Postdexamethasone Cortisol Research Articles

HPA-axis hyperactivity and mortality in psychotic depressive disorder: Preliminary findings

The excess mortality associated with depressive disorders has been most often attributed to risks for suicide but diverse findings indicate that depressive disorders also increase risks for cardiovascular (CV) mortality. Among the possible mediators is the hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity that characterizes many cases of relatively severe depressive disorder and severity is characteristic of psychotic depressive disorder. The following describes a 17-year mortality follow-up of 54 patients with Research Diagnostic Criteria (RDC) psychotic major depression or schizoaffective, mainly affective, depression. All had baseline assessments that included a 1mg dexamethasone suppression test with post-dexamethasone samples at 8 a.m., 4 p.m. and 11 p.m. Regression analyses showed that both greater age and higher maximum post-dexamethasone cortisol concentrations predicted deaths due to CV causes (t=4.01, p<0.001 and t=3.03, p=0.004, respectively). The 4 who died from CV disease had a mean (SD) post-dexamethasone cortisol concentration of 18.0 (6.0)microg/dl while the mean (SD) value for the remaining 50 patients was 7.6 (6.6)microg/dl (t=3.03, df=53, p=0.004). Regression analyses showed the 11 p.m. post-dexamethasone value to be predictive of suicide (t=2.05, p=0.048). Conclusions should be tentative because an earlier follow-up of a more heterogeneous, but larger, sample did not find a relationship between DST results and CV mortality, and because only 4 CV deaths occurred in the present study. HPA-axis hyperactivity is probably only one of a number of factors that link depressive disorder to CV mortality.

Vasopressin–neurophysin and DST in major depression: Relationship with suicidal behavior

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters ( n = 13) and nonattempters ( n = 15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29 ± 0.13 ng/ml vs 0.36 ± 0.21 ng/ml, ( F = 1.1, df = 1, 27, p = 0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape.

Empty sella syndrome, hyperadrenocorticism and megaoesophagus in a dachshund

A five-year-old, entire, male dachshund was presented with a five day history of hypersalivation and regurgitation as well as polyuria and polydipsia for several months. Chest radiographs demonstrated megaoesophagus and aspiration pneumonia. Furthermore, hyperadrenocorticism was demonstrated by means of elevations in levels of serum alkaline phosphatase and cholesterol, decreased urinary specific gravity, increased response to adrenocorticotropic hormone stimulation, insufficient suppression of the post-dexamethasone plasma cortisol levels, an increased endogenous adrenocorticotropic hormone concentration and bilaterally enlarged adrenal glands on abdominal ultrasound. The dog became severely dyspnoeic and was euthanased after magnetic resonance imaging was performed. The magnetic resonance imaging and necropsy revealed the sellar region mainly filled with fluid, with only small tissue remnants, a condition defined as empty sella syndrome in human medicine. To the author's knowledge, this is the first dog described with empty sella syndrome and only the second dog described with hyperadrenocorticism secondary to ectopic adrenocorticotropic hormone production. However, the association between empty sella syndrome and hyperadrenocorticism may be no more than incidental.

Gastrointestinal symptoms are associated with hypothalamic-pituitary-adrenal axis suppression in healthy individuals

