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Effect of training on some metabolic changes associated with submaximal endurance exercise in the horse.

The effects of prolonged cantering before and after a 10 week training programme were studied in 6 horses. Determinations were carried on on venous blood for packed cell volume, glucose, glycerol, free fatty acids, beta-hydroxybutyrate, 11-hydroxycorticosteroids, pH and pCO2. Exercise caused a slight increase in glucose, lactate and pH, a moderate rise in PCV, glycerol and free fatty acids, and a marked rise in 11-hydroxycorticosteroids. A decrease in venous pCO2 occurred and a slight but not significant decrease in beta-hydroxybutyrate. Training was found to cause no significant difference in the changes seen. However, there was a tendency for exercise to result in higher 11-hydroxycorticosteroid levels after training.

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High fluid intake increases urine free cortisol excretion in normal subjects.

To test the hypothesis that increased fluid intake increases the urine free cortisol, we prescribed 5 liters of fluid intake per day or a normal fluid intake according to a randomized cross-over design in six normal volunteers. Each period lasted 5 days, with a 2-day washout period of normal fluid intake between the two periods. Urine free cortisol, 17-hydroxycorticosteroids, and creatinine were measured daily during each study period, and the average value over each 5-day period was calculated for each subject. High fluid intake caused a significant increase in the mean urine free cortisol [126 +/- 33 (SD) vs. 77 +/- 18 micrograms/day, P < 0.005]. The frequency of urine free cortisol results that exceeded the upper normal limit of 95 micrograms/day was also much higher during high fluid intake (23/30 vs. 6/30, P < 0.005). By contrast, urine 17-hydroxycorticosteroids (high fluid vs. normal fluid: 5.3 +/- 1.5 vs. 5.0 +/- 1.7 mg/day, respectively, P = not significant) and urine creatinine (1.51 +/- 0.48 vs. 1.45 +/- 0.37 g/day, P = not significant) did not differ between the two study periods. We conclude that high fluid intake (5 liters/day) increases free cortisol excretion without an increase in urine 17-hydroxycorticosteroids. Thus, mild to moderate increases in urine cortisol excretion may not indicate hypercortisolism in individuals who have a high fluid intake and urine volume.

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Emotional stress in childbirth and its modification by variations in obstetric management. Epidural analgesia and stress in labor.

Emotional stress before, during and after labor was measured in 20 primigravidae by serial estimation of plasma 11-hydroxycorticosteroids and by stress assessment interviews. The anticipation of epidural analgesia and internal fetal monitoring was a significant source of emotional stress to women awaiting induction of labor, despite explanation and attempted reassurance. During labor epidural analgesia reduced stress by abolishing pain, so eliminating the progressive rise in 11-hydroxycorticosteroids normally seen throughout labor. Epidural analgesia does not, however, block the potential for the adrenocortical response to stress and the physical work, emotional stress and surgical trauma of delivery stimulate a considerable output of 11-hydroxycorticosteroids.

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Hydrolysis of steroid glucuronides with beta-glucuronidase preparations from bovine liver, Helix pomatia, and E. coli.

We determined the enzymic activity of beta-glucuronidase preparations from bovine liver, Helix pomatia, and Escherischia coli with steroid glucuronides and nonsteroid glucuronides as substrates. We also studied the effect of Na2SO4 on the enzymic hydrolysis of several substrates with the three preparations of beta-glucuronidase. Na2SO4 increases the rate of hydrolysis of all substrates with beta-glucuronidase from bovine liver. Hydrolysis of a steroid glucoronide with beta-glucuronidase from Helix pomatia and E. coli is inhibited by Na2SO4. None of the three enzyme preparations gives complete hydrolysis of urinary steroid conjugates, because urine contains inhibitors, which can be removed by absorption chromatography of the urine on a column of neutral polystyrene resin Amberlite XAD-2. But when Amberlite XAD-2 is not used, hydrolysis of urinary glucuronides of androsterone, etiocholanolone, pregnanediol, estriol, and 17-hydroxycorticosteroids proves that, given an incubation time of 24 h, the beta-glucuronidase preparation from bovine liver, in the presence of Na2SO4, is suited for determining all of the above steroids except esriol; the preparation from Helix pomatia is good for determining estriol and 17-hydroxycorticosteroids; the preparation from E. coli is good for determining androsterone, 17-hydroxycorticosteroids, and especially estriol, the glucuronide, of which is maximally hydrolyzed in 2 h.

