Emile E. Werk

Cortisol production in epileptic patients treated with diphenylhydantoin.

Cortisol production and metabolism were compared in 21 patients with convulsive disorders before and during diphenylhydantoin (DPH) therapy up to 24 months. Cortisol secretion rates (CSR) were measured by the ‐urinary isotope‐dilution method, based on the specific activity in urine of the metabolites tetrahydrocortisol and tetrahydrocortisone. Cortisol metabolism was evaluated by the ratio in urine of 6‐hydroxycortisol to 17‐hydroxycorticosteroids (6‐OHF/17‐OHCS). During DPH therapy there was a positive correlation of CSR with the increase in ratio of 6‐OHF/17‐OHCS. A significant mean increase in CSR, of 35 per cent above control, was found when the ratio increased more than 0.14. Since the increase in 6‐OHF/17‐OHCS is probably related to enhancement of hepatic microsomal enzyme activity by DPH, it can be concluded that, in epileptic patients treated with the drug, cortisol production will increase if there is sufficient enzyme stimulation. No deleterious effect has been observed in association with these changes in cortisol production and metabolism.

The measurement, excretion, and source of urinary 6-hydroxycortisol in humans

Abstract A method, modified from previously reported techniques, for the measurement of 6-hydroxycortisol in human urine is described. 3 H-6 β-hydroxycortisol is employed as an internal recovery standard and 1 thin layer chromatogram used for isolation. The accuracy, precision and specificity of the method are documented. Levels are reported in a large group of endocrinologically normal males, females and older children. A positive correlation was observed in the excretion of 6-hydroxycortisol with that of 17-hydroxycorticosteroids and creatinine which supports the use of the ratio, 6-hydroxycortisol/ 17-hydroxycorticosteroids, as an indicator of cortisol metabolism. This ratio was found to be significantly higher in females than males. Ancillary studies support the concept that some of the urinary 6-hydroxycortisol may originate directly from the adrenal glands but the evidence is not consistent and hence this question is unsettled at the present time.

Further studies of adrenocortical function in patients with carcinoma of the lung

Abstract Investigation of adrenocortical function in patients with progressive bronchogenic carcinoma without Cushings syndrome has been extended with special reference to (1) disease progression (patients survival time); (2) cell type of carcinoma; (3) brain metastases; and (4) extra-adrenal cortisol metabolism. The concentrations of 17-hydroxycorticosteroids (17-OHCS) in plasma were usually normal in the patients who survived the longest, greater than thirty weeks; were increased abnormally in patients who survived five to thirty weeks; and were further increased, often markedly, in patients within five weeks of death. The mean urinary excretion of 17-OHCS per gram creatinine was significantly higher than in the control group at all survival periods and increased further as death approached. Within five weeks of death, despite a considerable scatter of values, 42 per cent of the patients showed increased urinary excretion of 17-OHCS per gram creatinine, whereas in patients who survived for more than thirty weeks the incidence was 20 per cent. The abnormally high steroid excretion in the group five weeks before death was found predominantly in patients with oat cell and undifferentiated cell carcinoma; the mean urinary levels of both 17-OHCS and 17-ketosteroids (17-KS) were significantly higher in these patients than in patients with squamous cell and adenocarcinoma. The mean response of 17-OHCS in plasma to ACTH stimulation was essentially normal and did not change as the interval to death shortened, but the response of 17-OHCS in urine diminished, suggesting a decline in adrenocortical reserve. Nine of forty-two patients demonstrated hyperresponsiveness to ACTH administration, as reflected in 17-OHCS in plasma and/or urine. An increased incidence of elevated steroid levels was found in patients believed to have brain metastases but, in general, it was probably related to the advanced stage of the disease rather than to specific brain involvement. In selective cases, however, brain metastases may have influenced adrenocortical hyperfunction. Although the increased urinary excretion of 17-OHCS suggests augmented adrenal cortisol secretion, there was in addition considerable evidence for altered extra-adrenal cortisol metabolism in patients as the carcinoma progressed, as follows: High levels of 17-OHCS in plasma were found often in conjunction with normal urinary excretion of 17-OHCS. Urinary output of unconjugated 17-OHCS increased proportionately more than total 17-OHCS in patients with the most advanced disease resulting in a higher ratio of unconjugated to total 17-OHCS. There was a proportionately slightly higher increase in urinary steroid levels of 17-KS and 17-ketogenic versus 17-OHCS following ACTH administration. It is concluded that a spectrum of adrenocortical hyperfunction and altered cortisol metabolism exists in patients with progressively invasive bronchogenic carcinoma as an integral part of the disease. The adrenocortical hyperfunction is most pronounced in patients with advanced oat cell and undifferentiated carcinoma, indicating a connection between the high incidence of Cushings syndrome reported in these types of patients.