Objective. The brain-gut axis has been proposed to influence symptoms in irritable bowel syndrome (IBS). In animal studies corticotropin-releasing hormone (CRH) challenge has been associated with decreased upper gastrointestinal motility and increased colonic motility. The purpose of this study was to investigate the association between gastrointestinal symptoms and the effect of CRH on the hypothalamic-pituitary-adrenal (HPA) axis using a weight-adjusted low-dose dexamethasone test in a group of healthy individuals (n=157). Material and methods. Pre- and post-dexamethasone morning serum cortisol was analysed. All participants completed questionnaires regarding symptoms of IBS (GSRS-IBS (Gastrointestinal Symptom Rating Scale-IBS) and symptoms of anxiety and depression (HADS (Hospital Anxiety and Depression Scale)). After exclusions, 124 subjects were available for analysis (F/M: 60/64, mean age 55.8 years, SD 15.4, range 21–80 years). Results. A positive correlation was found between the GSRS-IBS score and HADS score (rs=0.36; p<0.001). There was no linear correlation between either pre- (rs=0.145; p=0.11) or post-dexamethasone cortisol levels (rs=0.087; p=0.337) and GSRS-IBS scores. By subgrouping the subjects at the lower and higher 25th percentiles of their post-dexamethasone morning cortisol levels, we found a trend towards a higher GSRS-IBS score (median 7.0 versus 5.0; p=0.069) (multivariate adjusted OR 2.6; CI 0.80–8.3) and a significantly higher diarrhoea score (median 2 versus 0; p=0.021) (multivariate adjusted OR 5.7; CI 1.5–22), and a higher early satiety score (p=0.008) (multivariate adjusted OR 6.7; CI: 1.9–23) in the subjects with high post-dexamethasone cortisol levels (low HPA suppression) compared with the subjects with intermediate post-dexamethasone cortisol levels. Furthermore, individuals with low post-dexamethasone cortisol levels (high HPA suppression) showed a significant, higher score for diarrhoea (median 2.0 versus 0; p=0.010) (multivariate adjusted OR 6.1; CI 1.8–20) and early satiety (p=0.076) (multivariate adjusted OR 3.2; CI 1.0–10) compared with those with intermediate cortisol levels. Conclusions. A trend toward a non-linear relationship between IBS-like symptoms and post-dexamethasone cortisol levels was observed in healthy individuals, with significantly more symptoms of diarrhoea and early satiety in individuals with high or low post-dexamethasone cortisol levels in comparison with those with intermediate post-dexamethasone cortisol levels.

Hormonal differences between psychotic and non-psychotic melancholic depression

BackgroundThe dexamethasone suppression test (DST) is the main hormonal disturbance in psychotic depression compared to non-psychotic depression. However, although there have been many studies of individual hormonal axes in depression, few multi-axial studies have been reported. This study aims to examine hormonal differences between these groups of patients through three functional hormonal tests: DST, thyroid stimulating hormone response to thyroid releasing hormone (TSH–TRF) and growth hormone response to growth hormone releasing factor (GH–GRF). MethodsForty inpatients meeting DSM-III-R criteria for major depressive episode with melancholia (21 non-psychotic and 19 psychotic) were studied. Dexamethasone suppression test, TSH–TRF and GH–GRF tests were undertaken for all patients. ResultsIn the whole melancholic sample, 80.0% showed disturbances in at least one hormonal axis, 40.0% in two axes and 5.0% in all three axes. Basal and post-dexamethasone cortisol levels were significantly higher in psychotic than in non-psychotic patients. An association between post-dexamethasone cortisol and blunted GH–GRF response was demonstrated in those with psychotic depression. In the whole sample, GH blunting was found in 62.5% of patients, DST non-suppression in 37.5% and TSH blunting in 25.0% (no differences were found between psychotic and non-psychotic patients). LimitationsSample was restricted to melancholia and unknown factors may influence hormonal responses to stress. ConclusionsHormonal disturbances in depression are more evident when studying several axes, being the HPA and the GH axes the most prominents. Psychotic depression showed more HPA disturbance than non-psychotic depression. Influence of the HPA on the GH axis is discussed.

Cognitive Effects of Intravenous Hydrocortisone in Subjects with PTSD and Healthy Control Subjects

