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Effect of aminoglutethimide on urinary cortisol and cortisol metabolites in adolescents with Cushing's syndrome.

The effect of aminoglutethimide (AG) 4 X 250 mg (670 mg/m2 daily by mouth) on the excretion of the free cortisol (radio-immunoassay) and of its metabolites THE, THF-allo THF, cortolone and beta-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-beta-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 metabolites; (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 5beta-reductase and/or 3alpha-dehydrogenase, possibly stimulation of 20alpha- and 20beta-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.

Adolescent↗

Anti-tumour necrosis factor antibody treatment does not change serum levels of cortisol binding globulin in patients with rheumatoid arthritis but it increases androstenedione relative to cortisol.

BACKGROUND: Cortisol binding globulin (CBG) is produced by liver cells and is inhibited by proinflammatory cytokines such as interleukin (IL) 6. CBG serum levels are typically low during prolonged inflammatory processes. Thus, observed changes of cortisol during anti-tumour necrosis factor (TNF) treatment may be related to changes of CBG in rheumatoid arthritis (RA). OBJECTIVE: To investigate the course of CBG during anti-TNF treatment in RA. METHODS: 13 patients with longstanding RA, without prior prednisolone treatment, were included in this longitudinal study with subcutaneous adalimumab. RESULTS: Treatment with anti-TNF markedly decreased clinical markers of inflammation and serum IL6. Serum levels of cortisol, CBG, and the ratio of cortisol/CBG did not change markedly, whereas the ratio of serum CBG/IL6 increased (p = 0.004). In parallel, levels of adrenocorticotropic hormone decreased during the observation period. The ratio serum androstenedione/serum cortisol increased during the study (p = 0.036). CONCLUSIONS: During anti-TNF treatment relatively normal levels of CBG and a normal ratio of CBG/cortisol are found. Changes of cortisol in relation to IL6 during anti-TNF treatment, seen previously, may not be related to changes of CBG.

Adalimumab↗

Basal cortisol, dexamethasone suppression of cortisol, and MHPG in adolescents after the 1988 earthquake in Armenia.

OBJECTIVE: This study evaluated basal salivary cortisol, 3-methoxy-4-hydroxyphenylglycol (MHPG), and cortisol suppression following dexamethasone administration in adolescents exposed to two levels of earthquake-related trauma. METHOD: Five years after the 1988 earthquake, saliva samples were obtained from 37 adolescents from two cities in Armenia at different distances from the epicenter. Baseline saliva samples were obtained at 8:00 a.m., 4:00 p.m., and 11:00 p.m., following which 0.5 mg of dexamethasone was administered. Nine and 17 hours later, saliva samples were again obtained. Subjects were evaluated for posttraumatic stress and depressive reactions through use of self-report instruments. RESULTS: Significantly lower mean baseline 8:00 a.m. cortisol levels and greater day 24:00 p.m. cortisol suppression following dexamethasone were observed in the more symptomatic adolescents living in the city closer to the epicenter. Of the three symptom categories of posttraumatic stress disorder (PTSD), only intrusion (category B) symptoms were significantly correlated with basal morning cortisol levels and percent suppression by dexamethasone. The more highly exposed adolescents also exhibited a more rapid decline in MHPG levels over the course of day 1. CONCLUSIONS: The findings indicate that chronic posttraumatic stress reactions among adolescents exposed to catastrophic disaster are associated with hypothalamic-pituitary-adrenal (HPA) axis alterations. The findings are congruent with those previously described in adults with chronic PTSD. Persistent intrusion (category B) symptoms may constitute continued episodes of distress and evoke repeated physiological stress responses, which, over time, alter HPA axis function. The MHPG findings suggest that there may be diurnal changes associated with severity of posttraumatic stress symptoms.

Adolescent↗

Plasma adrenocorticotropin, cortisol, and aldosterone responses to corticotropin-releasing factor: modulatory effect of basal cortisol levels.

