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The response of urinary diurnal tetrahydroaldosterone (TH-aldo) excretion to fludrocortisone administration (0.3 mg q.i.d. for 3 days) was studied. In normal subjects (n = 13) and in patients with essential hypertension (n = 8), urinary TH-aldo decreased to 36 per cent (range 19–48) and to 51 per cent (range 33–61) of the control value, respectively. Twenty-four patients with primary aldosteronism were studied. Twenty-two of these showed no significant suppression of urinary TH-aldo in that the excretion of TH-aldo was 79 per cent of the control value or more. Nineteen of these patients were submitted to operation, and an adrenal aldosterone-producing adenoma was disclosed in every single case. Two patients with primary aldosteronism demonstrated a significant suppression of aldosterone production to 62 and 68 per cent, respectively. Adrenal micronodular hyperplasia was verified in one case and suspected in the other. A significant suppression of aldosterone production was observed in 4 of 5 patients with aldosteronism and normal or high plasma renin levels. The combination of low plasma renin and autonomy of aldosterone production offers a high degree of certainty for the presence of an aldosterone-producing adenoma.

Six patients with long-standing idiopathic primary adrenal insufficiency were given 25 mg of cortisone acetate orally on two occasions. Circulating serum cortisol levels were determined hourly for five hours after ingestion. Two patients were additionally studied with an oral dose of 20 mg of cortisol. Marked patient to patient variation in peak hormone and in fifth hour hormone levels was observed. Both values were lowest in the two chronically symptomatic patients who had been maintained on empiric glucocorticoid replacement. Specific information on blood cortisol levels in treated Addisonian individuals has not been previously reported.

The role of renal prostaglandins (PGE2 and PGF2α) and kallikrein in the renal escape from excess mineralocorticoid has been evaluated in 10 normal volunteers on a high sodium diet. Escape from 9-α-fluorohydrocortisone (9-α-FF) administered for 12 days (0.6 mg daily) occurred within 4–5 days when 345 ± 50 mmol sodium had accumulated. Indomethacin, a cyclooxygenase inhibitor, was then administered for 3 days while maintaining 9-α-FF. This was followed by a further cumulative gain of 105 ± 28 mmol sodium after which escape resumed. Potassium balance remained negative throughout the study. Both PGE2 and PGF2α excretion increased significantly under 9-α-FF from respective control values of 220 ± 50 and 818 ± 86 ng/24 h, to 610 ± 317 and 1213 ± 132 ng/24 h at the time of escape. Concomitantly urinary kallikrein increased from 1.1 ± 0.2 to 2.5 ± 0.3 units/24 h. Creatinine clearance increased from a mean baseline value of 111 ± 4 to 123 ± 4 ml/min during the same period. Indomethacin produced an inhibition of prostaglandin excretion without significant alteration of kallikrein excretion. Overall these results and particularly the transient sodium retention induced by indomethacin at the time of mineralocorticoid escape, suggest that prostaglandins may contribute to the escape phenomenon, whereas the role of kallikrein does not appear to be determinant.

Eighteen patients with Cushing's syndrome (16 pituitary-dependent Cushing's disease, 1 ectopic ACTH syndrome, 1 primary adrenal adenoma) were given a combination of aminoglutethimide and metyrapone, with the object of controlling cortisol overproduction using less toxic doses than would be required with each drug alone. A preliminary trial of this combination using doses of aminoglutethimide of 1 g or more a day was assessed over 2 weeks. Control of cortisol overproduction and clinical improvement was achieved but side effects led to withdrawal of the drugs in 6 out of the 12 patients. A lower dose trial of this combination over 2 weeks, using 750 mg/day of aminoglutethimide also controlled cortisol overproduction and side effects led to drug withdrawal in only 2 out of 6 patients. Four of these patients were successfully controlled with even lower doses (500-750 mg/day of aminoglutethimide) for longer periods (26 days–1 year). This low regimen which consists of aminoglutethimide 500–750 mg daily, metyrapone 2 g daily, dexamethasone 0.5 mg b. d. and fludrocortisone 0.1 mg daily, is useful for preparing patients for operative treatments and may be used as a long-term treatment of milder cases.

