Pituitary-Adrenal Hormones

Bonnycastle and Bradley, Endocrinology (1960),520 found that pretreatment with PHT blocks the adrenal ascorbate depletion which follows unilateral adrenalectomy in rats. PHT also blocked intravenous vasopressin and subcutaneous epinephrine stimulation of adrenocorticotropic hormone (ACTH) release. The authors suggest the hypothalamus or pituitary as possible sites of inhibition of the release of ACTH.

520. Bonnycastle, D. D. and Bradley, A. J., Diphenylhydantoin and the release of adrenocorticotropic hormone in the albino rat, Endocrinology, 66: 355-363, 1960.

Krieger, Journal of Clinical Endocrinology and Metabolism (1962),198 found that administration of PHT (300 mg/day), for one to two weeks, in eight normal volunteers, affected pituitary-adrenal function by reducing metyrapone-stimulated ACTH release. The effects of injected ACTH were unaffected by PHT.

198. Krieger, D. T., Effect of diphenylhydantoin on pituitaryadrenal interrelations, J. Clin. Endocrinol. Metab., 22: 490-493, 1962.

Oliver and Troop, Steroids (1963),482 found that PHT (15 mg/kg), given to rats orally for twenty days, reduced the rise in plasma corticosterone levels produced by the stress of pentobarbital-induced anesthesia. The authors suggest that PHT diminishes the pituitary-adrenal response to this stress.

482. Oliver, J. T. and Troop, R. C., Plasma corticosterone levels in stressed rats following the administration of pentobarbital, morphine and diphenylhydantoin, Steroids, 1: 670-677, 1963.

Werk, MacGee and Sholiton, Journal of Clinical Investigation (1964), 377 in Studies in man, found PHT (300-400 mg/day) caused a net increase in excretion of 6-hydroxycortisol and an unconjugated polar metabolite. There was also a relative de-crease in conjugated tetrahydro derivatives.

377. Werk, E. E., Jr., MacGee, J., and Sholiton, L. J., Effect of diphenylhydantoin on cortisol metabolism in man, J. Clin. Invest., 43: 1824-1835, 1964.

Houck and Patel, Nature (1965),171 demonstrated that PHT (25 mg/day, for two days) prevented loss of dermal collagen and release of collagenase induced by cortisol administration to young rats.

171. Houck, J. C. and Patel, Y. M., Proposed mode of action of corticosteroids on the connective tissue, Nature, 206: 158-160, 1965.

Dill, Archives Internationales de Pharmacodynamie et de Therapie (1966),76 reported that PHT (100 mg/day) did not inhibit the initial elevation of the plasma level of corticosterone in rats stressed by laparotomy. However, PHT did reduce the duration of the effect.

76. Dill, R. E., Discrepancy of adrenal responses in diphenylhydantoin treated rats, Arch. Int. Pharmacodyn., 160: 363-372, 1966.

Rinne, Medicina et Pharmacologia Experimentalis (1967),303 found that patients on PHT released less ACTH in response to metyrapone than controls. The response of these patients to exogenous ACTH was normal and intravenous vasopressin caused normal release of ACTH from the pituitary gland. The author suggests that PHT alters ACTH release by regulating hypothalamic function.

303. Rinne, U. K., Site of the inhibiting action of diphenylhydantoin on the release of corticotrophin in epileptic patients, Med. Pharmacol. Exp., 17: 409-416, 1967.

Kuntzman and Southern, Advances in Biochemical Psychopharmacology (1969),1240 demonstrated that the metabolism of cortisol in liver microsomes of guinea pigs was markedly increased by pre-treatment with PHT (50-100 mg/kg, daily for four to ten days).

1240. Kuntzman, R. and Southern, A. L., The effects of CNS active drugs on the metabolism of steroids in man, Adv. Biochem. Psychopharmacol., 1: 205-217, 1969.

