EFFECT OF AMINOGLUTETHIMIDE ON URINARY CORTISOL AND CORTISOL METABOLITES IN ADOLESCENTS WITH CUSHING'S SYNDROME

The effect of aminoglutethimide (AG) 4 × 250 mg (670 mg/m² daily by mouth) on the excretion of free cortisol (radio-immunoassay) and of its metabolites THE, THF-alloTHF, cortolone and β-cortolone (gas chromatography on capillary column) was studied monthly during 3 – 5 months in four adolescents (one girl, three boys) aged 15.9 – 18 years with Cushing's syndrome due to bilateral adrenal hyperplasia, but without evidence of a pituitary tumour. Under AG, all compounds decreased to a minimum after 1 – 2 months. The decrease of THE- THF-allo THF was most marked, followed by cortolone-β-cortolone and free cortisol. The sum of the conjugated metabolites was normalized, but free cortisol remained high. A rebound was noted after 3 – 5 months of continued treatment. This was associated with clinical relapse (weight gain, increasing blood pressure). With AG, a non-steroidal peak appeared on the chromatograms. It is concluded that: (1) AG is only temporarily effective in diminishing the excretion of cortisol and its metabolities; (2) paradoxical increments of 17-ketosteroids as reported from colorimetric analysis are non-specific and are probably due to the non-steroidal peak; and (3) AG appears to modify steroid catabolizing liver enzymes (inhibition of 5β-reductases and/or 3a-dehydrogenase, possibly stimulation of 20a- and 20β-dehydrogenases). This could increase the biological half-life of cortisol and contribute to the clinical rebound, which is due to increased ACTH-secretion. Because of its excellent short-term effects, AG appears to be useful to prepare patients for bilateral adrenalectomy.     

THROMBOEMBOLIC COMPLICATIONS IN CUSHING'S SYNDROME

Thromboembolic events are thought to occur with increased frequency in Cushing's syndrome due to the predisposing factors, obesity, hypertension, a raised haematocrit and major surgery plus a ‘hypercoagulable state’. To examine this postulate further we have studied 43 patients with Cushing's syndrome retrospectively and 10 patients prospectively to determine the incidence of arterial and venous thrombosis, both spontaneous and post-operative. Arterial events were noted in four cases (9%) and deep vein thrombosis or pulmonary thromboembolism (PTE) occurred in six cases (11%). Post-operative PTE occurred in 2-7% of all operations. These vascular complications tended to occur in the older patients with Cushing's syndrome. In our series, clinically significant thromboembolic episodes appear no more common than expected and the indications for prophylactic anticoagulation (the older and more obese patients) may not be different from other patients undergoing major surgery. An incidental finding was of a greater frequency of hypertension in Cushing's patients due to an adrenal adenoma.     

CUSHING'S SYNDROME IN PREGNANCY—TREATMENT WITH METYRAPONE

A 23-year-old female presented with severe Cushing's syndrome in the 23rd week of pregnancy. Investigations showed plasma cortisol 770 nmol/l (08.00 h) and 850 nmol/l (23.00 h); plasma ACTH was 10 ng/l (08.00 h) and 27 ng/l (23.00 h); urinary free cortisol excretion was 2460 nmol/24 h. Dexamethasone 2 mg 6-hourly for 48 h suppressed the 08.00 h plasma cortisol only to 680 nmol/l. Abdominal C.T. scan showed a right adrenal adenoma. The patient was treated with metyrapone and a good clinical improvement ensued. Plasma cortisol was reduced to 300–500 nmol/l. Despite ultrasonographic evidence of normal fetal growth, urinary oestriol excretion was markedly deficient. Prior to the spontaneous onset of labour, there was a marked rise in plasma cortisol despite continuous metyrapone treatment. A normal female infant was born at 37 weeks' gestation. The maternal adrenal adenoma was subsequently removed. The deficiency of oestriol synthesis during the pregnancy may be explained by metyrapone-induced inhibition of C19-hydroxylation.     