Two hundred micrograms of corticotropin-releasing factor (CRF) were administered as an iv bolus injection to 10 normal subjects (5 men and 5 women). Mean plasma ACTH levels rose significantly (P less than 0.0005, by Friedman's nonparametric analysis of variance) from a basal value of 27 +/- 5 pg/ml (mean +/- SEM) to a peak value of 63 +/- 8 pg/ml 30 min after CRF administration. This ACTH response was followed by a rise in plasma mean cortisol levels (P less than 0.0005, by Friedman's test) from a baseline value of 12.3 +/- 1.4 micrograms/100 ml to a peak value of 21.0 +/- 0.7 micrograms/100 ml 60 min after CRF and a rise in mean plasma aldosterone levels from a basal value of 13 +/- 2 ng/100 ml to a peak value of 23 +/- 2 ng/100 ml. There was no significant difference between men and women in the responsiveness of ACTH, cortisol, and aldosterone to CRF administration. The individual basal cortisol levels were highly significantly and negatively correlated with the areas under the individual ACTH curves (r = -0.76; P less than 0.005, by Pearson's correlation test) and cortisol curves (r = -0.91; P less than 0.001, by Pearson's test). These data suggest a modulatory effect of physiological cortisol levels on the response of the pituitary-adrenal axis to CRF.

Adolescent↗

Quantitative comparison of aromatase induction by dexamethasone in fibroblasts from a patient with familial cortisol resistance and a patient with cortisol hyperreactive syndrome.

The ability of dexamethasone to induce aromatase activity was tested in fibroblasts from a patient with familial cortisol resistance, a patient with cortisol hyperreactive syndrome, and five normal subjects. Dexamethasone increased enzyme activity in all cases in a concentration-dependent manner (over a range of 1-1000 nmol/L). In fibroblasts from a patient with familial cortisol resistance, the response curve of dexamethasone-induced aromatase activity was shifted to the right compared to that of normal cells. However, the maximal induction of the enzyme at 1 mumol/L dexamethasone was unchanged in cortisol-resistant fibroblasts. On the other hand, in fibroblasts from the patient with the cortisol hyperreactive syndrome, the half-maximal effect of dexamethasone was similar to that in normal cells, but maximum induction of aromatase activity was 2 times greater than that in normal cells. The glucocorticoid antagonist RU 486 inhibited dexamethasone-induced aromatase activity in these patients' cells and in normal cells in a concentration-dependent manner, indicating that the altered effects of dexamethasone on aromatase induction observed in each cell type were mediated through glucocorticoid receptors.

Aromatase↗

Cortisol in saliva--reference ranges and relation to cortisol in serum.

The aim of this study was to establish morning and evening reference ranges for cortisol in saliva. Another objective was to compare the concentrations of the mainly free cortisol in saliva to those of total cortisol in serum as determined with a commercial radioimmunoassay. The concentrations were determined in matched samples of saliva and serum collected at 8 am and 10 pm from 197 healthy volunteers. The saliva samples were stable for at least 7 days at room temperature and for 9 months at -20 degrees C. Reference ranges, the central 95%, were estimated to 3.5-27.0 nmol/l at 8 am and < 6.0 nmol/l at 10 pm. The intra-assay coefficient of variation (CV) was below 5% and total CV below 10%. The relation between the cortisol concentrations in serum and saliva was non-linear with r = 0.86 for serum concentrations < 450 nmol/l and r = 0.44 for serum concentrations > or = 450 nmol/l. In conclusion, the satisfactory precision of the analysis and the simple non-invasive sampling procedure suggest that saliva may be used for cortisol measurements in situations where blood sampling is difficult to perform.

Adult↗

Poly-maleic acid anhydride (PMA) coupled cortisol antibody in routine determination of urinary free cortisol.

Antibodies against cortisol-21-hemisuccinate conjugated to bovine serum albumin was raised in rabbits and conjugated with poly-maleic acid anhydride. The conjugate was used in a solid phase radioimmunoassay to measure the urinary excretion of unconjugated cortisol. Cortisol was extracted with methylene chloride, the extract purified by chromatography on Sephadex LH-20, and the cortisol content measured with the radioimmunoassay. The intra-assay variation of the method was 6 per cent and the interassay variation 10 per cent. In 95 normal adult persons the excretion of free cortisol was 11--70, mean 30 micrograms/24 h. No sex or age difference was found. In 8 children aged 7--14 years the excretion was 8--46 micrograms/24 h.