Choi, Thrasher, Werk, Sholiton and Olinger, Journal of Pharmacology and Experimental Therapeutics (1971),896 studied the effect of PHT on the metabolism of injected radiolabeled cortisol in humans. PHT increased cortisol turnover kinetics, but did not affect normal plasma cortisol binding.

896. Choi, Y., Thrasher, K., Werk, E. E., Sholiton, L. J., and Olinger, C., Effect of diphenylhydantoin on cortisol kinetics in humans, J. Pharmacol. Exp. Ther., 176: 27-34, 1971.

Werk, Thrasher, Sholiton, Olinger and Choi, Clinical Pharmacology and Therapeutics (1971),1679 studied, for up to twenty-four months, cortisol production and metabolism in twenty-one patients with convulsive disorders, with and without PHT therapy. During PHT therapy there was a positive correlation between cortisol secretion rates, measured by isotope dilution method, and an increase in urine ratio of 6-hydroxycortisol to 17-hydroxycorticosteroids. The cortisol secretion rate was found to increase significantly when the ratio of the hydroxycortisol to corticosteroids increased more than 0.14.

1679. Werk, E. E., Thrasher, K., Sholiton, L. J., Olinger, C., and Choi, Y., Cortisol production in epileptic patients treated with diphenylhydantoin, Clin. Pharmacol. Ther., 12: 698-703, 1971.

Haque, Thrasher, Werk, Knowles and Sholiton, Journal of Clinical Endocrinology and Metabolism (1972),1128 found that PHT markedly increases the metabolism of dexamethasone in humans.

1128. Haque, N., Thrasher, K., Werk, E. E., Jr., Knowles, H. C., J r., and Sholiton, L. J., Studies on dexamethasone metabolism in man: effect of diphenylhydantoin, J. Clin. Endocr., 34: 44-50, 1972.

Evans, Walker, Peters, Dyas, Riad-Fahmy, Thomas, Rimmer, Tsanaclis and Scanlon, British Journal of Pharmacology (1985),2485 found that morning concentrations of cortisol in saliva and plasma of epileptic patients receiving PHT were the same as those observed in healthy volunteers not receiving PHT. However, cortisol half-life, as determined by an intravenous dexamethasone method, was significantly reduced in the PHT-treated patients. Because there was a correlation between the half-life of cortisol and antipyrine, the authors suggest that the reduced half-life of cortisol may relate to the degree of microsomal enzyme induction in PHT-treated patients. The authors state that the normal morning levels of cortisol observed in PHT-treated patients, in spite of the reduced half-life, may be explained by increased cortisol secretion, which compensates for increased cortisol metabolism.

See also Refs. 171, 268, 451, 483, 486, 776, 964, 1351, 1480, 1627, 1678, 2382, 3053.

2485. Evans, P. J., Walker, R. F., Peters, J. R., Dyas, J., Riad-Fahmy, D., Thomas, J. P., Rimmer, E., Tsanaclis, L., Scanlon, M. F., Anticonvulsant therapy and cortisol elimination, Br. J. Clin., Pharmac., 20: 129-32,1985.

171. Houck, J. C. and Patel, Y. M., Proposed mode of action of corticosteroids on the connective tissue, Nature, 206: 158-160, 1965.

268. Natelson, S., Walker, A. A., and Pincus, J. B., Chlordiazepoxide and diphenylhydantoin as antagonists to ACTH effect on serum calcium and citrate levels, Proc. Soc. Exp. Biol. Med., 122: 689-692,1966.

451. Sholiton, L., Werk, E. E., Jr., and MacGee, J., The in vitro effect of 5,5’-diphenylhydantoin on the catabolism of cortisol by rat liver, Metabolism, 13: 1382-1392,.1964.

483. Woodbury, D. M., Timiras, P. S., and Vernadakis, A., Modification of adrenocartical function by centrally acting drugs and the influence of such modification on the central response to these drugs, Hormones, Brain Function, and Behavior, 38-50, H. Hoagland, Ed., Academic Press, New York, 1957.

