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Summary Experience of 26 patients with carcinoma of the prostate treated by adrenal suppression with aminoglutethimide is reviewed. 60% of hormone resistant tumours showed some response. A fall in plasma testosterone beyond that achieved by oestrogens was not observed. A high incidence of side-effects was noted. A limited role for aminoglutethimide in the management of prostatic carcinoma is suggested. Our thanks are due to the Consultant Surgeons, St Peter's Hospitals who referred their cases to us for investigation. We acknowledge with thanks the help of Dr I. F. Sommerville and Mr M. D. Mansfield, Department of Clinical Endocrinology, Chelsea Hospital for Women, who performed testosterone assays. Aminoglutethimide was supplied by Ciba Laboratories Ltd, Horsham, Sussex. This work was supported by a grant from the St Peter's Research Trust.

We report the association of severe osteopenia with Cushing's syndrome due to micronodular adrenal disease in 2 young adults. Except for the osteopenia, other clinical manifestations of the disease were not striking. In each case, the adrenal glands were small and contained many micronodules composed of large cells with brown or black pigment. Ten cases with similar pathology have been reviewed. In each case plasma ACTH was low when measured and urinary corticoid excretion did not decrease in response to dexamethasone administration. The difficulty in appreciating the presence of Cushing's syndrome clinically in these patients suggests that appropriate screening tests for Cushing's syndrome should be performed in patients with osteopenia of unknown etiology. The clexamethasone suppression test and measurement of urinary free cortisol excretion are recommended.

A-9-year-old boy with growth failure, acidosis, and persistent hyperkalemia was evaluated. Glomerular filtration rate, serum aldosterone and cortisol values, and hematologic data were within normal ranges. There was no suggestion of hyperkalemic periodic paralysis. Urinary acidification was normal, but the bicarbonate threshold was low (21–22 mEqll). During treatment with a thiazide diuretic, serum potassium and bicarbonate concentrations became normal. When the diuretic was discontinued, hyperkalemia occurred at a normal serum bicarbonate concentration. It is assumed that this patient has a specific defect in renal excretion of potassium; this is the second report of a patient with this defect.

Immunosuppressive drugs significantly increasing numbers of A. galli and incidences of infection were: cortisone, cortisol, 9-α-fluorohydrocortisone, 2-methyl-9-α-fluorohydrocortisone, prednisone, prednisolone, 6-mercaptopurine, 2, 6-diaminopurine, 6-thioguanine, 5-bromodeoxyridine, 5-fluorouracil, methotrexate, chlorambucil, and actinomycin D. These drugs and/or worm burdens significantly suppressed weight gains of hosts, and neither altered the male:female ratio of worms nor their growth. The following drugs neither altered worm burdens nor increased incidences of infection: corticosterone, 2-azaadenine, 8-azaguanine, azathioprine, 6-azauridine, busulfan, thio-TEPA, triethylenemelamine, vincristine, acriflavine, reserpine, and l -phenylalanine. Worm burdens and incidences of infection were increased significantly in chickens surgically bursectomized when 3 or 14 but not 35 days old. Chicks bursectomized in ovo with testerosterone propionate on Day 5 or 14 of incubation and infected on Day 14 after hatching developed significantly increased worm burdens and incidences of infection. Applying the Kolmogorov-Smirnov test for goodness of fit to data on increased worm burdens showed that the immunosuppressive drugs or bursectomy had a normalization effect on the statistical distribution.