Antibodies↗

Generation of a novel monoclonal antibody against cortisol-[C-4]-bovine serum albumin conjugate: application to enzyme-linked immunosorbent assay for urinary and serum cortisol.

Measurement of cortisol levels in body fluids is important for monitoring pituitary gland and adrenal functions. To develop a specific and standardized enzyme-linked immunosorbent assay (ELISA), a novel monoclonal anti-cortisol antibody has been generated using a reasonably designed haptenic derivative. Spleen cells were prepared from the BALB/c or A/J mouse, which had repeatedly been immunized with a conjugate of 4-(2-carboxyethylthio)cortisol (CET) and bovine serum albumin, to be fused with P3/NS1/1-Ag4-1 myeloma cells. After four fusion experiments, one hybridoma clone secreting a practical antibody has been established. The resulting monoclonal antibody CS#38 (isotype gamma1, kappa) showed an affinity constant (K(a)) for cortisol of 1 x 10(9) M(-1) and provided a practical calibration curve (detection limit, 0.26 ng per assay) in a homologous ELISA system employing horseradish peroxidase-labeled CET as a labeled antigen. Cross-reactivities with related C-21 steroids were acceptably low: 11-deoxycortisol (4.3%), cortisone (4.0%), corticosterone (1.9%), progesterone (1.6%), 17alpha-hydroxyprogesterone (12%), 6beta-hydroxycortisol (8.4%), and tetrahydrocortisol (< 0.1%). Urinary and serum cortisol levels of healthy volunteers were determined by this method after methylene chloride extraction to be 39.0 +/- 17.0 microg/day (n = 7) and 80.8 +/- 38.9 ng/mL (n = 10), respectively, both of which are in the reference range.

Adult↗

Saliva cortisol, physical exercise and training: influences of swimming and handball on cortisol concentrations in women.

The aim of this study was to observe the influence of physical exercise and training on saliva cortisol concentrations in women. Three groups of adult women were studied: one group of sedentary controls (n = 7) and two groups of sportswomen who competed in either handball (n = 14) or swimming (n = 10) at a national level. These sportswomen gave six saliva samples during a day that included exercise which was part of their annual training programme. We noticed a significant increase in saliva cortisol concentration after exercise in the handball players (6 p.m. vs 7.30 p.m. P < 0.05) which did not appear in the swimmers or the sedentary group. There was no difference between the sedentary group and the swimmers for each sample of the day. These results showed that the type of sport played seemed to influence the concentration of saliva cortisol, the type of stress involved, the respective haemodynamic conditions of swimming and running and thermal stress also playing a part. Moreover, it seemed that the level of performance influenced the secretion of cortisol in the saliva.

Adult↗

Enterochromaffin cells in the stomach of the rat after prolonged administration of cortisol and both cortisol and salmon calcitonin.

Young adult male Wistar rats (eight controls and ten experimental animals per group) were injected parenterally for 28 days: 1) cortisol or 2) cortisol and salmon calcitonin. Morphological changes of the stomach wall and enterochromaffin cells, stained immunocytochemically for serotonin, were assessed. In the group treated with cortisol superficial desquamation and erosions of the gastral mucosa were found. In this group the number of enterochromaffin cells was significantly decreased and low intensity of the immunocytochemical reaction of these cells was observed. In the cortisol-calcitonin-treated group there were no apparent changes of the gastral mucosa and the enterochromaffin cells presented a normal picture comparable to that of controls.

Animals↗

Differential effects of scopolamine on nocturnal cortisol secretion, sleep architecture, and REM latency in normal volunteers: relation to sleep and cortisol abnormalities in depression.

