Multiple effects of 5,5'-diphenylhydantoin on the thyroid hormone system

The studies described above indicate the likelihood of a significant effect of DPH on cellular functions that are regulated by T3 at concentrations of DPH that occur during treatment of patients with Dilantin. Thus, it is possible that sensitive measures of cellular thyroid status in man, if available, might indicate that DPH treatment causes a mild hypothyroid state which may be partially compensated for by an activity of DPH as a partial thyroid hormone agonist. This review illustrates the complex array of interactions of DPH with multiple elements of the thyroid hormone system ranging from effects on T4 and T3 metabolism, serum protein binding, serum and cellular concentration of thyroid hormones, nuclear T3 binding and biologic actions of T3, to effects on hypothalamic and pituitary regulation of TSH. At the present time, no single biological mechanism common to these manifold interactions is apparent. Moreover, many of these interactions are not yet completely understood despite clinical and basic biological investigation for over 20 years. Continued investigation would appear fruitful especially for further understanding of hypothalamic regulation of TSH secretion, of cellular uptake of T3, and of the use of DPH as a partial thyroid hormone agonist. Finally, since DPH attenuates the effect of T3 at the level of the nuclear T3 receptor, the drug may serve as a prototype of agents that may be useful in the management of thyrotoxicosis.