Combined T4/T3 Therapy: Placebo or Tomato?

An Assessment of the October 2003 T4/T3 Studies

by Ken Woliner, M.D., A.B.F.P.

In the October 2003 issue of "The Journal of Clinical Endocrinology and Metabolism" (volume 88, no 10), two research articles were published describing no additional benefit of substituting a small amount of T3 (triidothyronine) for T4 (levothyroxine) in patients treated for hypothyroidism. These articles were accompanied by an editorial stating that there is insufficient evidence to change from the current standard-of-care practice of using T4 therapy alone. I asked Dr. Kenneth Woliner, one of our resident thyroid experts, to discuss these articles, and why a considerable number of patients continue to desire treatment with both T4 and T3 therapy. Here’s his response! -- - Mary Shomon

October, 2003 -- This month, the Journal of Clinical Endocrinology and Metabolism has published two excellent research articles (see abstracts) comparing standard T4 thyroid replacement therapy with the combination of T4/T3 thyroid replacement therapy in the treatment of hypothyroidism. Both of these studies yielded ‘negative’ results (they found no benefit on symptom relief by adding T3 medication). These articles were accompanied by an editorial stating that there is insufficient evidence to change from the current standard-of-care practice of using T4 therapy alone.

A considerable number of patients remain unsatisfied with therapy based exclusively on T4 medications and continue to desire treatment with both T4 and T3 therapy. A placebo is a treatment that has no effect of its own, but patients think it will work better, so they mentally convince themselves they feel better with it. Is T3 therapy a placebo? Or are there other explanations for these negative results?

THE STUDIES IN QUESTION

The two studies that were recently published in JCEM each sought to look into the possibility that patients would do better with combination T4/T3 therapy than on T4 therapy alone. The Walsh study reported “negative” results with no significant difference between T4 and combined T4/T3 therapy for cognitive function, quality of life, subjective satisfaction with treatment, and with eight of ten visual analog scales assessing symptoms. In this study, anxiety and nausea were significantly worse for combined treatment than for T4 alone.¹ Likewise, the Sawka study also did not report any improvement in self-rated mood and well-being scores, but did not report any detrimental effects of combined therapy either.² Both studies concluded that their data did not support the routine use of T3 in addition to T4 in the treatment of hypothyroid patients. These studies contradict previous reports by Bunevicius showing improvement with the addition of T3 to standard T4 therapy. ^4,5

Both of these new studies appear to be done correctly. There appears to be no financial bias of the investigators. The participants and examiners were properly blinded as to what therapy they each subject received. The studies were powered high enough to detect a treatment effect in the general population. Do these results now mean that T3 therapy should never be used? No, they do not.

DEFINING HYPOTHYROIDISM

To begin to understand why they do not clearly show that T3 therapy is useless, I think we should discuss what the true definition of hypothyroidism really is. Hypothyroidism is a medical condition that occurs when there is an absolute or relative deficiency of thyroid hormone in the body. Thyroid deficiency symptoms can include fatigue, weight gain from fluid retention, dry skin and cold intolerance, yellow skin, coarseness or loss of hair, hoarseness, goiter, reflex delay (especially the relaxation phase), ataxia (difficulty walking), constipation, memory and mental impairment, decreased concentration, depression, irregular or heavy menses and infertility, myalgias (muscle aches), hyperlipidemia (high cholesterol), bradycardia and hypothermia (low heart rate and low body temperature), myxedema fluid infiltration of tissues (non-pitting edema caused by something else besides water retention), and other symptoms. ⁶ Most hypothyroid patients experience only some of these symptoms. Therapy for hypothyroidism usually entails some type of exogenous thyroid hormone replacement therapy with partial to complete resolution of the above symptoms.