Scopolamine (SCOP) (3.0 mu/kg and 6.0 micrograms/kg) and saline were administered intramuscularly at 11:00 PM to eight normal male volunteers in a randomized design, and the effects on the sleep electroencephalogram (EEG) and nocturnal cortisol secretion (via blood sampling every 15 min) were evaluated. Compared to saline, SCOP produced a significant dose-related delay in rapid eye movement (REM) latency. In contrast, neither dose of SCOP significantly affected nocturnal plasma cortisol concentrations. These results suggest that the central cholinergic system that regulates the onset of REM sleep is more sensitive to dysregulation than the cholinergic system that controls the degree of nocturnal cortisol secretion. If central cholinergic overactivity is responsible for both the REM sleep latency and cortisol abnormalities in depressed patients, then our findings with SCOP might help explain why the incidences of these abnormalities are different.

Adult↗

Cortisol secretion in vitro by the interrenal of coho salmon (Oncorhynchus kisutch) during smoltification: relationship with plasma thyroxine and plasma cortisol.

An in vitro system for the incubation of interrenal tissue (head kidney fragments) from coho salmon, Oncorhynchus kisutch, was developed in order to examine changes in interrenal sensitivity to ACTH1-24 during smoltification, using cortisol secretion as the endpoint. Time-course studies indicated that maximal cortisol accumulation in incubation media was achieved after 3 hr exposure to ACTH. There was no correlation between head kidney weight, body weight, or sex and the response of the interrenal to ACTH1-24 in vitro. Approximately monthly or bi-weekly experiments were performed during the smoltification period (February-July): tissue was preincubated in hormone-free media for 3 hr, washed twice, and then challenged with 5 X 10(-10)-5 X 10(-7) M (1.5-1500 ng/ml) ACTH1-24 for 3 hr. The pattern of cortisol secretion was similar in February, early March, and late March in the dose range of 5 X 10(-10)-5 X 10(-8) M ACTH1-24. A marked, significant increase in sensitivity to ACTH and in the steroidogenic capacity of the tissue occurred in April, but by May the response was similar to that in the pre-April period. Enhanced sensitivity and steroidogenic capacity were found in interrenal tissue taken from coho salmon in June and July. Maximal in vitro responsiveness of interrenal tissue to ACTH in April was correlated with peak plasma thyroxine titers and enhanced hypoosmoregulatory ability, but not with peak plasma cortisol titers, which occurred in May.

Adrenal Glands↗

The conversion of cortisol into its principal metabolites, their tissular concentrations and transplacental transfer during 3H-cortisol infusion of mother and fetal guinea-pigs.

During continuous infusion of 3H-cortisol in the circulation of the guinea-pig mother or fetus, radioactive metabolites appear in both maternal and fetal blood. These cortisol-derived compounds were identified principally as cortisone, tetrahydrocortisol (THF) and tetrahydrocortisone (THE). There were unidentified others in low quantities. The cortisone of the maternal plasma is 100% maternal in origin since that of the fetal plasma is 50% fetal in origin between days 62 and 66 and increased thereafter. An identical profile was noted for THF. THE seemed to be synthetized in the fetal guinea-pig and was transferred to the mother in increasing amounts near term. Liver concentrations of cortisol were higher than those of plasma in the mother. Maternal liver appeared to be the main organ of cortisol metabolism in the mother-fetus unit, but maternal adrenal may contribute to this metabolism.

Adrenal Glands↗

Interaction between cortisol and cortisol-binding protein in silver foxes (Vulpes fulvus).

1. Selection of silver foxes for domestic behaviour resulted in the parallel lowering of both cortisol and cortisol-binding protein (CBP) levels in the blood plasma. 2. During seasonal cycles (summer-winter) and after stress an increase in cortisol levels is followed by a decrease in CBP activity. 3. It is concluded that there are two types of interaction between cortisol and CBP in silver foxes: parallel changes in the process of domestication and opposite changes under the influence of environmental factors.

Animals↗

Cortisol and behavior: 2. Application of a latent state-trait model to salivary cortisol.