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[Adrenal function in patients with chronic obstructive lung diseases].

The hydrocortisone and ACTH blood levels, 17-hydroxycorticosteroids urine excretion and suprarenal function stimulation with Synacthen were studied in 22 patients with chronic obstructive pulmonary disease and 12 healthy persons as controls. The results show the presence of reliably higher hydrocortisone and 17-hydroxycorticosteroids levels in patients with low partial oxygen pressure as well as a higher ACTH plasma level and a strong Synacthen stimulation. After a comprehensive treatment including oxygen therapy the blood concentrations of hydrocortisone, ACTH, 17-hydroxycorticosteroids fell to levels found in healthy persons. The study shows that hypoxemia stimulates the suprarenal-cortex secretion.

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[Effect of lithium on the serotonin and kynurenine paths of tryptophan metabolism].

Lithium carbonate in dosages from 50--100 mg/kg leads to an increase of tryptophanepyrrolase activity in the liver of rats from 50--80%, 5 hours following a single-time intraperitoneal administration and does not exert any influence after 1,3 and 20 hours. The same dosages (50 and 100 mg/kg) of lithium lead to an increase of II-hydroxycorticosteroids in in the blood plasma of rats to 2.5 times and could be prevented by a preliminary administration of dexametasone. A chronic administration of lithium (50 mg/kg) during 10 days did not exert any influence on the triptophanepyrrolase activity and the level of 11-hydroxycorticosteroids in the blood plasma of rats. These data permit of assume that an increase of tryptophanepyrrolase activity by lithium is moderated by an increase of II-hydroxycorticosteroids in the blood.

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Observations on cardiovascular and neuroendocrine disturbance in the Guillain-Barré syndrome.

Cardiovascular disturbances were found to be a common feature of patients with the Guillian-Barré syndrome who were severely paralysed, requiring assisted ventilation. Glycosuria was noted in association with these disturbances, and in five patients investigated we found impaired glucose tolerance tests at the height of the paralysis. Catecholamine and 17-hydroxycorticosteroid urinary excretions were found to be high in four patients investigated when the neuropathy was most severe, and in one patient plasma cortisol levels were high with loss of diurnal variation. With recovery from paralysis cardiovascular disturbances became less marked, catecholamine and 17-hydroxycorticosteroid urinary excretions reverted to normal, glucose tolerance improved but remained abnormal in three patients during the period of observation. It is suggested that increased levels of catecholamines and cortisol contributed to the development of impaired glucose tolerance and cardiovascular disturbances.

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Changes of adrenal hormones in goats with experimentally induced arthritis.

An experiment was carried out to clarify the mechanism of occurrence of arthritis in goats. In it changes of the adrenal hormones in blood and urine were examined in goats with experimentally induced arthritis. Four groups of goats were used. A goat of group B was inoculated with anaerobic Corynebacterium organisms isolated from a joint of a field case. Group H was treated with hormones (deoxycorticosterone acetate and adrenalin). Group BH was inoculated with those organisms and treated with these hormones. The other group served as an untreated control. Arthirits was induced to three of the four goats of group BH. The blood level of 11-hydroxycorticosteroids and the urine level of 17-hydroxycorticosteroids were higher in group BH than in any other group at the time of appearance of clinical signs. The hypofunction of the adrenal cortex was seen in two of three goats with induced arthritis. Serotonin increased transitorily in group BH around the time of appearance of clinical signs, but there was finally no difference in its level among goats with or without induced arthritis. There was no definite tendency in the fluctuation of level of adrenalin or noadrenalin.

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ISLET-CELL CARCINOMA (ZOLLINGER-ELLISON SYNDROME) WITH FULMINATING ADRENOCORTICAL HYPERFUNCTION AND HYPOKALEMIA.

The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyperfunction. The pathogenesis and clinical and laboratory features of Cushing's syndrome associated with such tumours are characteristic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peripheral edema predominate, and the classical signs of Cushing's syndrome may be absent. High levels of plasma 17-hydroxycorticosteroids and urinary 17-hydroxycorticosteroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, commonly occur. Hypokalemic alkalosis unresponsive to replacement therapy may cause death. In the case reported herein, the intriguing possibility exists that two hormone-like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing's syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis.

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Effect of concomitant administration of magnesium trisilicate on GI absorption of dexamethasone in humans.

