Suppression Of Cortisol Secretion Research Articles

A comparative assessment of the adrenotoxic effects of cadmium in two teleost species, rainbow trout, Oncorhynchus mykiss, and yellow perch, Perca flavescens

Rainbow trout ( Oncorhynchus mykiss) and yellow perch ( Perca flavescens) have a different sensitivity to cadmium (Cd) in vivo (trout<LC50<perch). Metals and particularly Cd impair cortisol secretion by adrenocortical cells in both species. The purpose of the present study was to assess in vitro the effect of Cd on cortisol secretion by adrenocortical cells of trout and perch, to compare the sensitivity of adrenal steroidogenesis in these two teleosts. Adrenocortical cells were exposed to Cd for 60 min, then stimulated with ACTH, dbcAMP or with pregnenolone, a cortisol precursor. Cd inhibited ACTH-stimulated cortisol secretion in a dose-dependent manner in both fish species, however, the EC50s (concentration resulting in 50% inhibition of cortisol secretion) was significantly lower in trout (EC50=0.09 mM) than perch (EC50=0.26 mM). To test the specificity of Cd to act as an endocrine disrupter, the LC50 (concentration that kills 50% of the cells) was also evaluated to determine the LC50/EC50 ratio (LC50/EC50 O.mykiss=175.6>LC50/EC50 P.flavescens=37.7). Adrenocortical cells of trout were more sensitive than those of perch and Cd had a higher endocrine-disrupting potential and specificity in trout than in perch. However, in both species, Cd had the same effect on ACTH, dbcAMP and pregnenolone-stimulated cortisol secretion, with pregnenolone maintaining cortisol secretion until cell viability was impaired. These results confirm that for both species, Cd interferes in the signalling pathway of cortisol synthesis in a step prior to the pregnenolone formation. Data provided by the present study revealed important differences in vulnerability of adrenal steroidogenesis between rainbow trout and yellow perch.

Paradoxical Inhibitory Effect of Serotonin on Cortisol Production from Adrenocortical Lesions Causing Cushing's Syndrome

In the human adrenal gland, serotonin (5‐HT) stimulates cortisol production through a paracrine mechanism involving 5‐HT4 receptors positively‐coupled to adenylyl cyclase. A hyperresponsiveness of adrenocortical tissue to 5‐HT has also been described in several cases of ACTH‐independent bilateral macronodular adrenal hyperplasias (AIMAHs) and adenomas causing Cushing's syndrome. In the present study, we report two cases of cortisol‐producing adrenocortical lesions, i.e. one AIMAH (case 1) and one adenoma (case 2), whose secretory activity was inhibited in vitro by 5‐HT. The potencies (pIC50) and efficacies (Emax) of 5‐HT to inhibit cortisol secretion were 8.2 ± 0.4 and − 64.1% ± 7.5% in case 1, and 9.2 ± 0.5 and − 32.3% ± 3.8% in case 2. The specific 5‐HT4 antagonist GR 113808 failed to influence the 5‐HT‐induced decrease in cortisol production by the two tissues, indicating that the paradoxical inhibitory effect of 5‐HT could not be accounted for by activation of eutopic 5‐HT4 receptors. These results suggest that the tissues expressed aberrant 5‐HT receptors. In conclusion, the present study provides the first evidence for an inhibitory effect of 5‐HT on cortisol secretion in adrenocortical lesions causing Cushing's syndrome. Our data also suggest that expression of illegitimate membrane receptors by cortisol‐producing adrenal hyperplasias and/or adenomas may convert a paracrine stimulatory factor into an inhibitory signal.

