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

Division of Endocrinology and Metabolism, Department of Medicine, Montefiore Hospital and Medical Center, and the Albert Einstein College of Medicine, Bronx, New York 10467

Address all correspondence and requests for reprints to Martin I. Surks, M.D., Montefiore Hospital and Medical Center, Division of Endocrinology and Metabolism, 111 East 210 Street, Bronx, New York 10467.

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. (J Clin Endocrinol Metab 56: 940, 1983)

^* Presented in part at the 63rd Annual Meeting of The Endocrine Society, Cincinnati, OH, June 17–19, 1981. This work was supported by NIH Grants CA-24604-03 and CA-16463-07.

Received April 19, 1982.

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