On the basis of peripheral (nonbrain) neuroendocrine findings in subjects with posttraumatic stress disorder (PTSD), it has been hypothesized that these individuals also have a greater central (brain) sensitivity to glucocorticoids. In nonpsychiatric subjects, it has been found that working and declarative memory performance is selectively impaired by acute glucocorticoid administration. We hypothesized that subjects with PTSD, as compared to nonpsychiatric controls, would show greater impairments in verbal declarative memory and working memory, but not attention, following exogenous glucocorticoid administration. These data are part of a larger study using functional neuroimaging and peripheral HPA axis measures in these same subjects. Subjects underwent a 0.5-mg dexamethasone suppression test and measurement of basal cortisol, basal plasma lymphocyte glucocorticoid receptor number, and postdexamethasone cortisol on a separate day. Under double-blind randomized crossover conditions, 17-mg hydrocortisone or placebo was administered by intravenous (i.v.) bolus to 15 medication-free PTSD subjects (4 female) and 12 nonpsychiatric control subjects (4 female) matched by age, sex, and education level. Participants then underwent positron emission tomography (PET) scanning and 90 min after the initial drug/placebo administration, cognitive testing was then performed. By repeated measures ANCOVA (covaried for baseline performance on that neuropsychological test), neither attention tasks of digit span forward nor backward showed significant change. However, there were significant drug (F = 17.644, df = 1,25 P < 0.001), group (F = 4.383, df = 1,25 P = 0.048), and drug by group interactions (F = 4.756, df = 1,25 P = 0.040) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The subject group with PTSD experienced a greater decline in verbal declarative memory performance following hydrocortisone administration. For working memory, there were significant group (F = 6.048, df = 1,25 P = 0.022) and drug by group interactions (F = 6.048, df = 1,25 P = 0.022) for verbal declarative memory. By t-test, there was not a difference in baseline performance on this measure between subject groups. The hydrocortisone administration led to impairment in working memory in the group of subjects with PTSD, but not in the control subject group. Exploratory correlations between percent cortisol suppression following dexamethasone and baseline plasma lymphocyte glucocorticoid receptor number with declarative and working memory measures among subject groups separately and in a combined way revealed a negative correlation between lymphocyte glucocorticoid receptor density and working memory (r = -0.54, df = 25, P = 0.008). Brain sensitivity to glucocorticoids appears to be greater in subjects with PTSD. Heightened vulnerability of declarative memory in subjects with PTSD may indicate hippocampal involvement, whereas working memory vulnerability suggests additional brain regions (prefrontal, cingulate, temporal, and parietal cortices) and neurotransmitter systems (dopamine and serotonin) particularly sensitive to glucocorticoids in persons with PTSD.

Endogenous subclinical hypercortisolism: Diagnostic uncertainties and clinical implications

Subclinical hypercortisolism (SH) is a newly characterized hormonal disorder that is almost exclusively detected in the context of incidentally discovered adrenal masses. The diagnostic criteria used for the definition of this condition are at present controversial. Amongst the various tests used for the detection of this abnormality (dexamethasone suppression, urinary free cortisol, ACTH levels, midnight serum or salivary cortisol concentrations, ACTH responses to CRH stimulation), the dexamethasone suppression tests (DST) seem to better accomplish the task of unmasking subtle abnormalities of cortisol secretion. Several versions of DST have been used: the 1-mg overnight, the 3-mg overnight and the classical 2-day low-dose DST. This latter test has the theoretical advantage that, by more efficiently suppressing pituitary ACTH secretion, it may provide a measure of the residual (ie non- ACTH-dependent) cortisol secretion from the adrenal mass. In this way, post-dexamethasone cortisol concentrations may quantify the degree of autonomous cortisol hypersecretion. In fact, post-dexamethasone cortisol concentrations have a negative correlation with basal ACTH levels and a positive correlation with midnight cortisol concentrations as well as the size of the incidentally discovered adrenal mass. Most of the existing data indicate that SH detected in the context of adrenal incidentalomas may have some clinically significant implications. In fact, patients with higher post-dexamethasone cortisol concentrations demonstrate higher lipid levels and lower bone mass densities. It has also been suggested that SH may be responsible for biochemical and phenotypic changes reminiscent of the metabolic syndrome. In summary, SH does exist and is associated with a negative impact in patients' health; however, hormonal cut-off criteria for decision-making remain to be defined.

Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function

Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function. Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined. Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients' post-dexamethasone cortisol correlated with WM commission errors (r(s) = 0.64, p = 0.0006). No such relationship was evident in controls. Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function.