The excretion of steroids by an infant with pseudohypoaldosteronism is reported. The patient presented with symptoms of hyperkalaemia and hyponatraemia, and was maintained for a period on a high salt intake and mineralocorticoids. However, he collapsed on the 48th day of life and could not be resuscitated.The urinary steroids were identified by combined gas chromatography–mass spectrometry and quantitation was achieved by gas chromatography. The following steroids were identified: tetrahydroaldosterone, tetrahydrocortisone, α- and β-cortolone, 1 β-hydroxytetrahydrocortisone, 1 β-hydroxycortolone, tetrahydrocorticosterone (THB), tetrahydro-11-dehydrocorticosterone (THA), 3α, 20α, 21-trihydroxy-5β-pregnan-ll-one, 5-pregnene-3β, 16α, 20α, 21-tetrol, and 5-androstene-3β, 16αa, 17β-tiiol.The patient evidently secreted an excess of aldosterone so the disorder was probably due to a form of renal-tubule unresponsiveness to this hormone. Some of the urinary steroids normally excreted in large amounts during infancy (16α-hydroxy DHA, 16-oxo-androstenediol, and 16α-hydroxypregnenolone) were not detected in the urine samples, and it is suggested that the precursor of these steroids (pregnenolone) was being fully utilised in the synthesis of aldosterone and cortisol.

It has been found that alkaline aqueous solutions of various boric acids readily solubilize steroid molecules containing a cis-1,2-diol grouping. Both triamcinolone (9α-fluoro-l6α-hydroxy-prednisolone) and its synthetic precursor “F-3” (9α-fluoro-16α-hydroxy-hydrocortisone) demonstrate this property. It is proposed that the structure of the product formed between the steroid and alkaline borate involves two steroid molecules and one tetrahedral boron atom. Some physicochemical data are presented to substantiate this view.

Kallikrein excretion was measured by the esterase activity of precipitated urinary proteins. There was a highly significant correlation between sodium excretion and kallikrein excretion in normal subjects. The same was true of patients with essential hypertension adjusting to a low-salt diet. Patients with renal failure had a greatly increased excretion of kallikrein which was related to the sodium excretion per ml. of glomerular filtrate. During the escape from the sodium-retaining effect of fludrocortisone there was a sharp rise in kallikrein excretion. This may be the mechanism by which the " escape " is brought about. A water-load of one litre caused a pronounced rise in kallikrein excretion without a change in sodium excretion. The data show that the kidney has two relatively independent mechanisms related to kallikrein excretion: one in response to a water-load and the other in response to a salt-load. Kallikrein might be the intrarenal hormone released in response to changes in the pressure distal to the afferent arteriole which regulates sodium excretion per nephron.

Histone acetylation in the kidney of the adrenalectomized rat was increased 5 min after a physiological dose of aldosterone. The increase was exclusively in the histone F2a1. The increase in histone acetylation was given by 9α-fluorocortisol, deoxycorticosterone and cortisol, but not by progesterone. The increase in histone acetylation was abolished by prior treatment of the animals with the anti-mineralocorticoid agent, SC14266 [potassium 3-(3-oxo-17β-hydroxy-4,6-androstadien-17-yl) propionate]; the basal degree of histone acetylation was unaffected. Pretreatment of the animals with actinomycin D or cyclo-heximide did not affect the stimulation, showing the stimulation was not due to increased synthesis of enzyme.

To test the theory that ascites formation in patients with liver disease is initiated by renal sodium retention of unknown cause, we administered mineralocorticoid 9-α-fluorohydrocortisone (Florinef), to 14 patients with alcoholic liver disease. The trial involved patients with and without a past history of ascites, but all were free of ascites and were able to excrete sodium normally at the time of study. In most patients the usual “escape” from mineralocorticoid-induced sodium retention did not occur. Formation of ascites occurred in nine of 16 trials and was accompanied by a rise in plasma volume in each case. These findings show that renal sodium retention can lead to plasma volume expansion and ascites formation in some patients with alcoholic liver disease and portal hypertension. Thus the observations lend support to the “overflow” theory of ascites formation. The reason for the ab­normal response to mineralocorticoid administration in these patients is unknown. Natriuretic hormone deficiency is suggested as a possible explanation.

