Pituitary-Thyroid Function

Oppenheimer, Fisher, Nelson and Jailer, Journal of Clinical Endocrinology and Metabolism (1961),276 observed lowered serum protein-bound iodine (PBI) levels in thirty-six patients receiving PHT. Despite the lowered PBI levels there was no clinical evidence of hypothyroidism in any of the patients. The authors found no evidence of a direct effect of PHT on the thyroid gland uptake or hormone synthesis. They suggest that PHT lowers serum PBI by interfering with the binding of thyroxine to plasma protein.

276. Oppenheimer, J. H., Fisher, L. V., Nelson, K. M., and Jailer, J. W., Depression of the serum protein-bound iodine level by diphenylhydantoin, J. Clin. Endoc. Metab., 21: 252-262, 1961.

Cantu and Schwab, Archives of Neurology (1966),44 found that the administration of PHT (300-400 mg daily) to thirty-nine adult patients for two weeks was associated with reduction in PBI levels, but there was no change in normal thyroid function. Triiodothyronine (T3) uptake by red blood cells and thyroid 131I uptake were unchanged in the five patients in whom these were measured.

44. Cantu, R. C. and Schwab, R. S., Ceruloplasmin rise and PBI fall in serum due to diphenylhydantoin, Arch. Neurol., 15: 393-396, 1966.

Mendoza, Flock, Owen and Paris (1966),494 demonstrated that PHT increased metabolism of thyroxine (T4) in rats. PHT also produced a decrease in concentration of PBI, although it did not alter the uptake of 131I-T3, from plasma by erythrocytes.

494. Mendoza, D. M., Flock, E. V., Owen, C. A., Jr., and Paris, J., Effect of 5,5’-diphenylhydantoin on the metabolism of L-thyroxine-131 I in the rat. Endocrinology, 79: 106-118, 1966.

Heyma, Larkins, Perry-Keene, Peter, Ross and Sloman, Clinical Endocrinology (1977),1898 in a randomized controlled trial of the effect of long-term PHT therapy, found that triiodothyronine (T3) and thyrotropin concentrations were not affected by PHT. Thyroxine (T4) concentrations were reduced. This appeared to be due to diminished protein binding and enhanced degradation of T4. The authors note that an increased rate of conversion of T4 to T3 may explain why patients on PHT seldom exhibit clinical features of hypothyroidism, even though T4 concentrations may be low.

1898. Heyma, P., Larkins, R. G., Perry-Keene, D., Peter, C. T., Ross, D. and Sloman, J. G., Thyroid hormone levels and protein binding in patients on long-term diphenylhydantoin treatment, Clin. Endocrin, 6: 369-76, 1977.

Ginsberg, Chen and Walfish, Annals of Endocrinology (Paris) (1979),2541 studied the effect of PHT on the rat hypothalamus-pituitary-thyroid system. In intact rats treated with PHT (5 mg/100 g body weight/day), for seven days, serum T4 was lower and there was no increase in thyroid stimulating hormone (TSH), in response to TRH injection. In thyroidectomized rats receiving T4, replacement, PHT lowered serum T4 and T3, but did not change the T4 /T3 ratio. There was also no increase in TSH. In another experiment, PHT inhibited the expected rise in TSH in rats subjected to cold, implying inhibition of endogenous TRU activity. The authors conclude that PHT has multiple sites of action on rat thyroid function.

2541. Ginsberg, J., Chen, H. J., Walfish, P. G., Multiple sites of action of diphenylhydantoin on rat thyroid regulation, Ann. Endocrinol., 49a, 1979.

Gambert and Garthwaite, Hormone and Metabolic Research (1980),2194 found that PHT increased basal levels of thyroid stimulating hormone and prolactin in hypothyroid rats. This effect was not observed in euthyroid animals.

