Diphenylhydantoin Inhibits the Thyrotropin Response to Thyrotropin-Releasing Hormone in Man and Rat

We studied the effect of diphenylhydantoin (DPH) on TRH-stimulated TSH secretion in four patients (three of whom had hypothyroidism; one treated with L-T₄), in euthyroid rats, and in dispersed rat anterior pituitary cells in short term tissue culture. DPH treatment of four patients (100 mg, three times daily for 14 days) caused a 22% decrease in mean serum T₄ (P < 0.06), a 31% decrease in mean serum free T₄ (P < 0.01), and a 6% decrease in mean serum T₃. Mean basal serum TSH was unchanged, but the integrated TSH response after TRH injection (500 μg, iv) decreased 28% (P < 0.06) and 51% (P < 0.01) after 7 and 14 days of DPH treatment, respectively. Changes in the integrated PRL response to TRH did not correlate with those in TSH. Injection of DPH into euthyroid rats (5 mg/100 g BW·day for 9 days) caused a significant decrease in mean serum T₄ but no change in TSH release after TRH treatment. However, 1 h after a large dose of DPH (20 mg/100 g BW), there was a marked reduction (58%) in TRH-induced TSH release. DPH injections into athyreotic rats (5 mg/100 g BW every 8 h for 48 h) caused a significant increase in pituitary TSH (P < 0.01) but no significant decrease in plasma TSH. DPH inhibited TSH release from cultured anterior pituitary cells. In the presence of 10^-7 M TRH, DPH (10^-4 M) caused a 74% decrease in TSH release (P < 0.001); the inhibition produced by T₃ (10^-7 M) was only 14% (P < 0.05). These studies suggest that DPH inhibits TRH-induced TSH release in man, euthyroid rats, and cultured rat anterior pituitary cells. Thus, in DPH-treated patients with decreased serum T₄ and free T₄, the observed normal serum TSH when one would expect elevated serum TSH may result from drug-induced inhibition of TRH action on TSH release.