24 HOUR MELATONIN SECRETORY PATTERN IN CUSHING'S SYNDROME

The concentrations of plasma melatonin and cortisol were determined every 20 min during a 24 h period in 6 women aged 24 to 45 years with Cushing's syndrome of differing aetiologies (4 adrenal adenomas, 2 adrenal hyperplasia). Melatonin was assayed after chloroform extraction according to the method of Rollag and Niswender (1976). Abnormal melatonin secretory patterns were found in all the patients; 24 h melatonin concentration means varied from 130 to 413 pg/ml and were not significantly higher than the 24 h mean in 4 controls (215 ± 126 pg/ml). All six subjects however showed a significant increase of melatonin during the day period (302 ± 109 as compared with controls 129 ± 65 mg/ml, mean ± SD; P<0.005). No relationship could be found between abnormal melatonin levels and the sexual status of the patients (4 with amenorrhoea, 2 normally menstruating women). An alteration of melatonin secretory pattern is present in Cushing's syndrome, whatever the aetiology. It is suggested that hypercortisolism, by itself, may modify the pattern of melatonin secretion.     

EXPERIENCE WITH TRILOSTANE IN THE TREATMENT OF CUSHING'S SYNDROME

Five patients with pituitary dependent Cushing's syndrome and two with adrenal carcinoma were treated with increasing doses of trilostane (up to 1440 mg daily). There was no consistent fall in serum cortisol levels. In addition there was no rise in the levels of precursors immediately preceding the proposed site of action of trilostane. These results suggest that trilostane does not effectively block the enzyme 3β-hydroxysteroid dehydrogenase Δ4,Δ5 isomerase in patients with Cushing's syndrome and that it should no longer be recommended for their treatment.     

CUSHING'S SYNDROME OF NINETEEN YEARS' DURATION

A case of Cushing's syndrome of 19 years' duration is described. The disease began at the age of 12 years and caused an abrupt cessation of growth. The adrenals were responsive to stimulation with corticotrophin and suppression with dexamethasone. After irradiation of the pituitary gland had failed to improve the patients' condition, bilateral adrenalectomy was performed. Postoperatively exfoliation and skin itching caused much trouble, and it was 14 months before his corticosteroid requirements reached the usual maintenance level.     

CHANGES IN BLOOD PRESSURE AND PLASMA NORADRENALINE IN SHORT-TERM HYPOTHYROIDISM

Thirteen patients who had undergone thyroidectomy for thyroid cancer stopped thyroid hormone replacement prior to follow-up radioactive iodine scans. Thyroxine was replaced by triiodothyronine (T3) for 4 weeks and T3 was stopped 2 weeks before the scan and 16 to 19 days before blood pressure measurement and venipuncture for obtaining plasma noradrenaline samples. During this time, a small but significant decrease in systolic blood pressure occurred, both supine and standing, while the corresponding plasma noradrenaline levels increased significantly. These findings indicate that the acute cardiovascular effect of brief thyroid hormone withdrawal is a decrease in blood pressure rather than the increase often observed in chronic hypothyroidism, and that plasma noradrenaline levels may increase much sooner than previously reported after onset of hypothyroidism.     

FREE-RUNNING CIRCADIAN PLASMA CORTISOL RHYTHM IN A BLIND HUMAN SUBJECT

The plasma cortisol rhythm in man has been presumed to be an endogenous circadian rhythm, synchronized by some external stimulus to an exact 24-h period. Sleep/wake and 'social activity' cycles have been considered as candidates for this synchronizer. Previous studies have suggested that the dark/light phase shifts associated with the sleep-wake cycle may be the external synchronizer, rather than the sleep/wake cycle itself. A totally blind, but otherwise normal subject was studied for a period of 50 days. Her hourly sleep/wake status and hourly integrated mean plasma cortisol concentrations were determined, and the data were subjected to non-parametric mathematical analysis. The subject was found to have a free-running rhythm in plasma cortisol with a period of approximately 24.5 h. Her sleep/wake rhythm, determined by similar analysis, had a period of exactly 24 h. In addition to the dominant 24.5-h cortisol rhythm, there appeared to be a minor 24-h cortisol rhythm with a peak that coincided approximately with the time of awakening. It was not possible to determine whether this sleep/wake-related peak represented a minor component of the circadian rhythm, synchronized by some stimulus associated with sleep/wake activity, or merely an acute response to awakening itself. Nevertheless, the two rhythms exhibited 'beating' behaviour, resulting in maximal peak cortisol concentrations when they were in synchrony and minimal peak concentrations when they were not. It is concluded that environment dark/light phase shifts are the dominant synchronizer of the circadian rhythm in plasma cortisol concentrations in man, as they are for a variety of circadian rhythms in other living things.     