2194. Gambert, S. R. and Garthwaite, T. L., The effect of diphenylhydantoin on basal and stimulated thyroid stimulating hormone (TSH) and prolactin secretion in euthyroid and hypothyroid rats, Horm. Metab. Res., 12:636-7, 1980.

Faber, Lumholtz, Kirkegaard and Friis, Annals of Endocrinology (1983),2486 studied the turnover of 1251-or 1311-labeled T4, T3 and reverse T3 in patients before and after treatment with PHT (350 mg/day) for two weeks. PHT reduced the bioavailability of T4, increased the T4 to T3 conversion rate and increased the nondeiodinative metabolic pathways of T4.

2486. Faber, J., Lumholtz, 1. B., Kirkegaard, C., Friis, T., Turnover studies of T4, T3 and rT3 in L-T4 treated hypothyroid subjects receiving phenytoin, Ann. Endocrinol., 44(4): 63a, 1983.

Mann and Surks, Endocrinology (1983),2761 reported that PUT influenced specific T3, binding by nuclear T3, receptors in hepatic tissue from euthyroid and athyreotic rats. PHT (20 mg/100 g body weight) resulted in a 14-24% decrease in specific nuclear binding in nuclei from euthyroid rats and 24% in athyreotic rats compared to control. Similar effects of PHT (10-300 µM) were noted in in vitro studies using solubilized T3 receptors.

2761. Mann, D. N., Surks, M. I., 5,5-diphenylhydantoin decreases specific 3,5,3’-triiodothyronine (T3) binding by rat hepatic nuclear T3 receptors, Endocrinology, 112(5): 1723-31, 1983.

Surks, Ordene, Mann and Kumara-Siri, Journal of Clinical Endocrinology and Metabolism (1983),2994 studied the effect of PHT on thyrotropin releasing hormone (TRH)-induced thyroid stimulating hormone (TSH) secretion in humans and rats. In four patients, PHT (100 mg t.i.d.), for fourteen days, decreased serum T4 (22%), free T4 (31%), and free serum T3, (6%). Basal TSH levels were unchanged, but the integrated TSH response after TRH injection decreased. In euthyroid rats, PHT (5 mg/100 g body weight daily, for nine days) caused no change in TRH-induced TSH release. When PHT (5 mg/100 g body weight, every eight hours for 48 hours) was given to athyreotic rats, significant increases in pituitary TSH, but not in plasma TSH, were observed. PHT (100 µM) caused a 74% decrease in TSH release by cultured anterior pituitary cells in the presence of TRH. The authors suggest that PHT inhibits TRH-induced TSH release.

2994. Surks, M. I., Ordene, K. W., Mann, D. N., Kumara-Siri, M. H., Diphenylhydantoin inhibits the thyrotropin response to thyrotropin-releasing hormone in man and rat, J. Clin. Endocrinot. Metab., 56: 940-5, 1983.

Franklyn, Sheppard and Ramsden, European Journal of Clinical Pharmacology (1984),2507 measured free T4 and T3, in thirty-one patients on chronic PHT therapy. They found significant reduction in levels of both hormones and suggest that PHT not only alters thyroid hormone protein binding, but also cellular metabolism of thyroid hormones.

2507. Franklyn, J. A., Sheppard, M. C., Ramsden, D. B., Measurement of free thyroid hormones in patients on long-term phenytoin therapy, Eur. J. Clin. Pharmacol., 26(5): 6334, 1984.

Davis, Lynam, Franklyn, Docherty and Sheppard, European Neuroendocrine Association Abstracts (1985),2434 found that both T3 and PHT (50-150 µM) reduced prolactin messenger RNA levels in cultured rat pituitary cells, supporting the premise that PHT may act as a partial T3 agonist. The authors suggest that PHT has therapeutically relevant intracellular, as well as cell membrane, effects.

2434. Davis, J. R., Lynam, T. C., Franklyn, J. A., Docherty, K., Sheppard, M. C., Tri-iodothyronine and phenytoin reduce prolactin messenger RNA levels in cultured rat pituitary cells, J. Endocr., 109: 359-64, 1986.