The “stiff-man” syndrome and hyperthyroidism

Abstract A case of severe fluctuating muscular rigidity and myoclonic spasms, an example of the stiffman syndrome in association with hyperthyroidism is described. Treatment of the hyperthyroidism was followed by a decrease in the marked generalized muscular rigidity and spasms, but moderate hypertonicity persisted. Extensive studies did not reveal the specific nature of the neuromuscular disturbance but were consistent with a central nervous system origin.

The uptake and metabolism of (1,2-3H)-testoster-one by the brain of functionally hepatectomized and totally eviscerated male rats

Following intravenous infusion of (1,2-3H)-testosterone, the uptake of radioactivity in the brain of control, functionally hepatectomized, and totally eviscerated castrate male rats was compared to that noted in blood. Total evisceration resulted in concentrating radioactivity in brain to significantly higher levels per unit weight than in blood sampled at comparable time intervals, although no statistical difference was noted in the functionally hepatectomized and control animals. Extracts of the one hour samples were separated by chromatography into radioactive testosterone, 5α-dihydrotesCosterone, and 5α-androstane-3α,17β-diol. Significant proportions of the latter two metabolites were found in the brain of all groups of rats. The finding of a higher concentration in brain than blood of 5α-dihydrotestosterone in the functionally hepatectomized and of 5α-dihydrotes-tosterone and 5α-androstane-3α,17β-diol in the totally eviscerated groups suggests that under these in vivo conditions rat brain is capable of converting testosterone to androgenic metabolites.

The in vitro effect of 5,5′-diphenylhydantoin on the catabolism of cortisol by rat liver

Abstract The alteration of the catabolism of cortisol by rat liver slices produced by the incorporation of 5, 5′-diphenylhydantoin (DPH) in an in vitro system has been evaluated. Using appropriate control incubations, DPH markedly augmented over control values the side-chain reduction of cortisol in male rat liver incubates, whereas significant enhancement of ring-A reduction was produced in female rat liver incubates. 6-hydroxylation was decreased by DPH in both. The major metabolite of DPH, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), proved equally effective in producing these alterations. No explanation for the observed results was forthcoming from this study but it is suggested that DPH may result in the enhanced production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) in rat liver slice incubates in turn augmenting the usual catabolic pathways for cortisol.

Altered cortisol metabolism in advanced cancer and other terminal illnesses: Excretion of 6-hydroxycortisol

Abstract Excretion of 6-hydroxycortisol (6-OHF) and other corticosteroid fractions in urine were measured in patients with and without progressive cancer. The change in ratio of 6-OHF:17-OHCS (chloroform-extractable) was employed as the principal index of abnormality in cortisol metabolism. Patients with advanced cancer demonstrated the most marked elevation above normal in this ratio. Occasionally the ratio exceeded 1.0, which indicates greater excretion of 6-OHF than of 17-OHCS. Terminal patients without cancer who had prolonged deteriorating courses also showed an elevation in 6-OHF:17-OHCS, but to a lesser degree than that noted in patients with cancer. Patients with chronic stabilized and acute illnesses usually had normal ratios. Analyses of other corticosteroid fractions suggested that the increase in excretion of 6-OHF and an unidentified, more polar compound was compensated for by a decrease in cortolcortolone metabolites. Considering the high level of steroid secretion, a relative decrease in tetrahydro derivatives was probably present also. Thus this study demonstrates further the abnormal metabolism of cortisol in patients with advanced cancer, the mechanism for which is not apparent.

The Effects of Ephedrine and Theophylline on Dexamethasone Metabolism in Bronchial Asthma

The effect of ephedrine (nine patients) and theophylline (seven patients) on dexamethasone metabolism was studied before and after three weeks of drug therapy in 16 asthmatics. Five patients were studied similarily but treated with placebo. After treatment with ephedrine, there was a mean decrease in plasma dexamethasone half-life (t1/2) of 132 minutes, or 36 per cent (P less than 0.025), and mean increase in metabolic clearance rate (MCR) of 148 liters/day, or 42 per cent (P less than 0.001). Increase in the excretion of urinary radioactivity, predominantly in the conjugated fractions, was noted. In contrast, theophylline and placebo therapy resulted in no significant changes in dexamethasone t1/2 or MCR. The rate of urinary excretion of radioactivity was reduced after theophylline treatment. Since ephedrine accelerates labeled dexamethasone clearance while theophylline does not, caution is necessary when prescribing ephedrine for asthmatics requiring long-term therapy with dexamethasone and probably other corticosteroids. It would appear from the present investigation that theophylline is a more appropriate bronchodilator for these patients.

Clinical Alcohol Hypoglycemia and Isolated Adrenocorticotrophic Hormone Deficiency

Abstract A 43-year-old man is described who fulfills the usual criteria for both alcohol hypoglycemia and isolated adrenocorticotrophic hormone (ACTH) deficiency. This is the fifth such patient rep...