Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index

Previous studies have shown that, in patients with primary alterations in t hyroid hormone secretion, the level of the natural logarithm of serum TSH ( lnTSH) is negatively related to the level of free T-4. Because such patient s can generally be assumed to exhibit normal tissue responsivity to thyroid hormone, we were interested in determining whether the lnTSH/free T-4 inde x (FTI) relationship in patients with established thyroid hormone resistanc e (THR) exhibit a lower slope than patients with normal tissue sensitivity to thyroid hormone. We have therefore analyzed the relationship between the lnTSH and the FTI in members of three families with documented THR. In the se patients, a given dose of T-4 was maintained for a 1- to 2-month period, to achieve hormonal equilibration. Two of the families, though not related , exhibited the same mutation, E460K. The third was identified as A317T. As anticipated, the slope of the lnTSH/FTI ratio was significantly lower in t he patients with THR than in T-4-treated patients who were presumed to have normal sensitivity to thyroid hormone. The slope of the lnTSH/FTI relation ship seemed to be characteristic of the specific mutation involved in the t hree genotypes (wild-type and two mutations) examined. Further, the in vivo slope of the lnTSH/FTI relationship seemed to be linearly related to the T -3 association constant of the in vitro translated receptor. These findings support the potential usefulness of measuring the slope of lnTSH, as a fun ction of the FTI, in quantitating pituitary THR.