The influence of dose and dose rate on the incidence of neoplastic disease in RFM mice after neutron irradiation

The effect of circadian rhythm and alterations in posture on plasma aldosterone concentration was studied in 13 patients with primary aldosteronism (six adenoma, five idiopathic hyperplasia, two carcinoma) to define the regulatory mechanism in each of these pathologic subtypes. Blood samples for aldosterone, cortisol, renin, and potassium concentrations were obtained every 4 h during prolonged recumbency (32 h) and upright posture (16 h). During recumbency, aldosterone and cortisol followed a normal circadian pattern in patients with adenoma and hyperplasia, with peak values at 0400-0800 h and the nadir at 1600-2400 h. Normalized aldosterone and cortisol values correlated significantly in both groups (adenoma r=+0.66, P less than 0.001; hyperplasia r=+0.42, P less than 0.01). With upright posture, aldosterone levels declined parallel to the normal circadian fall in cortisol in patients with adenoma (r=+0.68, P less than 0.001); whereas aldosterone levels increased in patients with hyperplasia parallel to small increments in renin (r=+0.65, P less than 0.001) and potassium (r=+0.64, P less than 0.001). During the administration of dexamethasone, aldosterone no longer correlated with cortisol in patients with adenoma but continued to correlate with renin during upright studies in patients with hyperplasia (r=+0.77, P less than 0.01). Aldosterone circadian rhythm was abnormal in patients with carcinoma and no effect of posture was noted. Unilateral adrenalectomy restored the normal postural relationship in four patients with adenoma. These studies suggest that aldosterone secretion is under continuous ACTH control regardless of posture in patients with adenoma, whereas persistent adrenal responsiveness to small increments in renin and/or potassium mediate the postural increase in plasma aldosterone in patients with hyperplasia. True adrenal autonomy occurs only in patients with adrenal carcinoma and when ACTH is suppressed in those with adenoma.     

In familial hyperaldosteronism type I, hybrid gene-induced aldosterone production dominates that induced by wild-type genes

We compared the aldosterone-producing potency of the angiotensin II-sensitive wild-type aldosterone synthase genes and the ACTH-sensitive hybrid 11 beta-hydroxylase/aldosterone synthase gene by examining aldosterone, PRA, and cortisol day-curves (2-hourly levels over 24 h) in patients with familial hyperaldosteronism type I, before and during long-term (0.8-13.5 yr) glucocorticoid treatment. In 8 untreated patients, PRA levels were usually suppressed, and aldosterone correlated strongly with cortisol (r = 0.69-0.99). Fourteen studies were performed on 10 patients receiving glucocorticoid treatment that corrected hypertension, hypokalemia, and PRA suppression in all. ACTH was markedly and continuously suppressed in 6 studies, 3 of which demonstrated strong correlations between aldosterone and PRA (r = 0.77-0.92). ACTH was only partially suppressed in the remaining 8 studies; aldosterone correlated strongly: 1) with cortisol alone in 5 (r = 0.71-0.98); 2) with cortisol (r = 0.90) and PRA (r = 0.74) in one; 3) with PRA only in one (r = 0.80); and 4) with neither PRA nor cortisol in one. Unless ACTH is markedly and continuously suppressed, aldosterone is more responsive to ACTH than to renin/angiotensin II, despite the latter being unsuppressed. This is consistent with the hybrid gene being more powerfully expressed than the wild-type aldosterone synthase genes in familial hyperaldosteronism type I.     

Suppressibility of plasma adrenocorticotropin by hydrocortisone: potential usefulness in the diagnosis of Cushing's disease