LACK OF EFFECT OF ETHANOL ON PLASMA CORTISOL IN MAN

The effects of acute administration of ethanol were studied in a total of 18 normal male subjects. Sixteen men were given oral ethanol (2·5 ml/kg vodka or gin) and four received intravenous infusions of ethanol (1 ml/kg), at two times of day, 0900 h and 1800 h. Neither intravenous nor oral ethanol caused a specific rise in plasma cortisol, in contrast to previously reported work. There was no evidence for circadian variation in response. Since ethanol does not release plasma cortisol in normal individuals, the pathogenesis of ‘alcohol-induced pseudo-Cushing's syndrome’ should be re-considered.     

URINARY FREE CORTISOL EXCRETION IN PATIENTS WITH HYPERSEROTONINAEMIA FROM THE CARCINOID SYNDROME

To determine if patients with chronic hyperserotoninaemia from the carcinoid syndrome have increased basal adrenocortical function, I have determined the urinary free cortisol excretion of seventeen patients with carcinoid tumours and the carcinoid syndrome, twelve patients with carcinoid tumours without the carcinoid syndrome and seventeen normal subjects. There was no significant difference in the urinary free cortisol excretion of the patients with carcinoid tumours and the carcinoid syndrome (133 +/- 20.0 nmoles/24 h), patients with carcinoid tumours without the carcinoid syndrome (115 +/- 29 nmoles/24 h) and the normal subjects (96 +/- 9 nmoles/24 h). There was no correlation between the urinary free cortisol secretion and urinary 5-hydroxyindoleacetic acid or serum serotonin concentration in the patients with the carcinoid syndrome. There was a suggestion that patients with 5-hydroxytryptophan (5-HTP) secreting carcinoid tumours had higher urinary free cortisol excretion than patients with predominantly serotonin (5-HT) secreting carcinoid tumours. This may be due to the fact that the non-polar 5-HTP molecule penetrates the blood-brain barrier more effectively than the polar 5-HT molecule. 5-HTP is then converted to 5-HT within the brain. None of the twenty-nine patients with carcinoid tumours had clinical or laboratory evidence of the ectopic ACTH syndrome.     

VALUE OF BASAL PLASMA CORTISOL ASSAYS IN THE ASSESSMENT OF PITUITARY-ADRENAL INSUFFICIENCY

A basal plasma cortisol value taken in a physically unstressed state in 68 patients with or without hypothalamic-pituitary-adrenocortical disease was compared with the maximal plasma cortisol concentration during an insulin tolerance test. There was a strong positive correlation between the values. Basal cortisol levels above 300 nmol/l (RIA method) almost excluded ACTH-cortisol insufficiency and those below 100 nmol/l strongly suggested dysfunction. A repeated basal cortisol estimation within a month was especially valuable in categorizing patients with levels between 100 and 200 nmol/l. We suggest that a basal cortisol measurement may be used as a first laboratory test in patients evaluated for possible hypothalamic-pituitary-adrenocortical insufficiency; in many patients, this approach obviates more sophisticated and expensive testing.     

STUDIES OF DIURNAL CHANGES IN PLASMA RENIN ACTIVITY, AND PLASMA NORADRENALINE, ALDOSTERONE AND CORTISOL CONCENTRATIONS IN MAN

Diurnal studies were performed on ten normal volunteers taking a normal sodium diet. Half-hourly blood samples were taken throughout 25 h and assayed for plasma renin activity (PRA) and the plasma concentrations of noradrenaline, aldosterone and cortisol. Sleep was recorded polygraphically and scored by standard criteria. Circadian rhythms were demonstrated for plasma cortisol, aldosterone and noradrenaline concentrations, but not for plasma renin activity. The nadir of the rhythm for the noradrenaline concentration appeared to be related to sleep itself rather than to any chronological index. Only PRA was effected by the stage of sleep, falling sharply during periods of REM sleep. Plasma cortisol and aldosterone concentrations showed a positive correlation over the 24 h. There was, however, no correlation between PRA and plasma aldosterone concentrations, except when the subjects arose after their night's recumbency. Plasma noradrenaline concentration did not correlate with the concentration of any of the other hormones measured.     