Moderate to nearly complete protection of the heart muscle against stress-induced necrotizing myocardial lesions in corticoid- or dihydrotachysterol-preconditioned rats was achieved through administration of drugs with direct or indirect antiadrenergic properties: reserpine, guanethidine (catecholamine depletion); mecamylamine (ganglionic blockade); chlorpromazine (inhibition of sympathetic-stimulating reflexes at the hypothalamic level), and Dibenamine (blockade of circulating catecholamines). In otherwise untreated animals, the norepinephrine content of the heart muscle was increased by injection of norepinephrine as well as by its liberation under stress. In corticoidpretreated rats, by contrast, both norepinephrine injection and stress were followed by losses of norepinephrine from the heart, presumably due to the extensive destruction of myocardial tissue under these conditions. Antiadrenergic drugs produced intermediary effects upon the cardiac content of norepinephrine by counteracting its accumulation as well as its depletion resulting from tissue necrosis. It is concluded that the stress-induced severe myocardial structural lesions in hormone-preconditioned animals are directly attributable to the reflex liberation of potentially cardiotoxic adrenosympathogenic catecholamines which accompanies all stressful situations.

In the rat, it has been possible to prevent the production of various forms of nonocclusive experimental cardiac necroses by prophylactic treatment with certain steroid compounds. The models used were Electrolyte Steroid Cardiopathies with Necrosis elicited by fluorocortisol or digitoxin in combination with sodium phosphate, sodium perchlorate, excess fat intake or the stress of restraint. The production of fatal myocardial necrosis by various combinations of these agents could be most effectively inhibited by those steroids which had previously been shown to possess actions which counteracts the toxic effects of various other types of injurious agents.

Summary Neither cortisone nor 9α-fluorohydrocorti-sone acetate alone provides adequate steroid replacement in adrenalectomised patients: cortisone because its mineralocorticoid action is insufficient in comparison with its glucocorticoid action, and 9α-fluorohydrocortisone acetate because the converse is true. By using both these steroids a proper balance can be achieved. One patient, who has been studied in detail for a year following bilateral adrenalectomy, is being satisfactorily maintained with 0.1 mg. 9α-fluorohydrocortisone acetate and 20 mg. cortisone twice daily by mouth.

While it has been known for many years that avascular necrosis of the femoral head can occur in the absence of any obvious aeetiological factor, the proportion of patients receiving steroid therapy who develop this lesion, while low, is much higher than that in the adult population in general. This is a report of 6 such cases, occurring in a series of 34 patients with functioning renal grafts. The reasons for the development of the lesion are discussed, with special consideration of the possible role of infection in the aetiology.

Sodium metabolism, aldosterone excretion, and response to salt and salt-retaining steroid hormones were studied in six patients with orthostatic hypotension. One patient demonstrated definite, and three others minimal, renal salt wasting; two conserved sodium normally. Aldosterone excretion was normal in two patients and reduced in one. Treatment response did not correlate with renal salt wasting or aldosterone excretion. Improvement with treatment correlated with positive sodium balance and weight gain. Dietary sodium restriction blocked the steroid effect, indicating salt and steroids acted mainly through sodium and water retention. Other data in two subjects suggested the salt-retaining hormones may have had an additional effect. Blood pressure diminished in each patient during dietary sodium deprivation and increased with salt administration. Fludrocortisone (Florinef) acetate, given with salt, consistently increased blood pressure further. Thus, full benefit from steroid therapy in these patients required attention to dietary sodium intake.

The precise relationship of molecular structure to biologic activity of 11, 17-oxygenated steroids has been described. Preliminary observations on the antirheumatic and electrolytic effects of new antirheumatic synthetic steroids have been cited. The major portion of the paper has been devoted to a report of the serious adverse side effects of prednisone observed in a group of 39 patients with rheumatoid arthritis treated for periods extending up to 2 years. Special consideration has been given to the occurrence and management of peptic ulcers, pathologic fractures, polyarteritis nodosa, and mental disturbances complicating steroid therapy. Six deaths that occurred in this group have been analyzed in detail. The clinical reports and necropsy findings in each of these 6 cases have been summarized and briefly discussed.