Influence of mirtazapine on urinary free cortisol excretion in depressed patients

Mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on urinary free cortisol (UFC) excretion was investigated in depression. Twenty patients (six men, 14 women) suffering from major depression according to DSM-IV criteria were treated with mirtazapine for 3 weeks. The patients received 15 mg mirtazapine on day 0; 30 mg mirtazapine on day 1; and 45 mg mirtazapine per day from day 2 to the end of the study (day 21). UFC excretion was measured before treatment (day 1), at the beginning (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Urine samples were collected from 08:00 to 08:00 h the following day. On the days of urine sampling, the severity of depressive symptoms was assessed using the 21-item version of the Hamilton Rating Scale for Depression (21-HAMD). There was a significant reduction of UFC excretion during 3-week mirtazapine therapy, which was already obvious after the first day of treatment (day 0). However, there were no significant across-subjects correlations between UFC reduction and decrease in 21-HAMD sum scores. Apparently, the mirtazapine-induced rapid reduction of cortisol secretion in depressed patients is not necessarily correlated with a favorable therapeutic response.

The organochlorine o,p′-DDD disrupts the adrenal steroidogenic signaling pathway in rainbow trout ( Oncorhynchus mykiss)

The mechanisms of action of o,p′-DDD on adrenal steroidogenesis were investigated in vitro in rainbow trout ( Oncorhynchus mykiss). Acute exposures to o,p′-DDD inhibited ACTH-stimulated cortisol secretion while cell viability decreased significantly only at the highest concentration tested (200 μM o,p′-DDD). Stimulation of cortisol secretion with a cAMP analogue (dibutyryl-cAMP) was inhibited at a higher concentration than that needed to inhibit ACTH-stimulated cortisol synthesis in cells exposed to o,p′-DDD. Forskolin-stimulated cortisol secretion and cAMP production, and NaF-stimulated cAMP production were inhibited in a concentration-dependent manner by o,p′-DDD. In contrast, basal cortisol secretion was stimulated while basal cAMP production was unaffected by o,p′-DDD. Pregnenolone-stimulated cortisol secretion was enhanced by o,p′-DDD at a physiologically relevant pregnenolone concentration, while o,p′-DDD inhibited cortisol secretion when a pharmacological concentration of pregnenolone was used. Our results suggest that the cAMP generation step is a target in o,p′-DDD-mediated disruption of ACTH-stimulated adrenal steroidogenesis in rainbow trout but that other downstream targets such as steroidogenic enzymes responsible for cortisol synthesis might also be affected.

Conscious Expectation and Unconscious Conditioning in Analgesic, Motor, and Hormonal Placebo/Nocebo Responses

The placebo and nocebo effect is believed to be mediated by both cognitive and conditioning mechanisms, although little is known about their role in different circumstances. In this study, we first analyzed the effects of opposing verbal suggestions on experimental ischemic arm pain in healthy volunteers and on motor performance in Parkinsonian patients and found that verbally induced expectations of analgesia/hyperalgesia and motor improvement/worsening antagonized completely the effects of a conditioning procedure. We also measured the effects of opposing verbal suggestions on hormonal secretion and found that verbally induced expectations of increase/decrease of growth hormone (GH) and cortisol did not have any effect on the secretion of these hormones. However, if a preconditioning was performed with sumatriptan, a 5-HT(1B/1D) agonist that stimulates GH and inhibits cortisol secretion, a significant increase of GH and decrease of cortisol plasma concentrations were found after placebo administration, although opposite verbal suggestions were given. These findings indicate that verbally induced expectations have no effect on hormonal secretion, whereas they affect pain and motor performance. This suggests that placebo responses are mediated by conditioning when unconscious physiological functions such as hormonal secretion are involved, whereas they are mediated by expectation when conscious physiological processes such as pain and motor performance come into play, even though a conditioning procedure is performed.