CUSHING'S SYNDROME, NODULAR ADRENAL HYPERPLASIA AND VIRILIZING CARCINOMA

A 48-year-old hypertensive diabetic woman rapidly became virilized. Urine 17-oxo-and oxogenic steroids and plasma testosterone, androstenedione, DHEA, DHEA-sulphate and androstenediol were greatly elevated. Plasma cortisol was constantly high and was not suppressed by dexamethasone. Circulating immunoreactive ACTH was consistently detectable at 18–24 ng/l. A 450 g carcinoma arising from a nodular hyperplastic right adrenal gland was resected. Production by the tumour of 17α-hydroxypregnenolone, 17α-hydroxyprogesterone and five C-19 steroids, but very little prenenolone, progesterone or cortisol, was shown by blood sampling, tumour culture and dramatic falls after operation. The plasma cortisol fell to half, with no diurnal variation, consistent with persistent Cushing's syndrome, and the plasma ACTH rose to 55 ng/l. She died 3 months later from a myocardial infarction. Autopsy revealed a pituitary basophil adenoma at a site where radiologically there had been an indentation in the fossa floor for at least 7 years. The left adrenal gland showed nodular hyperplasia. Therefore we conclude that mild pituitary-dependent Cushing's syndrome may have been present for many years before development of a virilizing carcinoma. This case demonstrates that adrenal carcinoma in man can sometimes develop as a consequence of nodular adrenal hyperplasia which may in turn be due to long-standing trophic hyper-stimulation.     

PLASMA ACTH AND CORTISOL PROFILES IN ADDISONIAN PATIENTS RECEIVING CONVENTIONAL SUBSTITUTION THERAPY

Plasma ACTH and cortisol profiles were studied over 24 h in five Addisonian patients maintained in good health by conventional gluco- and mineralocorticoid treatment. Patients received their usual treatment (15--30 mg cortisol daily) in divided doses at 08.00 and 16.00 hours. Plasma cortisol concentrations differed from those of control subjects in being higher from 08.00 hours-noon and 17.00-18.00 hours and were unmeasurable (less than 20 nmol/l) during the period of active cortisol secretion (03.00-08.00 hours) observed in normal subjects. Peak plasma ACTH levels (618- greater than 1600 ng/l) occurred at 08.00-09.00 hours in the Addisonian patients and were much greater than those seen in control subjects (60-220 ng/l). Despite this, plasma ACTH fell promptly within 3 h of the morning dose to less than 100 ng/l and levels were indistinguishable from those seen in normal subjects over the period 12.00-02.00 hours. These results show that there are substantial differences between treated Addisonian and control subjects in respect of plasma cortisol and ACTH concentrations. The findings may lead to a better understanding of ACTH-cortisol relationships in disease states, including congenital adrenal hyperplasia where control of excessive ACTH secretion is clinically desirable.     

PLASMA ACTH RESPONSES TO CORTISOL INFUSION ARE SIMILAR IN PATIENTS WITH PRIMARY HYPOADRENALISM AND PATIENTS STUDIED SOME YEARS AFTER BILATERAL ADRENALECTOMY FOR CUSHING''S SYNDROME

It has been suggested that the first-phase feedback of steroid feedback on ACTH secretion is abnormal in Cushing's disease patients studied after adrenalectomies. We have performed hydrocortisone infusions (100 mg over 2 h) in 15 patients who had previously undergone bilateral adrenalectomy for Cushing's disease. None had had any pituitary-directed therapy and none had a pituitary macroadenoma. Their responses were compared with a group of seven hypoadrenal patients. A significant rise in serum cortisol was observed between 5 and 10 min in both groups. The first significant fall in ACTH occurred between 30 and 45 min in both groups. There was no abnormality of first-phase feedback in the Cushing's group and our results do not therefore support previous speculation that such an abnormality provides evidence for a higher central nervous system (CNS) aetiology of Cushing's disease.