Repeatedly normal cortisol suppressibility by dexamethasone in 2 patients with Cushing's disease led to the present study of the prevalence of this phenomenon in 58 patients with otherwise incontrovertible evidence of Cushing's disease. Because as many as 23% of these patients manifested this phenomenon, we investigated the suppressibility of plasma ACTH: 1) during i.v. infusion of hydrocortisone, after a priming dose (7 mg), at 3 mg/h in 8 patients and 8 normal controls; and 2) for 2 h, after oral hydrocortisone, 0.25 mg/kg, in 13 patients and 16 controls. The data showed invariable suppression of plasma ACTH to < or = 10 pg/mL (< or = 2.2 pmol/L) after 120 min of the infusion or at 90 min after oral hydrocortisone in 16 fasting normal subjects given oral hydrocortisone between 0800 and 0830 h. Plasma ACTH exceeded 10 pg/mL (2.2 pmol/L) at the same times in 14/14 patients with active Cushing's disease, including 3 patients whose cortisol suppressibility by dexamethasone had been misleadingly normal and in 4/7 patients with intermittent hypercortisolism. Occasional variations in plasma cortisol elevations after the oral dose require that plasma cortisol concentration be monitored at 60 min after the oral hydrocortisone dose, because the present evidence supports the validity of the conclusion that a plasma ACTH concentration below 10 pg/mL excludes Cushing's disease only when plasma cortisol concentration at 60 min lies between 16 and 38 microg/dL. Further evaluation of ACTH suppressibility by cortisol would be worthwhile, to confirm its potential value in facilitating positive diagnosis of Cushing's disease when dexamethasone suppressibility seems misleading.     

Breast and ovarian cancer prone women and prophylactic surgery temptation

Aldosterone suppression by dexamethasone, and high 18-hydroxycortisol and 18-oxocortisol levels are used to differentiate glucocorticoid-remediable aldosteronism (GRA) from other forms of primary aldosteronism. These methods are time consuming, expensive, and impractical for large studies. Moreover, diagnosis of GRA requires a confirmatory genetic test. We evaluated 117 patients with primary aldosteronism referred to our centers by the use of a long PCR technique to reveal the chimeric gene of GRA. In 60 of 117 patients, the response of aldosterone to dexamethasone (2 mg/day for 4 days) was also assessed. None of our patients, including 2 pairs of siblings, was positive for the chimeric gene. The results of long PCR were confirmed by Southern blotting. Despite a negative genetic test, 6 patients (1 with aldosterone-producing adenoma and 5 with idiopathic hyperaldosteronism) had plasma aldosterone suppressed by dexamethasone (i.e. < or = 2 ng/dL). Of 117 patients, 43 were identified as having aldosterone-producing adenoma and 74 as having idiopathic hyperaldosteronism. In our experience, the long PCR technique is a reliable and simple test to at least exclude GRA in patients with primary aldosteronism. A short term dexamethasone suppression test of aldosterone can be misleading in identifying GRA. The prevalence of GRA in primary aldosteronism remains to be established.     

Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol

CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) are 93% identical mitochondrial enzymes that both catalyze 11beta-hydroxylation of steroid hormones. CYP11B2 has the additional 18-hydroxylase and 18-oxidase activities required for conversion of 11-deoxycorticosterone to aldosterone. These two additional C18 conversions can be catalyzed by CYP11B1 if serine-288 and valine-320 are replaced by the corresponding CYP11B2 residues, glycine and alanine. Here we show that such a hybrid enzyme also catalyzes conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol. These latter two steroids are present at elevated levels in individuals with glucocorticoid suppressible hyperaldosteronism (GSH) and some forms of primary aldosteronism. Their production by the recombinant CYP11B enzyme is enhanced by substitution of further amino acids encoded in exons 4, 5, and 6 of CYP11B2. A converted CYP11B1 gene, containing these exons from CYP11B2, would be regulated like CYP11B1, yet encode an enzyme with the activities of CYP11B2, thus causing GSH or essential hypertension. In a sample of 103 low renin hypertensive patients, 218 patients with primary aldosteronism, and 90 normotensive individuals, we found a high level of conversion of CYP11B genes and four cases of GSH caused by unequal crossing over but no gene conversions of the type expected to cause GSH.     

Time course of the corticosteroid-dopaminergic interaction during metyrapone and dexamethasone administration

Recent studies performed with depressed patients and normal subjects suggest that corticosteroids may alter dopaminergic activity. We measured the time course of the interaction between corticosteroid and plasma homovanillic acid (HVA) levels in 10 young healthy subjects after the administration of 2 mg of dexamethasone in session 1 and after the administration of 4.5 g of metyrapone in session 2. Plasma levels of adrenocorticotropic hormone (ACTH), 11-desoxycortisol, cortisol, HVA, and prolactin (PRL) were measured at 08:00, 09:00, 12:00, 15:00, and 16:00 h on a baseline day and during both drug-administration sessions. Dexamethasone administration resulted in a significant decrease in plasma levels of ACTH, 11-desoxycortisol, and cortisol at all time points and to a significant decrease in PRL secretion in the early morning. Plasma HVA levels were unchanged after dexamethasone administration. Metyrapone administration resulted in a significant decrease in cortisol levels and a significant increase in ACTH and 11-desoxycortisol levels. Plasma HVA levels were significantly increased in the early morning, while PRL levels were unaltered. These results are discussed in relation to the neurochemical and behavioral changes associated with steroid administration and interpreted with regard to a possible association between HVA and PRL in the effects of corticosteroids on dopaminergic activity.     