Studies on erythrocyte insulin receptors were performed in a boy with type I diabetes mellitus and superimposed adrenocortical insufficiency before and during treatment with hydrocortisone and 9-α-fluoro-hydrocortisone. The development of the adrenal insufficiency was associated with a progressively increased sensitivity to insulin which reverted after therapy. The maximum specific insulin binding of the erythrocytes was low during threatening addisonian crisis (6.9%) but normalized during hydrocortisone treatment (12.0%). These findings suggest that the increased insulin sensitivity characteristic for adrenocortical insufficiency is not an effect of an increased insulin receptor concentration and that hypocortisolaemia is associated with a down-regulation of the insulin receptors.

A case of Cushing's syndrome is described with bilateral adrenal hyperplasia. Basal excretion of urinary total 17-OHCS and 17-KS were within the normal range, but the excretion of 17-OHCS was not suppressed by 16 mg dexamethasone daily in divided doses for five days. The adrenal glands were stimulated normally by corticotrophin and the hypophysis by cortisol lack. The blood corticotrophin was estimated to be not significantly different from the levels found in normal persons. It is concluded that the failure of suppression indicates either that the adrenal glands were functioning in part autonomously or more likely that the pituitary corticotrophin regulating mechanism was more completely disturbed than is usually found in Cushing's syndrome, due to bilateral adrenal hyperplasia.

The urinary steroids excreted by an infant with a salt-wasting syndrome due to a suspected defect in the 18-oxidation of corticosterone have been analysed by gas chromatography-mass spectrometry. The excretion of tetrahydroaldosterone was low (3.5 μg/24 h) whilst the excretion of 3α, 11β,21-trihydroxy-5α-pregnan-20-one (allo-tetrahydrocorticosterone) and other corticosterone metabolites was high (total about 2 mg/24 h). The excretion of cortisol metabolites was apparently normal for age (total about 2 mg/24 h) but 3α,11β,17α,21-tetrahydroxy-5α-pregnan-20-one (allo-tetrahydrocortisol) rather than tetrahydrocortisone, was the major component of the group. The excretion of an 18-hydroxycorticosterone metabolite 3α,18,21-trihydroxy-5β-pregnane-1 1,20-dione (18-hydroxytetrahydroCompound A) was higher than normal for infants of this age (between 50 and 200 μg/24 h), suggesting that the defect was in 18-hydroxysteroid dehydrogenase rather than 18-hydroxylase. In addition, 18-hydroxytetrahydrocorticosterone, another metabolite of 18-hydroxycorticosterone was tentatively identified and it was found that the rate of excretion of this compound was of similar magnitude to 18-hydroxytetrahydroCompound A. The salt balance of the infant has been successfully controlled by salt administration (77 mEq./24 h) and treatment with Fludrocortisone (0.5 mg/day).

Recently a hypothesis has been proposed suggesting a negative feedback in the regulation of cortisol (F) and melatonin (Mel). To study a possible influence of F on Mel regulation we examined 13 children with congenital adrenal hyperplasia (CAH) on two occasions: once 3 days after cessation of F substitution (group 1; n = 13) and once during treatment with dexamethasone (1 mg/m2/day) and fludrocortisone (0.1 mg/m2/day) (group 2; n = 11) 11 children matched by sex and age served as controls (group 3). While serum 17 OH-progesterone levels, an indicator for the activation of the hypothalamo-pituitary-adrenal axis in CAH, were significantly (P < 0.001) elevated in untreated patients (group 1), serum Mel levels were not different among the 3 groups nor was the diurnal secretion pattern of Mel affected. Nocturnal serum Mel concentrations, however, correlated with the age of the subjects (r = 0.55, P < 0.001 at 23.00 h), displaying high values in early childhood that declined with progressing age. The presented data do not support the view of a classical feedback mechanism in the regulation of Mel and F in humans. However, it confirms the description of a tremendous fall of nocturnal Mel concentrations during childhood.

To examine the influence of prostaglandins (PGs) and sodium-volume status on the urinary excretion and action of arginine-vasopressin (AVP), we studied the response to a hypertonic saline infusion (2.5% NaCl, 0.06 ml/kg/min for 3 h) in 8 healthy males under three different conditions: 1) on an ad libitum salt diet (C), 2) after 4-day treatment with indomethacin (IDM) 150 mg/d, 3) after 4-day treatment with fluorohydrocortisone (9αFF) 0.6 mg/d. The rise of urine osmolality and the decrease of free water clearance were identical in all three studies. Basal urinary PGE2, PGF2α and AVP were decreased during IDM and unchanged during 9αFF, compared to C. The increment of urinary AVP was similar during C and IDM but significantly greater with 9αFF (P < 0.02) although urinary PGs were higher at the end of the infusion. In conclusion, despite markedly different hormonal patterns and sodium status in the three protocols, the antidiuretic response to an osmolar load is preserved suggesting an adaptive mechanism maintaining a constant balance between AVP and PGs.