Franklyn, Davis, Ramsden and Sheppard, Journal of Endocrinology (1985),2506 studied the effect of PHT on the binding of T3 to isolated nuclei from rat anterior pituitary tissue. PHT (50-200 µM) inhibited nuclear binding of T3, in a dose-dependent fashion. PHT also decreased TRH-stimulated TSH release from rat anterior pituitary cells. The authors conclude that PHT can influence thyroid hormone action at the receptor level.

2506. Franklyn, J. A., Davis, J. B., Ramsden, D. B., Sheppard, M. C., Phenytoin and thyroid hormone action, J. Endocrinol., 104: 201-04, 1985.

Gingrich, Smith, Shapiro and Surks, Endocrinology (1985),2540 reported that PHT (100-400 µM) inhibited triiodothyronine (T3,)-stimulated growth rate in a rat pituitary tumor cell line (GC) that produces growth hormone. PHT also inhibited production of growth hormone messenger RNA and growth hormone itself over the same concentration range. The authors suggest that PHT decreases T3 effects by inhibiting T3 nuclear-receptor binding.

Lim, Loidi, Kennedy, Topliss and Stockigt, Metabolism (1995),3521 examined the effects of nonsteroidal anti-inflammatory drugs (NSAID), diuretics, and PHT on thyrotropin (TSH) release in male wistar rats at anterior pituitary cells in primary culture. One to two million cells were obtained from the each of the 12 pituitary lobes and viability of the cells as assessed by tyrpan blue exclusion was greater than 90%. Rat Prolactin was assayed by double-antibody RIA using material supplied by the NIDDK pituitary program.

Results indicated that PHT did not significantly alter TSH concentration in the medium. Inhibition of TRH- stimulated TSH release by PHT suggests that the drug may have multiple sites of action, including direct inhibition of TSH release by the thyrotrophs. PHT was reported to inhibit the uptake of noradrenaline in vitro but not in vivo. In addition the high levels of Glu and GABA in the brain are intracellular, in which case it may be argued that Glu and GABA concentrations in the micro-environment of the uptake sites are sufficiently small. The high affinity transports of these transmitters were considered to be the main processes served to reduce extracellular concentrations to low levels. Thus, the ability of PHT to inhibit Glu and GABA transport may contribute significantly to the anticonvulsant properties of the drug.

3521. Lim, C.F., Loidi, N.M., Kennedy, J.A., Topliss, D.J., and Stockigt, J.R., Effect of loop diuretics and nonsteroidal anti-inflammatory drugs on thyrothrpin release by rat anterior pituitary cells in vitro, Metabolism, 44(8): 1008-12, 1995.

Lim, Loidl, Kennedy, Topliss and Stockigt, Experimental and Clinical Endocrinology and Diabetes (1996),3522 evaluated the effects of nonsteroidal antiinflammatory drugs (NSAID), diuretics, the synthetic flavonoid EMD 21388, and phenytoin (PHT) on [125I]T3 cellular uptake in rat anterior pituitary cells in vitro. PHT at 25 æmol/L had no significant effect, while 50, 100, and 200 æmol/L inhibited [125I]T3 uptake by 12%, 23%, and 37% respectively. At 100 æmol/L, inhibition ranged from 9-76% with the diuretics; 35-52% with the NSAIDs; 49% with EMD 21388. Aspirin had no effect. The authors note that PHT's inhibition of T3 uptake is in opposition to its previously documented inhibitory effect on thyroid-stimulating hormone (TSH) release.

3522. Lim, C.F., Loidl, N.M., Kennedy, J.A., Topliss, D.J., and Stockigt, J.R., Drug effects on triiodothyronine uptake by rat anterior pituitary cells in vitro, Exp. Clin. Endocrinol. Diabetes, 104(2):151-7, 1996.