Carbonic anhydrase inhibition by acetazolamide in rabbits lowered the intraocular pressure and induced a slight (8%) increase in the resistance to aqueous outflow, as recorded by an in vitro perfusion technique, either 3 hr after a single intravenous dose, at which time the pressures had returned to normal, or 5 hr after repeated injections of acetazolamide, a type of administration known to maintain continuously the lowered pressures. Salt depletion did not change the reactivity of the outflow resistance to the pressure-lowering effect of acetazolamide. Salt depletion and pretreatment with fludrocortisone did not enhance the magnitude of the pressure drop after administration of acetazolamide. The duration of the response was significantly prolonged, however, an effect probably due to the slower elimination of acetazolamide in these rabbits. Neither systemic administration of fludrocortisone nor adrenalectomy had any positive effect on the outflow resistance. Salt depletion significantly reduced the resistance to aqueous outflow by 20%. The reason for this effect is not known. The effect could not be blocked by pretreating the rabbits with a peripheral aldosterone antagonist, spironolactone.

Conclusion1. Intravenous administration of 9 α-fluorohydrocortisone and 2-methyl-9α-fluorohydrocortisone in doses sufficient to produce profound electrolyte effects in 6 salt-depleted and 6 salt-loaded subjects produced no significant change in glomerular filtration rate, with the exception of one salt-depleted subject, in whom there was an increase in both glomerular filtration rate and effective renal plasma flow following 2MeFF. 2. 2MeFF had a more profound sodium-retaining effect than did FF. Even in salt-depleted subjects, the sodium-retaining effects of both compounds were demonstrable. 3. FF had a more profound potassium-losing effect than did 2 MeFF. Kaliuresis was greater in the salt-loaded than in the salt-depleted subjects. 4. Plasma concentrations of sodium, potassium, and chloride did not change significantly during the 4 hour study after intravenous administration of the steroids.

UNTIL comparatively recently, knowledge of steroid excretion in adrenocortical hyperfunction was more valuable in the adrenogenital syndrome than in Cushing's syndrome, owing to the availability of reliable and well-established methods for the estimation of urinary 17-ketosteroids, upon which the diagnosis and management of adrenal virilism are largely based. In Cushing's syndrome, the urinary 17-ketpsteroids may be either normal or only slightly elevated. However, with the development of sensitive and relatively simple methods for the estimation of urinary 17-hydroxycorticoids, it has been found that these compounds are more often raised, and to a greater extent, than the 17-ketosteroids. When the diagnosis of Cushing's syndrome has been made, it is important to determine the nature of the adrenocortical abnormality—whether it be malignant tumor, simple hyperplasia or benign adenoma. Techniques have been tried, similar to those which have been found to be useful in cases of the adrenogenital syndrome. Th...

2-Methyl-9-fluorocortisol was injected into intact rats in the absence of NaCl dietary supplements during 8 months. All animals became hypertensive and developed myocarditis, nephrosclerosis, and periarteritis nodosa. There were marked cardiac hypertrophy and arteriolosclerosis of the coronary arteries. Evaluation of the basic and maximum work capacity of the heart revealed that the myocardium was functionally equivalent in the control and treated animals. Consequently, sensitization by the intake of large amounts of NaCl is not indispensable for the production of hypertension and cardiovascular lesions with 2-methyl-9-fluorocortisol. In addition, as revealed by the cardiac function tests used, there is no strict parallelism between histologic and functional impairment of the heart.

Parents and siblings of patients with cystic fibrosis were found to have decreases in concentrations of sweat sodium and chloride proportionate to those of control adults and children after the administration of 3.0 mg. per square meter of 9-alpha-fluorohydrocortisone for 2 days. Thus the heterozygous state was not detected. Patients with cystic fibrosis, including 1 adult, showed no significant decrease in these sweat electrolytes with the same challenge. This lack of response to corticosteroids could be used to confirm the diagnosis of cystic fibrosis in adults since abnormally high sweat electrolyte concentrations are more difficult to detect in this age group.