In unilaterally nephrectomized rats, 9α-fluorocortisol (9α-FF), in doses of 0.3 and 1.0 mg given daily by intramuscular injection, induced an increase in blood pressure that was independent of additional sodium supply. 9α-FF reduced weight gain and, in the dose of 1.0 mg, increased fluid turnover when 0.9 % saline was given to drink. Haematocrit values were elevated, whether saline or water was given as drinking fluid. The serum sodium concentration was increased when saline was offered, but normal with water as drinking fluid. The serum potassium concentration was diminished in all groups that received 9α-FF. The renin content of the kidney was markedly depressed in all groups that had 9α-FF. The degree of suppression was similar in the groups that had saline and those that had water to drink. Under 9α-FF, plasma concentration of angiotensin II was virtually zero when saline was given to drink, but about ¼ to ½ normal when drinking fluid was water. It is concluded that the type of hypertension developing under high doses of 9α-FF resembles glucocorticoid rather than mineralocorticoid hypertension.

In 31 patients with primary aldosteronism routine clinical and laboratory data, the effect of orthostasis on plasma aldosterone (PA), plasma renin activity (PRA) and cortisol (PC), effect of fludrocortisone or high sodium intake on basal PA and night-day fluctuations of basal PA and PC with and without suppression of pituitary ACTH by dexamethasone were determined to differentiate patients with a unilateral aldosterone producing tumour (adenoma, APA, n = 20; carcinoma, CA, n = 1) from those with idiopathic bilateral adrenal hyperplasia (IAH, n = 10). Mean systolic and diastolic blood pressure, age, serum sodium, serum potassium and urinary excretion of sodium and potassium were not significantly different in both groups of patients. Normokalaemic primary aldosteronism occurred both in patients with APA (n = 2) and in patients with IAH (n = 1). Mean basal PA and mean urinary excretion rate of aldosterone-18-glucuronide were higher though not significantly different in patients with APA or CA than in those with IAH. A substantial number of the patients with APA (n = 5) and with IAH (n = 3) showed urinary excretion rates of aldosterone-18-glucuronide ≦ 13 μg/24 h. Mean PA and PRA significantly increased (P < 0.025) in patients with IAH in response to posture. However, these changes also occurred at times in some patients with APA. Both fludrocortisone and high sodium intake produced a variable and no group-specific effect on basal PA. Night-day variations in PA were positively correlated with those in PC in all patients with APA (n= 12) and in 5 of 8 patients with IAH. A dissociation of PA and PC, however, was only observed in patients with IAH. Finally, the effect of dexamethasone on plasma aldosterone curves was variable in both groups of patients. Our results indicate that under the described conditions analysis of routine clinical and laboratory data and of peripheral PA, PRA and PC are of limited value in differentiating patients with APA or CA from those with IAH.

In normal rats on a standard sodium diet, the administration of 9-alpha-fluorohydrocortisone (9aFF) induced a rapid increase of blood pressure in parallel to an increase of plasma volume. Water and potassium balances became negative. Urinary sodium excretion remained unchanged or increased after high doses, whereas urinary sodium concentration and faecal sodium excretion were reduced. The diurnal rhythm of water and sodium excretion changed: during the night-period, renal water and sodium excretion were diminished, whereas during the day-period both were enhanced. Thus, some effects of 9aFF on electrolyte and water balance are similar to those of DOC, while other effects are similar to those of cortisone. It is postulated that a shift of fluid from intracellular to extracellular compartments, which increases plasma volume, is of critical importance for the 9aFF-induced blood pressure elevation in rats.