See also Refs. 488, 490, 491, 492, 1125, 1479, 2271, 2425, 2644, 2689, 2760, 2917, 2996, 3018, 3042.

488. Levy, R. P. and Marshall, J. S., Short-term drug effects on thyroid function tests, Arch. Intern. Med., 114: 413-416, 1964.
490. Oppenheimer, J. H. and Tavernetti, R. R., Studies on the thyroxin-diphenylhydantoin interaction: effect of 5,5’-diphenylhydantoin on the displacement of L-thyroxine from thyroxine-binding globulin (TBG), Endocrinology, 71: 496-504, 1962.
491. Oppenheimer, J. H. and Tavernetti, R. R., Displacement of thyroxine from human thyroxine-binding globulin by analogues of hydantoin. Steric aspects of the thyroxine binding site, J. Clin. Invest., 41: 2213-2220,1962.
492. Oppenheimer, J. H., Role of plasma proteins in the binding, distribution and metabolism of the thyroid hormones, New Eng. J. Med., 278: 1153-1162, 1968.
1125. Hansen, J. M., Skovsted, L., Lauridsen, U. B., Kirkegaard, C., and Siersbaek-Nielsen, K., The effect of diphenylhydantoin on thyroid function, J. Clin. Endocrinol. Metab., 39: 785-786, 1974.
1479. Romero, E., Marañon, A. and Bobillo, E. R., Antithyroid action of hydantoin derivatives, Rev. Iber. Endocr., 101: 363-375, 1970.
2271. Aanderud, S., Aarbakke, J., Sundsfjord, J., Metabolism of thyroid hormones in isolated rat hepatocytes: studies on the influences of carbamazepine and phenytoin, Acta. Endocrinol., 104(4): 479-84, 1983.
2425. Dana-Haeri, J., Oxley, J., Richens, A., Pituitary responsiveness to gonadotrophin-releasing and thyrotrophin-releasing hormones in epileptic patients receiving carbamazepine or phenytoin, Clin. Endocrinol., 20: 163-8, 1984.
2644. Kaneko, S., Otani, K., Fukushima, Y., Sato, T., Narita, S., Kurahashi, K., Ogawa, Y., Nomura, Y., Shinagawa, S., Effects of antiepileptic drugs on hGH, TSH, and thyroid hormone concentrations during pregnancy, Int. J. Biol. Res. Pregnancy, 3(4): 148-51, 1982.
2689. Langer, P., The effects of salicylates and similar acting substances, (diphenylhydantoin, dinitropbenol, etc.) on the hypophyseal-thyroid gland axis, Vnitr. Lek., 30: 48-54, 1984.
2760. Mann, D. N., Kumara-Siri, M. H., Surks, M. I., Effect of 5,5-diphenylhydantoin on the activities of hepatic cytosol malic enzyme and mitochondrial alpha-glycerophosphate dehydrogenase in athyreotic rats, Endocrinology, 112(5): 1732-8, 1983.
2917. Rousso, I., Pharmakiotis, A., Gatzola, M., Karatza, E., Tourkantonis, A., Sklavounou-Tsouroutsoglou, S., Effects of phenobarbital, diphenylhydantoin and carbamazepine on thyroid function in epileptic children, Acta Endocrinol., 107(265); 48-9,1984.
2996. Suzuki, H., Yamazake, N., Suzuki, Y., Hiraiwa, M., Shimoda, S., Mori, K., Miyasaka, M., Lowering effect of diphenylhydantoin on serum free thyroxine and thyroxine binding globulin (TBG), Acta Endocrinol., 105 (4): 477-81, 1984.
3018. Timiras, P. S., Hill, H. F., Hormones and epilepsy, Antiepileptic Drugs: Mechanisms of Action, Glaser, G. H., et al., Eds., Raven Press, New York, 655-66, 1980.
3042. Valimaki, M., Effects of drugs and nonthyroid disorders on thyroid hormones, Duodecim., 98(17): 1247-56, 1982.