Studies in hypothyroid rats show that, when infused with a combination of thyroxine (T4) plus triiodothyronine (T3) to normalize thyrotropin (TSH), euthyroidism in all organs is only ensured when T(4) and T(3) are administered in a ratio as normally secreted by the rat thyroid. As substitution with T(4)-only results in an abnormal serum T(4)/T(3) ratio, it is also possible that in humans, euthyroidism does not exist at the tissue level in many organs, considering that iodothyronine metabolism in the human and the rat share many similar mechanisms. Recent reports in which cognitive function and well-being are compared in patients with primary hypothyroidism substituted with T(4)-only versus substitution with T(4) plus T(3) result in controversial findings in that either positive or no effects were found. In all these studies T(3) was used in the plain form that results in nonphysiologic serum T(3) peaks. In these studies it is suggested that substitution with T(3 )should preferably be performed with a preparation that slowly releases T(3) to avoid these peaks. In the study reported here we show that treatment of hypothyroid subjects with a combination of T(4) plus slow-release T(3) leads to a considerable improvement of serum T(4) and T(3) values, the T(4)/T(3) ratio and serum TSH as compared to treatment with T(4)- only. Serum T(3) administration with slow-release T(3) did not show serum peaks, in contrast to plain T(3).
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