Previously, we reported elevated plasma immunoreactive ANP (irANP) levels from the 2nd to the 9th day of administering either prednisone, 50 mg/day, or 9α-fludrocortisone acetate (9αF), 0.6 mg/day, to normal humans. To investigate the course of plasma irANP levels during the first 48 h of corticosteroid adminstration, 9 healthy men (mean age ± sem, 24 ± 1 years) received in randomised sequence A) a 4-h iv infusion of prednisolone sodium tetrahydrophthalate followed by oral administration of prednisone for 2 days; or B) a 4-h infusion of aldosterone followed by oral administration of 9αF for 2 days. Basal supine plasma irANP levels averaged 32 ± 5 ng/l in study A and 30 ± 6 ng/l in study B; they were unchanged or even deceased up to 24 h of glucocorticoid or mineralocorticoid administration, but rose (P < 0.01) to 56 ± 9 and 62 ± 12 ng/l at 48 h, respectively, of the two interventions. During glucocorticoid treatment, blood pressure (BP) and indices of the sodium-fluid volume state were unchanged after 48 h. During 9αF administration, body weight increased (1.1 ± 0.3%, P < 0.001), whereas urinary sodium excretion (63 ±7%, P < 0.001), hematocrit (4.1 ± 1.1%, P < 0.001), and plasma renin activity (38 ± 4%, P < 0.001) decreased. Conclusions: The increase in circulating irANP at 48 h of administration of either a glucocorticoid or a mineralocorticoid demonstrates a distinct but slow response of the ANP system to these corticosteroids in normal humans. ANP may play a potential role in mediating and/or modulating physiological and pathophysiological effects of corticosteroids.

Eighteen patients with Cushing's syndrome (16 pituitary-dependent Cushing's disease, 1 ectopic ACTH syndrome, 1 primary adrenal adenoma) were given a combination of aminoglutethimide and metyrapone, with the object of controlling cortisol overproduction using less toxic doses than would be required with each drug alone. A preliminary trial of this combination using doses of aminoglutethimide of 1 g or more a day was assessed over 2 weeks. Control of cortisol overproduction and clinical improvement was achieved but side effects led to withdrawal of the drugs in 6 out of the 12 patients. A lower dose trial of this combination over 2 weeks, using 750 mg/day of aminoglutethimide also controlled cortisol overproduction and side effects led to drug withdrawal in only 2 out of 6 patients. Four of these patients were successfully controlled with even lower doses (500-750 mg/day of aminoglutethimide) for longer periods (26 days-1 year). This low regimen which consists of aminoglutethimide 500-750 mg daily, metyrapone 2 g daily, dexamethasone 0.5 mg b.d. and fludrocortisone 0.1 mg daily, is useful for preparing patients for operative treatments and may be used as a long-term treatment of milder cases.

9α-Fluorohydrocortisone (9α-FHC) is used in hypotensive circulatory disorders because of its mineralocorticoid action. In order to determine the influence of this drug on the feedback mechanism of the hypothalamopituitary-adrenal axis, 10 healthy subjects were submitted twice to a shortened metyrapone test before and after the administration of 9α-FHC. The concentrations of 11-oxy- and 11-deoxycorticoids in plasma were measured by a competitive protein binding technique. Following the administration of 9α-FHC the plasma concentrations of 11-deoxycorticoids during the metyrapone tests were lowered considerably (about 52 %; t: 6.08, P < 0.001) compared to the tests under normal conditions. Even pathological test results (total suppression of the hypothalamus by 9α-FHC) were found, demonstrating that 9α-FHC strongly competes with cortisol in the feedback mechanism of the hypothalamopituitary-adrenal axis. In both test series the disappearance half time of 11-oxycorticoid concentrations in the plasma was 28 min, indicating that neither an insufficient nor a delayed decrease in 11-oxycorticoid concentrations is the reason for the low 11-deoxycorticoid plasma concentrations after 9α-FHC. The side effects of metyrapone such as dizziness, confusion and a decrease in blood pressure are not affected by the glucocorticoid dexamethasone or the mineralocorticoid, 9α-FHC.

Using techniques for simultaneous corticosteroid mass and isotope estimation, yield-, mass- and specific activity-time curves were constructed for products isolated from rat and duck adrenal tissue during incubation with radioactive precursors. The yield-time curves for labelled products elaborated from added [7α-3H] pregnenolone and [4-14C] progesterone in the duck, and [4-14C] progesterone in the rat, confirmed previous results which indicated that in both species progesterone and deoxycorticosterone are important intermediates in the formation of corticosteroids from the added precursors. The mass-time curves showed that the radioactive precursors and the tissues' endogenous precursors did not form a homogeneous pool in either case. This finding, together with the lack of true steady-state conditions, prevented rigorous application of the Zilversmit et al. (1943) treatment relating product specific activities with the biosynthetic pathway. However, inspection of the curves allowed tentative conclusions to be drawn from these experiments. In particular, it appears that endogenous and added radioactive precursors may be metabolised along similar pathways, and that deoxycorticosterone seems to be an important intermediate in both species.