Influence of Mirtazapine on Salivary Cortisol in Depressed Patients

Unlike other antidepressants, mirtazapine does not inhibit the reuptake of norepinephrine or serotonin but acts as an antagonist at presynaptic α₂-receptors, at postsynaptic 5-HT2 and 5-HT3 receptors, and at histaminergic H1 receptors. Furthermore, mirtazapine has been shown to acutely inhibit cortisol secretion in healthy subjects. In the present study, the impact of mirtazapine treatment on salivary cortisol secretion was investigated in 12 patients (4 men, 8 women) suffering from major depression according to DSM-IV criteria. Patients were treated with mirtazapine for 3 weeks, receiving 15 mg mirtazapine on day 0, 30 mg on day 1 and 45 mg per day from day 2 up to the end of the study (day 21). Response to mirtazapine treatment was defined by a reduction of at least 50% in the Hamilton Rating Scale for Depression after 3 weeks of therapy. Salivary cortisol concentrations were measured before treatment (day –1), at the beginning of treatment (day 0), after 1 week (day 7) and after 3 weeks (day 21) of treatment with mirtazapine. Saliva samples were collected hourly from 08.00 until 20.00 h. The area under the curve values served as parameter for the salivary cortisol secretion. Following analysis of variance with a repeated measures design, tests with contrasts revealed a significant reduction of cortisol concentrations already after 1 day of mirtazapine treatment that was comparable in responders and nonresponders. In addition to new pharmacological approaches such as CRH1 receptor antagonists, mirtazapine therefore appears to be an effective strategy to decrease hypercortisolism and restore HPA system dysregulation in depression. However, the importance of the acute inhibitory effects of mirtazapine on cortisol secretion for its antidepressant efficacy has to be further clarified.

Cytotoxic and Endocrine-Disrupting Potential of Atrazine, Diazinon, Endosulfan, and Mancozeb in Adrenocortical Steroidogenic Cells of Rainbow Trout Exposed in Vitro

An in vitro bioassay for detection and quantitative assessment of chemicals with the capacity to disrupt adrenal steroidogenesis has been developed and used to compare the cytotoxic and endocrine-disrupting potential of four pesticides. Enzymatically dispersed adrenocortical cells of rainbow trout (Oncorhynchus mykiss) were exposed in vitro to atrazine, diazinon, endosulfan, and mancozeb, and cortisol secretion in response to ACTH or dibutyryl-cAMP (dbcAMP) and cell viability were determined. The effective concentration, EC50 (concentration that inhibits cortisol secretion by 50%), the median lethal concentration, LC50 (concentration that kills 50% of the cells), and the LC50/EC50 ratio were established for the test pesticides. The pesticides were ranked as follows: EC50, endosulfan < diazinon < mancozeb < atrazine; LC50, diazinon < endosulfan < mancozeb < atrazine, with diazinon as the most cytotoxic. Endosulfan and mancozeb disrupted sites downstream of the cAMP-generating step of the cortisol synthetic pathway while atrazine seemed to act upstream from the cAMP step. The in vitro adrenal bioassay can be used for screening of adrenotoxicants and for mechanistic studies of adrenotoxicity.

Active Immunization against Adrenocorticotropic Hormone in Growing-Finishing Barrows: An Initial Trial and Evaluation

Adrenal glucocorticoids, secreted by the stimulus of adrenocorticotropic hormone (ACTH), are catabolic hormones in the pig. The present study was conducted to find whether active immunization against ACTH would suppress cortisol secretion accompanied by an increased growth rate in growing-finishing barrows. ACTH was conjugated to keyhole limpet hemocyanin or human histone using glutaraldehyde or 3-maleimidobenzoic acid N-hydroxysuccinimide, under a 2 (ACTH vs no hapten)×2 (carrier)×2 (crosslinker) factorial arrangement of treatments. Cross-bred barrows weighing approximately 25 kg were injected with an ACTH- carrier or carrier only conjugate every 4th wk and slaughtered at approximately 110 kg body weight. Antibodies against ACTH were detected in serum, as determined by ( 125 I)ACTH-binding activity, in most animals immunized against the ACTH conjugate, but not in carrier only-injected animals, except for the animals which had received the hapten conjugated to histone via glutaraldehyde. The ( 125 I)ACTH-binding activity of serum increased after the second booster injection, but overall ACTH antibody titer was very low. Main effect was not detected not only for the carrier and crosslinker but for the hapten in serum cortisol concentration, ADG, loin muscle area, backfat thickness and longissimus muscle composition including fat and protein. In addition, bound ( 125 I)ACTH percentage had no relation to cortisol concentration or to any of the above growth-related variables. Results suggest that ACTH or its conjugates used in the present study were not immunogenically potent enough to affect the glucocorticoid secretion and thus the growth of the immunized pigs. (Asian-Aust. J. Anim. Sci. 2002. Vol 15, No. 3 : 410-415)