A boy misdiagnosed as having the sodium-losing form of virilizing adrenal hyperplasia was treated with large doses of glucocorticoids and mineralocorticoids from the newborn period until he was more than 4 years of age. He developed iatrogenic Cushing's syndrome and associated glaucoma and dwarfism. The greatest catch-up linear growth took place when the mineralocorticoid had been discontinued and the glucocorticoid was being reduced, but was only of brief duration. Catch-up in skeletal maturation was greatest after complete withdrawal of steroid medication. At this time there was a normal response of urinary corticosteroids to ACTH stimulation and of serum growth hormone and plasma cortisol to insulin hypoglycemia; cortisol production rate was normal. Plasma cortisol values were in the low-normal range and responses to metyrapone were inadequate, suggesting that this boy's massive exposure to adrenocortical steroids had resulted in selective damage to his pituitary ACTH feedback mechanism. Glaucoma resulted in loss of all sight in the right eye.

Observations concerning the antirheumatic and physiologic effects of a new synthetic corticosteroid, dexamethasone, are presented. This preparation, the most potent of any steroid heretofore studied, did not cause sodium retention or potassium loss in doses sufficient to suppress rheumatoid disease. Increased nitrogen and calcium excretion were observed. Further clinical studies are indicated. For the present, it is suggested that the daily dose of dexamethasone should not exceed 4 mg. Es presentate observationes relative al effectos antirheumatic e physiologic del nove corticosteroide synthetic, dexamethasone. Iste preparato, le plus potente de omne le steroides usque nunc studiate, non causava retention de natrium o perdita de kalium quando usate in doses sufficiente a supprimer morbo rheumatoide. Augmentos del excretion de nitrogeno e de calcium esseva observate. Studios clinic additional es indicate. Por le momento, il es suggerite que le dose diurne de dexamethasone non excede 4 mg.

in this series (2), were shown to possess antiinflammatory activities much greater than those of the parent steroids, cortisone and cortisol (3). The present study was undertaken to delineate further the change in physiologic function resulting from the introduction of the extra double bond. A number of later reports of the metabolic effects of three of these steroids are now available (4-6).

IN 1954, Fried and Sabo (1) reported that substitution of a fluorine atom in the 9-alpha position of the hydrocortisone molecule produced a marked potentiation of glucocorticoid effects; Borman et al. (2) reported a corresponding mineralocorticoid enhancement. This new compound, 9-α-fluorohydrocortisone, promised to become of major importance in antiphlogistic and maintenance adrenocortical therapy. In the course of time, it has become apparent that the potentiations observed are unequal; salt and water effects are enhanced more than anti-inflammatory effects, and consequently fluid retention as an undesirable side-effect is likely to occur at any dosage level producing a satisfactory antiphlogistic response. Thus Boland and Headley soon observed the occurrence of edema in patients with rheumatoid arthritis under treatment with 9-α-fluorohydrocortisone. This complication occurred in 12 out of 13 patients; in 6 of the 12 slight to moderate elevation of blood pressure also developed (3). Though unsuitable f...

In a 22-month-old patient with the salt-losing form of CAH, renal contribution to acid-base balance was assessed both in a decompensated state 5 days after withholding 9-alpha-fluorohydrocortisone and in the compensated state one week after reinstitution of therapy. Renal bicarbonate threshold was 13 mmoles serum in decompensation and 20.5 mmoles serum in compensation. Acidification of the urine was appropriate in both states, although a slight quantitative difference in the 2 situations was observed. The data suggest that the renal acidosis in decompensated salt-losing form of CAH is mainly proximal tubular in origin.

Using a simple and rapid method, electrical potential differences across rectal and colonic mucosa have been measured at routine sigmoidoscopy in patients with irritable bowel syndrome and ulcerative colitis. In patients with irritable bowel syndrome, all of whom had diarrhoea, the mucosa was charged negatively on the luminal side and potential differences were not significantly different from those of normal subjects. In acute exacerbations of ulcerative colitis, the potential difference was reversed, the luminal side being positive. This characteristic change was seen even in mild attacks. The potential difference was usually restored to normal within a few weeks of commencing treatment. In some cases, however, it was persistently abnormal for months and failed to show the normal response to stimulation by the mineralocorticoid, fludrocortisone. The way in which measurements of potential difference can be useful in diagnosis, prognosis, and as a guide to treatment is discussed.