Establishment and characterization of a human T-lymphocyte cell line immortalized by SV40 and with abnormal expression of TCR/CD3

OBJECTIVE: Elderly women with proximal femur fracture show a prolonged increase in plasma cortisol, which could have undesirable catabolic effects. Suppression of cortisol by dexamethasone is impaired, suggesting resistance to glucocorticoid effects at feedback inhibitory sites. We therefore wished to find out whether peripheral glucocorticoid sensitivity is normal. DESIGN: Peripheral blood mononuclear leucocytes were used as a model tissue. Blood samples were taken from elderly women about 2 weeks after hip fracture and from elderly control women. Each patient was then given 1 mg dexamethasone at 2300 h followed by further sampling at 0800 and 1600 h the next day. METHODS: Glucocorticoid-receptor binding parameters were measured by incubating whole cells with [3H]dexamethasone for 2 h at 37 degrees C. Inhibition of cell proliferation by dexamethasone was assessed by addition of [3H]thymidine to cells cultured for 65 h with concanavalin A. Cortisol and dexamethasone concentrations were measured in the dexamethasone suppression test. RESULTS: As expected, the hip-fracture patients had raised morning cortisol concentrations and impaired suppression by dexamethasone. The cells of the patients had similar numbers of glucocorticoid receptors to those of the control subjects but higher values for Kd (i.e. a lower binding affinity). The cells of the patients incorporated less [3H]thymidine than the control cells in the absence of dexamethasone. The percentage inhibition by a saturating concentration of dexamethasone was unchanged but the concentration giving half-maximal inhibition was decreased (sensitivity was increased) at the higher of the two concanavalin A concentrations used. CONCLUSIONS: These experiments in mononuclear leucocytes give no evidence of peripheral resistance to glucocorticoids in hip-fracture patients with impaired suppression of cortisol by dexamethasone.     

Differential diagnosis in primary aldosteronism

The diagnosis of primary aldosteronism (PA) is based on the finding of the combination of elevated urinary and/or plasma aldosterone and suppressed renin activity in patients with hypertension and hypokalemia. However, PA consists of a number of subsets, and diagnostic criteria for a correct identification of surgically remediable forms are of great interest. The methods and the results concerning our series of 113 patients with PA are presented in this review. Aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were the most frequent forms, 51 and 44%, respectively. They had similar blood pressure levels, but hypokalemia was most frequently found in APA. Urinary and upright plasma aldosterone were similar, but supine plasma aldosterone was lower in IHA. Plasma aldosterone response to upright posture and angiotensin II infusion was absent in most cases of APA and present in IHA, but occasionally renin-responsive adenoma were found. Captopril failed to decrease plasma aldosterone in most patients with APA, and in a subgroup of patients with IHA. Patients with adenoma also had higher values of the aldosterone precursor 18-hydroxy-corticosterone, and of atrial natriuretic peptide, probably as a consequence of a greater degree of volume expansion. Among morphological studies, CT scan and adrenal radiocholesterol scintiscan provided similar results (85% accuracy): adrenal veins catheterization clarified almost all the remaining cases. Among the subsets of PA, 3 familiar cases of dexamethasone-suppressible hyperaldosteronism were recognized, with characteristically high levels of aldosterone, 18-hydroxy-corticosterone, 18-hydroxy-cortisol and 18-oxo-cortisol, due to the genetic abnormalities of the 11-18 hydroxylase system. Isolated cases of primary adrenal hyperplasia (with all functional tests resulting compatible with APA, but no tumour at surgery) and aldosterone producing carcinoma (1 case) have also been reported in the present study.     

