 of 11 published randomized studies that included 1,216 patients found no difference in the effectiveness between combination vs. monotherapy in symptoms, measures of well-being, body weight, serum lipids or adverse events. A previous meta-analysis of nine controlled studies found beneficial effects on mood, quality of life and psychometric performance in only one. Nonetheless, many patients prefer combination therapy.
Because the currently available forms of T3 have a short half-life and are absorbed rapidly, supraphysiologic levels result after each dose, peaking at two to four hours and lasting up to six to eight hours. This results in hyperthyroidism in peripheral tissues by bypassing the usual physiologic regulation of intracellular levels of T3.
It is possible that slow-release forms of T3 may avoid this concern. In a study of hypothyroid subjects, combination therapy with T4 and slow-release T3 did not result in supraphysiologic peaks, unlike the current formulations of T3. However, no study has yet been completed directly comparing combination T4/T3 therapy using slow-release T3 to levothyroxine alone.
Another question has been whether T4 monotherapy results in normal serum levels of T3. One study of hypothyroid rats found that normal levels of T3 are not achieved when infusing T4 alone. However, in rats, 40% of T3 is produced directly by the thyroid, unlike the 20% in humans. A study in thyroidectomized humans found that normal T3 levels were achieved on traditional T4 therapy. There was no difference in pre-thyroidectomy levels of serum T3 compared to post-thyroidectomy on T4 monotherapy.
Although adding T3 to T4 is controversial, some practitioners use combination therapy in selected patients. It is possible that new formulations of slow-release T3 may provide additional therapeutic options in the future. Before that becomes common practice, however, we need more data. For now and for most patients, levothyroxine remains the standard of care.
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