In two studies we applied a new stochastic model for the measurement of latent states and traits to salivary cortisol in healthy subjects. Data were analyzed by Linear Structural Relations (LISREL). In the first study, 48 students collected saliva samples on two occasions at 1300h with an interval of six weeks between occasions. Salivary cortisol levels were found to be mainly influenced by situational and/or interactional effects, which determined approximately 75% of the total variance of the hormone data, while only approximately 21% were determined by the latent trait. Measurement unreliability was found to be approximately 4%. In the second study, 54 young mothers collected saliva at 0800h, 1500h, and 2000h for three consecutive days, starting on the second day after delivery of a healthy baby. Early morning salivary cortisol showed high consistency across the three days. Approximately 60% of the total variance in the early morning cortisol samples was determined by the latent trait. For the 1500h and 2000h samples, however, the corresponding proportions of variances amounted only to 33% and 28%, respectively. These results appear to reflect the absence of a clear-cut circadian rhythm in some of the women on the second day after delivery.

Adult↗

Cortisol, the cortisol-dehydroepiandrosterone ratio, and pro-inflammatory cytokines in patients with current major depressive disorder comorbid with borderline personality disorder.

BACKGROUND: Major depression in young women is often comorbid with borderline personality disorder (BPD); however, adrenal steroids and pro-inflammatory cytokines in patients with comorbid current major depressive disorder and BPD (MDD/BPD) have not been systematically examined. Therefore, our study aimed at examining serum profiles of cortisol, cytokines, and the cortisol/dehydroepiandrosterone (cortisol/DHEA) ratio in MDD/BPD patients and a healthy comparison group. METHODS: Twelve medication-free female patients with MDD/BPD and 12 healthy women were included. Serum profiles of cortisol, DHEA, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1beta were sampled, and the molar cortisol/DHEA ratio was determined. RESULTS: Concentrations of serum cortisol, TNF-alpha, and IL-6, as well as the cortisol/DHEA ratios were significantly increased in MDD/BPD patients as compared with the healthy comparison group. CONCLUSIONS: Depressed patients with comorbid BPD display endocrine and immune alterations similar to those observed in cases of melancholic MDD without BPD. Elevated concentrations of serum cortisol, cortisol/DHEA ratios, and pro-inflammatory cytokines might indicate a state marker in these patients and might contribute to long-term metabolic alterations that have also been associated with MDD.

Adult↗

Cortisol, aldosterone, cortisol precursor, androgen and endogenous ACTH concentrations in dogs with pituitary-dependant hyperadrenocorticism treated with trilostane.

Trilostane is thought to be a competitive inhibitor of the 3beta-hydroxysteroid dehydrogenase (3beta-HSD), an essential enzyme system for the synthesis of cortisol, aldosterone and androstenedione. Due to its reliable clinical efficacy, trilostane is increasingly used to treat dogs with pituitary-dependant hyperadrenocorticism (PDH). The objective of our study was to investigate the effect of trilostane on precursor concentrations located before (17alpha-OH-pregnenolone, dehydroepiandrostenedione) and after (17alpha-OH-progesterone, androstenedione, 11-deoxycortisol, 21-deoxycortisol) the proposed enzyme inhibition, on end products of steroid biosynthesis (cortisol and aldosterone) and on endogenous adrenocorticotrophic hormone (ACTH) concentrations in dogs with PDH. Hormones of the steroid biosynthesis pathway were evaluated in 15 dogs before and 1h after injection of synthetic ACTH prior to (t(0)), in weeks 1-2 (t(1)) and in weeks 3-7 (t(2)) of trilostane treatment. Endogenous ACTH concentrations were measured at the same time points before performing the ACTH stimulation test. During trilostane treatment baseline and post-stimulation cortisol concentrations decreased significantly. Baseline serum aldosterone levels showed a significant increase; post-stimulation values decreased. Baseline and post-stimulation 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations increased significantly. 17alpha-OH-progesterone and androstenedione levels did not change. Post-stimulation 21-deoxycortisol concentrations decreased significantly, baseline 11-deoxycortisol concentrations increased significantly. Endogenous ACTH levels showed a significant increase. The significant increase in 17alpha-OH-pregnenolone and dehydroepiandrostenedione concentrations confirms an inhibitory effect of trilostane on the 3beta-HSD. Since 17alpha-OH-progesterone concentrations did not change, but cortisol concentrations markedly decreased, trilostane seems to influence additional enzymes of the hormone cascade, like the 11beta-hydroxylase and possibly the 11beta-hydroxysteroid dehydrogenase.

17-alpha-Hydroxypregnenolone↗