Diurnal rhythm of cortisol and aldosterone plasma levels in patients with chronic renal insufficiency

In patients with chronic renal failure (CRF) disturbances in cortical adrenal endocrine function were described previously. An increased plasma aldosterone level was documented in several studies [1-4]. The aim of this study was to investigate diurnal rhythms of plasma cortisol and aldosterone in CRF patients. In addition, in 3 patients on maintenance haemodialysis, the effect of dialysis procedure upon the plasma level of these hormones was studied. Ten patients with CRF of different etiologies, mean age 41.2 years, serum creatinine from 166-1336 mumol/L, creatinine clearance 4.2-29.2 ml/min, participated in the study. Blood samples were taken in the recumbent position at 6 am and at 6 h intervals thereafter for 24 h. Another group was made of 3 patients on maintenance haemodialysis for a mean 4.2 years. The effect of dialysis upon plasma cortisol and aldosterone levels was studied in the morning (7-11 h) and afternoon hours (14-18 h), with blood samples taken at one hour intervals. Patients were dialysed on cuprophan and polyacrilonitrile membranes. Plasma cortisol and aldosterone levels were determined using commercial RIA kits from Sorin Biomedica, Italy. The results obtained show that in 8 out of 10 patients with CRF in the predialysis period diurnal rhythm of cortisol was preserved. Investigation of the plasma aldosterone, with a 6 h sampling, however, shows in most of the patients studied no changes indicating a preserved diurnal rhythm. Investigation of the effect of haemodialysis treatment performed for 4 h on cuprophane as well as on PAN membrane, upon the plasma cortisol level has shown in morning hours the unchanged plasma cortisol level, compared to the same patients during the control study. Haemodialysis in the afternoon hours has produced, a small decrease of plasma cortisol during the first two hours, followed by an increase to the predialysis values. Plasma aldosterone levels during the morning and afternoon haemodialysis have shown variations similar to that observed in the same patients during the control study. CONCLUSIONS: This study has shown a preserved circadian rhythm of cortisol in kidney patients with CRF. A clear diurnal rhythm of aldosterone in these patients cannot be established. Investigation of the effect of haemodialysis procedure, performed on cuprophan and PAN, a more permeable membrane, upon the plasma levels of cortisol and aldosterone, has shown variations similar to that observed during the control study.     

Evaluation of radioimmunological methods for assay of plasma and urinary aldosterone

Two radioimmunological methods for assay of plasma and urinary aldosterone were carefully evaluated. In the plasma method a radioimmunoassay is preceded by chromatography on a Sephadex LH-20 column. The method for urine includes a preextraction, hydrolysis of the acid-labile conjugates of aldosterone, and a radioimmunoassay. Both methods fulfill the criteria of reliability and are suitable for both routine and demanding research assays. The plasma method, using columns of double length, is also applicable to analysis of aldosterone in plasma of newborn children, and pregnant females and in cord plasma. The concentration of plasma aldosterone in healthy subjects on an ad lib salt diet was 162 +/- 93 (S.D.) pmol/1 in the supine position and 312 +/- 217 (S.D.) pmol/1 upright. The urinary excretion of aldosterone in healthy subjects was 28.3 +/- 16.7 (S.D.) nmol/24 h.     

Effect of bedrest on circadian rhythms of plasma renin, aldosterone, and cortisol

Previous studies of normal men after 5 d of bedrest showed that circulatory instability on head-up tilt or standing is preceded by increased plasma renin activity (PRA) at bedrest. In the present study, the circadian rhythms of PRA, aldosterone, and cortisol have been observed in five normal men on a constant diet. In ambulatory controls, PRA and aldosterone increased normally after standing. On the third morning of bedrest, PRA was higher than before, and at noon, PRA was higher than in standing controls. The nocturnal peaks of PRA resulting from episodic renin secretion during sleep were higher after bedrest. Plasma aldosterone was also increased by bedrest. The findings are compatible with the theory that intermittent beta-adrenergic nerve activity during sleep is increased after bedrest, but other factors, such as loss of body sodium and a lower plasma volume, may also be involved.     