The oral absorption of dexamethasone in humans was compared to its absorption when coadministered with magnesium trisilicate. The bioavailability of dexamethasone was estimated by measuring the suppressive effect of the drug on the daily excretion of endogenous steroids. Administration of 1 mg of dexamethasone to six healthy male volunteers significantly decreased the urinary excretion of 11-hydroxycorticosteroids. However, the coadministration of magnesium trisilicate with dexamethasone decreased its absorption, as indicated by the increased urinary excretion of 11-hydroxycorticosteroids. The decrease in absorption was attributed to drug adsorption on the antacid surface. These results confirm previous in vitro findings.

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The clinical significance of disordered renal excretion of xanthurenic acid in depressive patients.

Xanthurenic acid is a metabolite of L-tryptophanicotinic acid ribonucleotide biosynthesis. The excretion of xanthurenic acid from urine 24 h after ingestion of 5 g L-tryptophan is increased in depressive patients, and 17-hydroxycorticosteroids are considered of primary importance to this disorder. However, in this study, the excretion of xanthurenic acid and 17-hydroxycorticosteroids did not correlate with the scores of the Raskin depression scale, Hamilton depression scale, Zung depression scale, or the Zung anxiety scale in depressive patients. The patients were treated with either pyridoxine plus L-tryptophan, a presumably serotonin-enhancing treatment (n = 10) or maprotiline, a noradrenaline-enhancing drug (n = 10). Repeated measurements showed no differences between treatments after 2 or 4 weeks of treatment. The improvement in xanthurenic acid excretion precedes clinical improvements in depression. The excretion of xanthurenic acid only at 2 weeks correlated significantly with the anxiety and depression scores at 4 weeks, making prediction of clinical improvement possible. The neurobiological mode of action on noradrenergic or serotonergic neurons of antidepressant medication is of questionable significance to their therapeutic effect.

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Differences in secretion characteristics in Cushing's disease with and without radiologically evident pituitary tumors.

In a group of 22 unselected patients with Cushing's disease 3 had a moderately enlarged pituitary fossa, while 6 patients showed asymmetry of the sella turcica at lateral tomography. This group of 9 patients with radiologically evident pituitary adenomas had:i) a higher average basal urinary excretion of 17-hydroxycorticosteroids which showed a greater day to day variation;ii) a greater (although insufficient) decrease of plasma cortisol in response to a single oral dose of 1 mg dexamethasone and larger postdexamethasone rebound excretion of urinary 17-hydroxycorticosteroids after 8 mg dexamethasone daily for two days; and iii) a larger maximal increase of plasma cortisol after lysine vasopressin administration than the other 13 patients. The increase in the size of a pituitary (micro-) adenoma in patients with Cushing's disease is accompanied by a more severe hypercortisolism and an increased responsiveness of the pituitary-adrenal axis to the manipulations mentioned.

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Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients.

The serum free fatty acid (FFA), cortisol and urinary creatinine, 17-hydzoxycorticosteroid and 17-oxosteroid concentrations of acquired immunedeficiency syndrome (AIDS-I: beginning and AIDS-II: end phase) and AIDS-related complex (ARC) patients were determined. Both groups were compared to a control group (healthy men). ARC and AIDS-I patients. The ratios of stearic (C18:0) to oleic (C18:1) acid were 75%, P less than 0.01 (ARC) and 45%, P less than 0.05 (AIDS-I) greater than normal, due to a decrease in the relative percentage of monounsaturated fatty acids by 25%, P less than 0.001 (ARC) and 20%, P less than 0.01 (AIDS-I). In contrast, the relative percentage of polyunsaturated fatty acids was 85% greater than normal (P less than 0.001) in ARC and 100% greater than normal (P less than 0.001) in AIDS-I patients. Total FFA levels did not differ from controls. Serum cortisol levels were 35% (P less than 0.01) above normal in ARC and 60% (P less than 0.001) above normal in AIDS-I patients. Urinary 17-hydroxycorticosteroids and 17-oxosteroids were very low (2-3-fold lower than normal values, P less than 0.001) in both groups of patients. Urinary creatinine did not differ from controls. In AIDS-II patients the total FFA concentration was below normal 35% (P less than 0.01) and the stearic/oleic acid ratio was 50% above normal (P less than 0.05). The relative percentages of monounsaturated and polyunsaturated fatty acids in this group were similar to those of controls. Serum cortisol concentrations were significantly higher, 50% (P less than 0.001), but the urinary 17-hydroxycorticosteroids and 17-oxosteroids were 2-fold lower (P less than 0.001) than those of controls. Urinary creatinine did not differ from controls. These significant differences from normal may be implicated in the pathophysiology of AIDS and could represent not only a good index of diagnosis and prognosis, but also indicate new therapeutic approach to the disease.