Inhibition of Cortisol Secretion in Dispersed Head Kidney Cells of Rainbow Trout (Oncorhynchus mykiss) by Endosulfan, an Organochlorine Pesticide

The effects of endosulfan, an organochlorine pesticide, on cortisol secretion in vitro were investigated in enzymatically dispersed head kidney cells of rainbow trout, Oncorhynchus mykiss. First, the conditions for maximal cortisol secretion were characterized by selecting the optimal concentrations of adrenocorticotropin (ACTH) (1 IU/ml) and N6, 2′-o-dibutyryladenosine 3′:5′-cyclic monophosphate (dbcAMP) (2 mM), incubation temperature (15°) and time period (60 min for ACTH, 120 min for dbcAMP), number of cells per incubation well (75 × 106/ml), and osmolarity of the medium (270 mosmol/L). Exposure of head kidney cells to endosulfan decreased ACTH- or dbcAMP-stimulated cortisol secretion and cell viability in a concentration-dependent pattern and the doses required to disrupt cortisol secretion were significantly lower than doses lethal to the head kidney cells. The median effective concentration of endosulfan (EC50, the dose that inhibits cortisol secretion by 50%) was 17.3 μM while the median lethal concentration (LC50, the dose that kills 50% of the cells) was 308 μM. Our study identified endosulfan as an environmental endocrine disrupting chemical that interferes with the normal secretory function of teleost interrenal steroidogenic cells. Multiple sites may be affected within the steroidogenic cells since dbcAMP could not restore cortisol secretion in endosulfan exposed cells.

A polymorphism of the 5′-flanking region of the glucocorticoid receptor gene locus is associated with basal cortisol secretion in men

There is growing evidence that cortisol secretion and/or metabolism is associated with cardiovascular risk factors. Previous studies have shown that cardiovascular risk factors are associated with stimulated cortisol secretion and not with basal cortisol secretion. With the restriction enzyme Tth111I, a variant of the 5′-flanking region of the glucocorticoid receptor gene locus (GRL) was identified. The genotypes were compared for measurements of cortisol secretion and cardiovascular risk factors in a cohort (N = 284) of randomly selected middle-aged men. The frequency of the 3.4/3.4-, 3.4/3.8-, and 3.8/3.8-kilobase (kb) genotypes was 49.6%, 41.4%, and 9.0% respectively. The 3.8-kb homozygotes showed higher total and evening cortisol levels with a trend for elevated levels over the day. Neither stimulated or suppressed cortisol secretion nor anthropometric, endocrine, metabolic, and hemodynamic cardiovascular risk factors were significantly different among the genotypes. Since the polymorphism studied herein is localized at the 5′-flanking region of the GRL, the results suggest that elevated basal cortisol secretion is associated with a polymorphism of the promoter region.

Role of Arachidonic Acid Metabolism in Acth-Stimulated Cortisol Secretion by Bovine Adrenocortical Cells

We have studied the effects of inhibitors of arachidonic acid (AA) metabolism, nordihydroguaiaretic acid (NDGA), a lipoxygenase (LPX) inhibitor, and indomethacin (INDO), a cyclooxygenase (COX) inhibitor, on cortisol secretion and StAR protein in primary cultures of bovine adrenal zona fasciculata (ZF) cells. NDGA inhibited cortisol secretion in response to both 10−12 M and 10−8 M ACTH. AA (10−4 M) partially reversed the inhibition of cortisol secretion by NDGA at 10−12 M ACTH but not at 10−8 M ACTH. On the other hand, INDO potentiated the cortisol response to 10−12 M ACTH. Neither NDGA nor INDO significantly affected StAR protein levels. These results suggest a StAR protein-independent role for the LPX and COX pathways in acute cortisol secretion, and support the hypothesis that LPX products of AA metabolism are key cellular signals when bovine ZF cells are acutely stimulated by physiological concentrations of ACTH (10−12 M).