Tests of central thermoregulatory function in a young man suffering from repeated episodes of hypothermia revealed defects in the heat-conserving mechanisms of peripheral vasoconstriction and shivering. Serial electroencephalographs suggested a deep midline cerebral lesion, but tests of hypothalamic-pituitary axis metabolic functions were normal. Necropsy revealed a localised but severe degenerative lesion in the anterior hypothalamus. Body-temperature regulation should be tested early in the clinical investigation of patients with suspected lesions of the hypothalamic-pituitary region.

Electrical potential difference (p.d.) across rectal mucosa was measured by a simple method in normal individuals and in patients with suspected hyperaldosteronism. P.d. was increased by fludrocortisone in a normal individual to an extent related to dose, while spironolactone reduced the effect. There was no " escape " of p.d. when fludrocortisone was given continuously over two weeks. Four of nine selected patients with hypertension and hypokalaemia had a high rectal p.d., and excision of an adrenal adenoma from one of them corrected hypertension and hypokalaemia while p.d. fell to normal. Two of three patients with hepatic cirrhosis and ascites had a high p.d. Changes of p.d. correlated well with changes in the sodium/potassium ratio of faecal dialysate. Measurement of rectal p.d. seems a useful simple screening-test for mineralocorticoid excess.

Cortisone, hydrocortisone and some of their Δ1- and fluorinated analogues have a pronounced diuretic effect in the rat; this is accompanied by increased urinary excretion of both Na+ and K+. Diuresis is maximal some 4 hr after oral administration, and in acute studies, the diuretic potency of some of the newer corticosteroids exceeds 100 times that of chlorothiazide.

Daily intramuscular injections of cortisone, prednisolone, triamcinolone, dexamethasone, fludrocortisone and 2-methylfludrocortisone markedly reduced the histamine and 5-hydroxytryptamine contents of the skin and small intestine of rats; there was an increase however, in the amine contents of the stomach. The sex hormones were weaker in these effects while deoxycortone and corticotrophin were inactive. When the skin was depleted of half of its 5-hydroxytryptamine by prolonged treatment with polymyxin B, the rate of recovery of this amine was retarded by the glucocorticoids. The glucocorticoid activity of a steroid and its ability to produce changes in the histamine and 5-hydroxytryptamine contents of tissues are related.

Overproduction of adrenal steroids, both glucocorticoids and mineralocorticoids, is one of the known causes of reversible hypertension. Clinical suspicion and liberal use of screening tests are necessary to differentiate these patients from those suffering from other types of hypertension. Disorders of the physiologic control mechanisms, functioning benign and malignant tumors and congenital enzymatic aberrations are known to underly hyperadrenal corticism. The diagnostic procedures used in the precise evaluation of the mechanisms operating in a particular case are outlined, and the present methods of treatment and their limitations are reviewed.

Summary: The clinical response to the combined regime of a monoamine oxidase inhibitor, cheese, and 9-alphafluorohydrocortisone has been evaluated in one patient with orthostatic hypotension. A significant elevation in supine blood pressure resulted following therapy, and tilt-table studies confirmed the efficacy of the medication in pre-venting an excessive fall in blood pressure in the erect position.

Alterations in renal tubular sodium and water reabsorption in chronic renal disease in man. Clearance studies were performed on subjects with GFR from 4 to 127 ml/min under conditions of maximal hydration and hypotonic mannitol loading. Nonelectrolyte solute excretion per GFR (UNESV/GFR) was calculated as [UOsm-2(UNa + UK)] V/GFR. Fractional sodium excretion (CNa/GFR) per level of UNESV/GFR in the low GFR group (GFR