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Urinary excretion of 6 beta-hydroxycortisol as an in vivo marker for CYP3A induction: applications and recommendations.

OBJECTIVE: To evaluate the usefulness of 6 beta-hydroxycortisol as a screen for CYP3A induction in early-phase drug development. METHODS: Five groups of 12 healthy elderly men were randomized to one of five treatment regimens: (1) 600 mg rifampin (INN, rifampicin) once daily, (2) placebo once daily, (3) 40 mg SB 216469 twice a day, (4) 60 mg SB 216469 twice a day, or (5) 40 mg SB 216469 three times a day. All medications were taken orally and administered for 7 consecutive days. Urine was collected over a 24-hour period for each subject before administration and on the last day of administration for each respective regimen for measurement of 6 beta-hydroxycortisol and 17-hydroxycorticosteroid concentrations. RESULTS: Subjects in the rifampin group had a significant increase from predose value in the 24-hour urinary excretion of 6 beta-hydroxycortisol and the ratio of 6 beta-hydroxycortisol to 17-hydroxycorticosteroid. All 12 subjects in the rifampin group had increases in 6 beta-hydroxycortisol excretion, whereas 11 of 12 had an increase in the ratio. The placebo and three active treatment groups did not show significant changes in either parameter. CONCLUSIONS: Urinary excretion of 6 beta-hydroxycortisol may be useful as a screening tool in early-phase development to assess the potential for an investigational drug to induce CYP3A.

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Estimation of prednisone intake in pemphigus vulgaris patients with the use of simple laboratory methods.

Prednisone is a widely used medication in dermatology, particularly in pemphigus patients. Simple objective laboratory methods are suggested for the evaluation of prednisone intake, taking advantage of the similar chemical structure of cortisol and prednisolone. A linear correlation was found between the dose of prednisone, above 40 mg/day, free urinary prednisolone, measured with an radioimmunoassay kit for cortisol that cross-reacts with prednisolone, and 17-hydroxycorticosteroids, measured by Metcalf's method. Approximately 9% of the prednisone administered was recovered as free prednisolone and about 40% as 17-hydroxycorticosteroids. It is suggested that these simple laboratory methods constitute a useful substitute for the more costly, sophisticated methods available at present for determining levels of prednisone and prednisolone.

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Increased excretion of kallikrein during dexamethasone administration in normal man on low and normal salt intake.

The effect of dexamethasone administration for 3 days on urinary kallikrein excretion was studied in 12 normal men with normal sodium intake (n = 6) or low sodium intake (n = 6). Urinary excretion of sodium, potassium, 17-hydroxycorticosteroids, aldosterone and water was also measured in all subjects. Dexamethasone administration was associated with a significant increase in urinary kallikrein excretion (F3, 30 = 6.9; P less than 0.001) regardless of sodium intake. No significant correlation could be established between the increase in urinary kallikrein excretion and changes in urinary sodium, potassium, 17-hydroxycorticosteroids, aldosterone or water. These results suggest that dexamethasone can exert a direct action on the renal kallikrein-kinin system.

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Urinary hormone levels: a population study of associations between steroid and catecholamine excretion rates.

Urinary levels of steroid metabolites (17-hydroxycorticosteroids and 17-oxosteroids) were measured in 408 males at two times during the normal working day. Hormone levels are expressed both as rates of excretion and as creatinine ratios and are compared with the values for adrenaline and noradrenaline previously measured in the same samples. Strong associations are found between catecholamines and steroids. Generally the greatest correlation is with hormones of the same biochemical class, although the 17-hydroxycorticosteroid level is more strongly correlated with the adrenaline level than is the level of noradrenaline.

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Relation between the amniotic fluid lecithin/sphingomyelin ratio, fetal cord blood corticosteroid levels and the duration of induced labour.

In serial samples of amniotic fluid from 24 patients in induced labour, the rate of change in the lecithin/sphingomyelin (L/S) ratio correlated significantly with the duration of labour. Cord serum 11-hydroxycorticosteroid levels were lowest in the group of patients in which the L/S rose during labour, and highest in the group in which the L/S ratio fell. Cord serum 11-hydroxycorticosteroid levels correlated positively with the duration of labour. It would seem unlikely that the changes in L/S ratio occurring during labour are mediated by endogenous corticosteroids.

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