Effect of administered potassium on the renin-aldosterone axis in young blacks compared with whites

BACKGROUND: We had observed previously that the aldosterone excretion rate and plasma aldosterone concentration were lower for black children than they were for white children. We did not know whether this was secondary to a lower intake of potassium or to suppression of the renin-angiotensin system in blacks. OBJECTIVE: To test the hypothesis that the secretion of aldosterone in response to potassium would be different in blacks than in a control group of whites. DESIGN: Black and white subjects were selected on the basis of their having aldosterone excretion rates that were in the lowest quartile for the entire original cohort. Since the blacks typically had lower aldosterone excretion rates than did the whites, the black participants were represented primarily by those with average rates of aldosterone production among blacks, whereas the whites were represented by those with the lowest aldosterone production rates among whites. The protocol consisted of a placebo-controlled, randomized cross-over study design. METHODS: Twelve blacks and 12 whites, aged 14.1 +/- 1.6 (mean +/- SD) and 15.4 +/- 2.1 years, respectively, were allocated randomly to double-blind treatment either with placebo or with 40 mmol/day potassium chloride for 7 days and then the alternate treatment Measurements of the plasma renin activity (PRA), plasma aldosterone concentration, and urinary aldosterone excretion were performed in an inpatient research unit at the end of the treatment. The blood pressure was monitored for 24 h. RESULTS: Treatment with potassium increased the plasma aldosterone concentration (P = 0.0006) and the urinary excretion of aldosterone (P = 0.0002) significantly both for blacks and for whites. There was no significant racial difference in the response to potassium. The PRA was overall 1.605-fold lower in the blacks than it was in the whites (P = 0.0124). The lowest PRA levels, such as those in the blacks when they were supine, tended to be increased with the potassium treatment. The blood pressure did not change significantly with the potassium supplement for either racial group. CONCLUSIONS: After we had supplemented the intake of potassium, aldosterone production increased in the blacks and in the control group of whites to the same extent The potassium treatment appeared to increase lower PRA levels. A lower intake of potassium could at least partially account for the suppression of the renin-aldosterone system in blacks.     

Pre-Cushing's syndrome not recognized by conventional dexamethasone suppression-tests in an adrenal "incidentaloma" patient

Pre-Cushing's syndrome has been recently diagnosed in 6-12% of patients affected with incidentally discovered adrenal masses. Some of these patients have been described to show transient hypoadrenalism after surgery, similarly to those affected with overt Cushing's syndrome. We studied a 70-year-old male patient with a large left adrenal mass, incidentally discovered, who displayed 24-h urinary free cortisol levels at the upper limit of the normal range, normal dexamethasone overnight and low-dose suppression tests and not suppressed ACTH levels, increased 17-hydroxyprogesterone response to ACTH stimulation and low upright plasma renin activity with normal serum aldosterone levels; furthermore, DHEAS level was low and 75 Selenium-cholesterol scintigraphy showed unilateral uptake concordant with the side of the mass. Soon after left adrenalectomy, he complained of acute hypoadrenalism requiring cortisol replacement therapy: ten months after surgery he is still hypoadrenal. Moreover, stimulated 17-hydroxyprogesterone and plasma renin activity in clino- and orthostatic posture have become normal. We propose that conventional dexamethasone suppression-tests may be not enough sensitive in this kind of patients and that in selected cases the absence of controlateral uptake at scintigraphy may be more reliable in predicting post-surgical hypoadrenalism.     

Corticotrophic macroadenoma of the pituitary associated with hypoadrenalism

A 60-year-old man underwent transfrontal surgery for a macroadenoma of the pituitary which presented with chiasmal compression, and immunohistochemical examination of the resected specimen revealed a corticotrophic tumour. Despite subsequent external irradiation, he was left with a large tumour remnant, which continued to grow. There were no clinical signs of Cushing's syndrome either before or after surgery and 24 h urine excretion of cortisol was not elevated. Plasma ACTH concentrations were marginally raised. However, there was loss of circadian variation in serum cortisol concentrations and administration of high-dose oral dexamethasone was followed by a marked and reproducible rise in both ACTH and cortisol. Two years later he developed symptoms and signs of hypoadrenalism and urine cortisol excretion was low, even though the paradoxical response to dexamethasone was preserved. Treatment with 0.5 mg dexamethasone each day was associated with partial resolution of his symptoms and urine cortisol concentration rose into the normal range. This treatment was maintained until his death in hospital in April 1988. The possible mechanism underlying the association between a corticotrophic tumour and hypoadrenalism are discussed.     