Effects ofin VitroExposures to Cadmium, Mercury, Zinc, and 1-(2-Chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane on Steroidogenesis by Dispersed Interrenal Cells of Rainbow Trout (Oncorhynchus mykiss)

Numerous environmental xenobiotics can act as endocrine disrupters in wildlife species. Fish chronically exposed to pollutants exhibit a deficiency in the synthesis of cortisol, a glucocorticosteroid hormone secreted by interrenal steroidogenic cells in response to ACTH by a mechanism mediated by cAMP. The capacity of a series of heavy metals (CdCl2, ZnCl2, HgCl2, and CH3HgCl) and 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane (o,p′-DDD) to disrupt cortisol secretion was determined in dispersed interrenal cells of rainbow trout (Oncorhynchus mykiss) exposedin vitroto the toxicant, by measuring cortisol secretion stimulated with ACTH or dibutiryl-cAMP (dbcAMP) and by assessing cell viability. The effect of cadmium in presence of zinc on the interrenal cells was also determined. The median lethal concentration (LC50, dose that kills 50% of the cells), median effective concentration (EC50, dose that inhibits cortisol secretion by 50%), and LC50/EC50 ratio were determined for each chemical to compare its endocrine toxicity and to test the specificity of the toxicants to act as endocrine disrupters. HgCl2had the lowest EC50 and LC50; it was the most toxic of the chemicals tested. The LC50/EC50 ratio was the highest for ZnCl2and CdCl2, indicating that these toxicants had the most specific endocrine toxicity. The mechanism of toxicity of heavy metals on cortisol-secreting cells involves a site situated downstream from the step generating cAMP, while o,p′-DDD seemed to impair a step located between adenyl cyclase activation and the ACTH binding. No evidence for a protector effect of zinc against cadmium toxicity was found.

Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.

Endocrine and metabolic aberrations in men with abdominal obesity in relation to anxio-depressive infirmity.

Abdominal obesity, anxiety, and depression have been found to cluster in several studies. To further characterize these associations, the following study was performed. In a population of 51-year-old men (N = 284), measurements of obesity (body mass index [BMI]) and body fat distribution (waist to hip ratio [WHR] and sagittal trunk recumbent diameter [D]) were analyzed in relation to dexamethasone (0.5 mg) inhibition of cortisol secretion, measured as salivary cortisol. Symptoms of anxiety and depression were defined by a validated questionnaire. Furthermore, testosterone, insulin-like growth factor-I (IGF-I), insulin, glucose, and serum lipid levels were measured. Twenty-five men (8.8%) had symptoms of anxiety and depression. BMI, WHR, and D correlated negatively with testosterone, except for BMI in the anxio-depressive (ADP) group. IGF-I showed no significant relationship. Furthermore, fasting insulin and the insulin to glucose ratio correlated positively and high-density lipoprotein (HDL) cholesterol correlated negatively with BMI, WHR, and D in the total study population and in the subgroups. Total and low-density lipoprotein (LDL) cholesterol showed no significant relationships. Correlation coefficients tended to be higher in ADP men. Dexamethasone inhibition showed a negative significant relationship with BMI (rho = -.47, P = .025), WHR (borderline, rho = -.37, P = .086), and D (rho = -.43, P = .046) only in the ADP group. Comparing the ADP group versus the group without anxio-depression (ADO) and high or low BMI (P = .008), WHR (P = .026), and D (P = .012) showed blunted dexamethasone inhibition only in ADP men with high anthropometric measurements. These findings suggest there is a subgroup with elevated BMI, WHR, and D in whom a blunted dexamethasone response is found associated with traits of anxiety and depression, conditions characterized by such an abnormality. The reason for the association might be insufficient control of cortisol secretion, followed by visceral fat accumulation.

Age-dependent decline in cortisol levels and clinical manifestations in patients with ACTH-independent Cushing's syndrome.