486. Christy, N. P. and Hofmann, A. D., The apparent lack of effect of diphenylhydantoin (Dilantin) upon adrenal cortical response to ACTH in man, Clin. Res., 6: 258-259, 1958.

776. Asfeldt, V. H. and Buhl, J., Inhibitory effect of diphenylhydantoin on the feedback control of corticotrophin release, Acta Endocrinol., 61: 551-560, 1969.

964. Dill, R. E., Adrenal cortical response in rats treated with diphenylhydantoin sodium, Anat. Rec., 148: 366, 1964.

1351. Meikle, W., Jubiz, W., West, C. D., and Tyler, F. H., Effect of diphenylhydantoin (Dilantin) on the metyrapone test demonstrated by a new assay for plasma metyrapone, Clin. Res., 17: 107, 1969.

1480. Rose, L. I., Williams, G. H., Jagger, P. I., Lauler, D. P., and Thorn, G. W., The paradoxical dexamethasone response phenomenon, Metabolism, 18: 369-375, 1969.

1627. Tyler, F. H., West, C. D., Jubiz, W., and Meikle, A. W., Ditantin and metyrapone: a clinically significant example of enzyme induction, Trans. Amer. Clin. Climal. Assoc., 81: 213-219, 1970.

1678. Werk, E. E., Choi, Y., Sholiton, L., Olinger, C., and Haque, N., Interference in the effect of dexamethasone by diphenylhydantoin, New Eng. J. Med., 281: 32-34, 1969.

2382. Chalk, J. B., Ridgeway, K., Brophy, T. R., Yelland, J. D., Eadie, M. J., Phenytoin impairs the bioavailability of dexamethasone neurological and neurosurgical patients, J. Neurol. Neurolsurg. Psychiatry, 47(10): 1087-90, 1984.

3053. Wada, A., Izumi, F., Yanagihara, N., Kobayashi, H., Modulation by ouabain and diphenylhydantoin of veratridine-induced 22 Na influx and its relation to 46 Ca influx and the secretion of catecholamines in cultured bovine adrenal medullary cells, Arch. Pharymacol., 328(3): 273-8, 1985.

Tsagarakis, Rees, Besser and Grossman, Journal of Molecular Endocrinology (1991),3520 employed an acute explant system of the rat hypothalamus in vitro to examine the role of calcium and calmodulin in the release of corticotrophin-releasing hormone-41 (CRH-41). Release of CRH-41, as determined by radioimmunoassay, was stimulated in a dose-dependent manner by the membrane-depolarizing agents KCl and veratridine. Stimulation was also observed with the calcium ionophore A23187. The calcium channel blocker verapamil (1 - 100 æmol/l) inhibited both KCl and veratridine-induced release in a dose-dependent manner (maximum inhibition of 75% and 60% respectively), thus providing further evidence that calcium entry is required for secretion of CRH-41 following membrane depolarization.

Trifluoperazine (1 - 100 æmol/l), an inhibitor of calmodulin-calcium interaction, decreased both KCl- and veratridine-evoked CRH-41 secretion in a dose-dependent fashion (maximum inhibition of 50% and 30% respectively). Similarly, phenytoin, a calmodulin-dependent kinase inhibitor, in the concentration range of 1 - 100 æmol/l, also decreased depolarization-induced CRH-41 release in a dose-dependent manner. The basal release of CRH-41 was unaffected by either treatment. Finally, both calmodulin inhibitors (10 æmol/l) decreased CRH-41 release induced by the calcium ionophore A23187 (10 æmol/l). The authors' data provide evidence for the role of calcium in membrane depolarization-induced stimulus-secretion coupling of rat hypothalamic CRH-41. Furthermore, inhibition of the stimulatory responses by two separate classes of calmodulin inhibitors suggests a role for calmodulin, at least in part, in this process.

3520. Tsagarakis S., Rees, L.H., Besser, G.M., and Grossman, A., Involvement of calmodulin in depolarization-induced release of corticotrophin-releasing hormone-41 from the rat hypothalamus in vitro, J. Mol. Endocrinol., 7: 71-75, 1991

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