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).