Adrenocortical cells change with age in both subcellular morphology and level of steroidogenesis. This study evaluates the influence of aging on hypercortisolism and clinical manifestations in patients with ACTH-independent Cushing's syndrome due to a cortisol-secreting adrenal adenoma (CS). Restrospective study. Thirty-six (33 females and 3 males) with CS. 31 healthy controls were age- and sex-matched to CS patients. Patient age at diagnosis was compared to the degree of hypercortisolism and clinical manifestations. The degree of hypercortisolism was estimated using serum cortisol levels and urinary free cortisol excretion. Positive clinical manifestations were quantified using 12 symptoms and signs which resulted in a clinical score for each patient. Endogenous creatinine clearance, estimated disease duration and gender were analysed as possible factors affecting adenoma-secreated cortisol. Patient age correlated negatively with serum cortisol level (r = -0.417, P = 0.0107, n = 36) and urinary excretion of free cortisol (r = -0.613, P = 0.0002, n = 31). Analysis of Spearman's rank correlation showed that the clinical score decreased with age (rho = -0.631, P = 0.0004, n = 33). Oedema, weakness/myopathy, hirsutism, striae and psychological changes were infrequent symptoms in the elderly. Using stepwise multiple regression analysis, we estimated the clinical score (Y) by factors of serum cortisol levels (X1:nmol/l), age (X2: years of age) and gender (X3: gender; female = 1, male = 0), i.e. Y = 4.771 + 0.004 X1 - 0.064 X2 + 2.548 X3 (r = 0.743, P < 0.0001, n = 33). Results suggested that aging both suppressed cortisol secretion and repressed manifestations directly as an independent factor, although its direct effect may be weak. Our findings indicated the importance of age as a factor modulating hormonal levels and possible clinical manifestations in patients with cortisol-secreting adenomas.

Corticotropin-independent macronodular adrenal hyperplasia: a clinicopathologic correlation.

To investigate the clinical presentation, laboratory findings, and pathologic characteristics of patients with corticotropin (ACTH)-independent macronodular adrenal hyperplasia. Retrospective review. Academic medical center. All patients with bilateral adrenocortical nodules associated with ACTH-independent hypercortisolism without clinicopathologic features of primary pigmented nodular adrenocortical disease with atrophic internodular adrenal cortex. Compare and contrast our findings with those previously reported; assess response to adrenalectomy. Nine patients met the criteria for corticotropin-independent macronodular adrenal hyperplasia. All patients had biochemical evidence of Cushing syndrome, although repetitive testing was frequently required. As a result, the diagnosis was delayed from 1 to 20 years. In all patients, both the low- and high-dose dexamethasone suppression tests failed to suppress cortisol secretion. No patient had elevated ACTH levels, and following curative bilateral adrenalectomy, no patient subsequently developed Nelson syndrome, with follow-up ranging from 1 to 8.5 years. Unique histologic features were identified in all cases. Amalgamating this series with other clinical reports plus basic research information, corticotropin-independent macronodular adrenal hyperplasia must be considered a separate and legitimate cause of Cushing syndrome.

Comparative Effect of Night and Daytime Sleep on the 24-Hour Cortisol Secretory Profile

To determine whether cortisol secretion interacts with daytime sleep in a similar manner to that reported for night sleep, 14 healthy young men were studied during two 24-hour cycles. During one cycle they slept during the night, during the other the sleep period was delayed by 8 hours. Secretory rates were calculated by a deconvolution procedure from plasma cortisol, measured at 10-minute intervals. The amount of cortisol secreted during night sleep was lower than during the corresponding period of sleep deprivation (12.7 +/- 1.1 vs. 16.3 +/- 1.6 mg; p < 0.05), but daytime sleep beginning at the habitual time of morning awakening failed to inhibit cortisol secretion significantly. There was no difference between the amount of cortisol secreted from 0700 to 1500 hours in sleeping subjects and in subjects who were awake during the same period of time (24.2 +/- 1.5 vs. 22.5 +/- 1.4 mg). Even if the comparison between sleeping and waking subjects was restricted to the period 0700-1100 hours or 0700-0900 hours, no significant difference was found. Neither secretory pulse amplitude nor frequency differed significantly in either period. However, detailed analysis of the secretory rates in day sleepers demonstrated a transient decrease in cortisol secretion at about the time of sleep onset, which began 10 minutes before and lasted 20 minutes after falling asleep. Spontaneous or provoked awakenings had a determining influence on the secretory profiles. Ten to 20 minutes after awakening from either night or day sleep cortisol secretion increased significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine A increases serum cortisol levels in rabbits.