Paternal exposures: impact on reproductive and developmental outcome. An overview

Corticosteroid 11 beta-hydroxylation is catalysed by 11 beta-hydroxylase and aldosterone synthase. Using plasma steroid ratios, the level of this process in patients with glucocorticoid-suppressible hyperaldosteronism (GSH) was compared with that in unaffected control subjects and in patients with Conn's syndrome. Based on both 11-deoxycortisol:cortisol (S:F) and 11-deoxycorticosterone:corticosterone (DOC:B) ratios, patients with GSH showed impaired resting 11 beta-hydroxylase activity. In GSH, but not in the other groups, the S:F ratio was significantly correlated with basal plasma aldosterone concentration. ACTH infusion increased the S:F ratio in all these patient groups, suggesting a common partial deficiency. The results also indicate that 11 beta-hydroxylation may be rate-limiting in normal subjects. In control subjects and patients with Conn's syndrome, the DOC:B ratio was not affected by ACTH. However, in GSH patients, this ratio fell markedly, indicating an increased efficiency of 11 beta-hydroxylation of DOC (but not S). This may be due to the activation by ACTH of the zona fasciculata chimaeric aldosterone synthase characteristic of this disease. Plasma aldosterone, corticosterone and DOC concentrations, appeared to be more sensitive to ACTH in GSH than the other groups. The defect in 11 beta-hydroxylation in GSH accounts for the increased levels of DOC reported in the condition, and may contribute to the phenotypic variability.     

Initial sign and clinical course of the most severe form of acute proliferative retrolental fibroplasia (type II) (author''s transl)

Hypothalamic-pituitary-adrenocortical function was investigated in 14 patients with anorexia nervosa. Impaired suppression of plasma cortisol by dexamethasone was revealed. In 14 patients with anorexia nervosa, circadian rhythm of plasma cortisol, insulin tolerance test, rapid ACTH test and overnight dexamethasone suppression test were examined. Levels of plasma cortisol were higher than those in control subjects throughout the day, and normal circadian rhythm of plasma cortisol was not observed. Basal levels of plasma ACTH were within normal range. tthe response of plasma cortisol to insulin-induced hypoglycemia was lower than that in control subjects, while the response of plasma cortisol in rapid Acth test was normal. In overnight suppression tests, in which one mg dexamethasone was administered orally, 11 of 14 patients showed no suppression of plasma cortisol and 3 other patients showed incomplete suppression. Elevated levels of plasma cortisol and the absence of normal circadian rhythm in patients with anorexia nervosa and malnutrition have already been reported by other investigators, and these abnormalities were ascribed to the delayed half life of plasma cortisol due to impaired cortisol metabolism. However, according to our investigation, it is difficult to explain the failure of dexamethasone to suppress cortisol only by the delayed half life of plasma cortisol, and it is supposed that some kind of abnormal hypothalamic control is also involved.     

The effects of dietary sodium on the diurnal activity of the renin-angiotensin-aldosterone system and the excretion of urinary electrolytes

Diurnal variations of five normal men were tested over three 24 h consecutive periods. The first experiment began at 0900 h after the subjects had fasted for 12 h and a normal sodium diet of about 70-80 mEq was given at 0900 h, 1200h, and 1630 h (total of about 220 mEq of Na). Significant variations in the plasma renin activity (PRA), in the plasma aldosterone (PA), and in the urinary Na and K outputs were found. The second experiment began at 1200 h with the first feeding time at 2100 h after fasting about 24 h and the subjects were given a normal sodium diet as in the first experiment, but with the meals given at 2100 h, 2400 h, and 0430 h. The diurnal variations in PRA, plasma aldosterone, and urinary electrolytes disappeared. From this study, it appears that the diurnal variation in urinary electrolyte excretion is a factor of the diurnal variation in PRA and plasma aldosterone. The diurnal variation in PRA and plasma aldosterone are related to the timing of sodium ingestion.     

Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis

Systemic symptoms in rheumatoid arthritis (RA) are mediated, at least in part, by elevated levels of circulating interleukin (IL)-6, and this cytokine is also a potent stimulus of the hypothalamic-pituitary-adrenal axis. To evaluate the 24-h circadian secretory dynamics of ACTH, cortisol, and IL-6 and their interactions in patients with early untreated RA, we recruited and studied five newly diagnosed, untreated RA patients early in the course of their disease and five age-, gender-, and race-matched control subjects. We collected serial blood samples over 24 h and measured plasma ACTH and cortisol every 30 min and IL-6 every hour. The 24-h collection was followed by administration of ovine CRH (oCRH) and post-oCRH serial blood samples over 2 h. We analyzed the 24-h overall levels of these hormones and their circadian variations and performed time-lagged cross-correlation analyses among them. The untreated RA patients had 24 h time-integrated plasma ACTH, plasma cortisol levels, and urinary free cortisol excretion that were not significantly different from control subjects, in spite of their disease activity. However, an earlier morning surge of plasma ACTH and cortisol in the patients was suggested. Plasma ACTH and cortisol responses to oCRH were similar in RA patients and controls. IL-6 levels were significantly increased in the RA patients compared with control subjects during the early morning hours (P < 0.05). There was pronounced circadian variation of plasma Il-6 levels. In the RA patients, we detected a positive temporal correlation between plasma levels of IL-6 and ACTH/cortisol, with elevated levels of IL-6 before the elevations of ACTH and cortisol by 1 and 2 h, respectively. In the same patients, we detected a negative effect of cortisol upon IL-6 exerted with a delay of 5 h. The data presented here suggest that although endogenous IL-6 may stimulate secretion of ACTH and cortisol, overall activity of the hypothalamic-pituitary-adrenal axis remains normal and apparently is insufficient to inhibit ongoing inflammation in early untreated RA patients.     

Aldosterone in obesity

Plasma aldosterone levels were measured in adults whose body mass index ranged from lean to obese. Blood was drawn while subjects rested supine for 30-90 minutes. Aldosterone was higher in obese subjects, but could not be explained by renin or K+. The best predictors of plasma aldosterone were abdominal obesity measured as waist/hip ratio or by CT scan, and insulin resistance measured by insulin or oral glucose tolerance tests, or euglycemic clamp. In one cohort, these correlations were limited to women; in the other, they were also found in men. In the women with a strong correlation between aldosterone and visceral fat, aldosterone also correlated with cortisol and DHEA-S. The data are consistent with an effect of visceral fat on adrenal steroidogenesis. Visceral adipocytes have a high rate of triglyceride turnover, and their circulation drains directly to the liver. In an experiment based on these characteristics, rat hepatocytes responded to fatty acids by releasing an unidentified secretagogue that stimulated aldosterone production by rat adrenal glomerulosa cells. The clinical data suggest that aldosterone participates in hypertension associated with the "Insulin Resistance Syndrome". The adrenal in viscerally obese subjects may be driven by a secretagogue released from the liver by fatty acids from abdominal adipocytes.     

Diurnal melatonin and cortisol secretion profiles in medicated schizophrenic patients

Although melatonin and/or cortisol secretions have been suggested as markers for both circadian and noradrenaline dysfunctions in psychiatric illnesses, especially in affective disorders, studies of melatonin and cortisol in schizophrenic patients are rare. We evaluated the circadian profiles of melatonin and cortisol secretion in schizophrenic patients and control subjects. A total of 21 medicated Taiwanese male paranoid schizophrenic inpatients (mean age, 27.3 +/- 7.2 yr) and 21 age- and sex-matched controls underwent 24-hour neuroendocrine screening. Melatonin and cortisol concentrations were measured at 2-hour intervals from 0800 h to 2200 h, and at 1-hour intervals from 2300 h to 0700 h. The standard dexamethasone suppression test was performed the next day to provide an index of hypothalamic-pituitary-adrenal axis (HPA) function. The results showed that the circadian rhythm of plasma melatonin secretion was disrupted in schizophrenics compared with controls, whereas the 24-hour profile of plasma cortisol was preserved. The melatonin to cortisol ratio was significantly higher in control subjects than in schizophrenic patients. Results of the dexamethasone suppression tests indicated that there were no functional changes in the HPA axis in schizophrenic patients. Five drug-naive schizophrenic patients studied simultaneously, but whose data were not included in the above analyses, had results consistent with those of the maintenance-medicated patients. Our findings suggest the presence of abnormal melatonin metabolism in Taiwanese schizophrenics, which may possibly be related to the pathophysiologic process itself. However, broader pathogenetic aspects of these neuroendocrine interrelations remain to be clarified.