P-glycoprotein (P-gp), a membrane protein that was originally found to be involved in the efflux of cytotoxic drugs out of the tumor cells, is also present in a variety of normal human and animal tissues, such as the adrenal cortex. The function of P-gp in the adrenal cortex has not been defined yet. The aim of our study was to determine whether the blockade of P-gp by cyclosporine A (CsA) dissolved in Cremophor EL (Crem) inhibits cortisol secretion in rabbits. In 14 rabbits, the baseline and ACTH stimulated serum cortisol levels were measured before and after CsA treatment. Seven rabbits were treated with 2 x 30 mg/kg CsA and seven with 2 x 90 mg/kg CsA injected s.c. Serum cortisol levels were determined by radioimmunoassay adjusted for expected values. The whole blood CsA levels were determined by a commercially available fluorescence polarization immunoassay. Serum cortisol levels, both baseline and ACTH stimulated, significantly increased after both low and high dose CsA treatment. The increase was dose dependent. The mean baseline cortisol levels increased from 5.7 (SD = 6.3) to 15.0 nmol/l (SD = 7.2) in the low dose group and from 7.7 (SD = 4.9) to 44.9 nmol/l (SD = 13.8) in the high dose group. The mean cortisol levels 8 h after ACTH stimulation increased from 53.3 (SD = 34.5) to 106.0 nmol/l (SD = 33.0) in the low dose group and from 47.7 (SD = 12.2) to 153.0 nmol/l (SD = 55.1) in the high dose group.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of neuroleptic treatment on cortisol and 3-methoxy-4-hydroxyphenylethyl glycol levels in blood.

Plasma cortisol and serum 3-methoxy-4-hydroxyphenylethyl glycol (MHPG) were determined before and after 5-6 weeks of neuroleptic treatment in patients with schizophrenia. Following drug treatment both plasma cortisol and serum MHPG levels in patients decreased and plasma cortisol levels were also lower than in unmedicated healthy controls. Indications of a relationship between the reduction of cortisol and MHPG levels were found. The data show that neuroleptic drug treatment inhibits cortisol secretion. It is speculated that this inhibition could be related to reduced noradrenergic activity.

Effects of diurnal sleep on secretion of cortisol, luteinizing hormone, and growth hormone in man.

Evidence has been provided for an influence of nocturnal sleep on the secretion of cortisol, LH, and GH in man. Although nocturnal sleep inhibits cortisol secretion during the first hours, it augments the secretion of LH and GH. To separate the effects of circadian rhythm from those of sleep, the present experiments examined the influence of diurnal sleep on the release of cortisol, LH, and GH in 12 young men. Subjects slept on 2 different occasions. After a night of wakefulness, subjects were assigned to bed at 0800 h the following morning. Lights were turned off either at 1100 or 1500 h to enable sleep. Effects of diurnal sleep were evaluated by comparing blood hormone concentrations during the interval from 1100-1500 h between subjects when sleeping and awake. Comparing hormonal concentrations during the 4 h of sleep after 1100 h with those during the 4-h sleep interval after 1500 h provided evidence for an influence of circadian rhythm on cortisol and LH release. Diurnal sleep, as has been shown for nocturnal sleep, augmented the secretion of LH and GH. However, in contrast to nocturnal sleep, diurnal sleep failed to suppress cortisol release, suggesting that sleep does not inhibit cortisol release at any point of its circadian rhythm, but only within a limited range of entrainment.