Cognitive Dysfunction, Hippocampal Atrophy and Glucocorticoid Feedback in Alzheimer’s Disease

The hippocampal formation is damaged early in Alzheimer's disease (AD). An association between temporal lobe volume and cognitive function has been shown in several studies. Increased limbic-hypothalamic-pituitary-adrenal (LHPA) axis function has been suggested to be related to hippocampal atrophy and cognitive impairment. Our hypothesis was that there is a clear link between hippocampal volume -- notably of the CA1 region -- memory (episodic and visuospatial) and decreased feedback sensitivity in the LHPA axis in AD. Sixteen medication-free outpatients with mild to moderate AD were included. Hippocampal volume was measured with magnetic resonance imaging. Dexamethasone suppression tests were performed using .5 mg and .25 mg dexamethasone. Three different components in the neuropsychological battery -- Rey 15 item memory test, Alzheimer's Disease Assessment Scale (ADAS) word recall and spatial span from Wechsler Adult Intelligence Scale - Revised neuropsychological instrument (WAIS-R NI) -- were found to represent episodic and visuospatial memory. Low hippocampal CA1 volume and high post-dexamethasone cortisol levels in combination were significantly associated with Rey 15 item memory and spatial span test outcomes. No association was found between LHPA feedback and hippocampal volume. Low hippocampal volume and a disturbed negative feedback in the LHPA axis link to specific cognitive impairments in Alzheimer's disease.

Relationship of non‐alcoholic hepatic steatosis to cortisol secretion in diet‐controlled Type 2 diabetic patients

To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 +/- 4 vs. 102 +/- 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 +/- 2 vs. 14.4 +/- 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist-hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations (P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals.

Defining the boundaries of atypical depression: Evidence from the HPA axis supports course of illness distinctions

Background Treatment outcome and brain laterality differ between early onset (<20 years) chronically (no well-being >2 months) depressed patients with atypical features (early/chronic atypical) and those with either later onset or less chronic illness (late/nonchronic atypical). Because hypothalamic–pituitary–adrenal (HPA) axis abnormalities have been hypothesized to distinguish atypical depression from melancholia, we examined whether HPA measures would also differentiate these two groups of depressed patients with atypical features. Methods Three-hour afternoon cortisol levels, stimulation of cortisol by afternoon dextroamphetamine, and suppression of cortisol by dexamethasone were investigated in 85 depressed patients with atypical features. The latter group was divided into early/chronic atypical and late/nonchronic atypical based on chart review of course of illness. Results Patients with early/chronic atypical had significantly lower mean 3 h afternoon cortisol levels ( N=21) and 4:00 p.m. post-dexamethasone cortisol levels ( N=20) than did those with late/nonchronic atypical ( N=43 with afternoon cortisol; N=26 with post-dexamethasone cortisol). Post-dextroamphetamine cortisol levels were numerically higher in the early/chronic atypical group ( N=15 vs. 19), but this failed to reach conventional significance (0.05< p<0.1). Arbitrary categorical distinctions of normal and abnormal did not separate these groups on any of the tests. Limitations Lack of demonstrated reliability of the chart review and retrospective determination of atypical features and course of illness limit the generalizability of these findings. Conclusions These HPA data are consistent with earlier treatment and brain laterality findings that course of illness distinguishes biologically distinct groups within depressed patients with atypical features. The DSM should consider adding course of illness requirements to its criteria for atypical features.

PTSD symptoms predict waking salivary cortisol levels in police officers

This study examines whether pre- or post-dexamethasone salivary cortisol is related to cumulative critical incident exposure, peritraumatic responses, or post-traumatic stress disorder (PTSD) symptom severity. Thirty active duty police officers completed the study protocol, which included measures of peritraumatic emotional distress, peritraumatic dissociation, duty-related trauma exposure, and PTSD symptoms. Salivary cortisol was consolidated into three outcome variables: (1) pre-dexamethasone free cortisol levels at 1, 30, 45, and 60 min after awakening, (2) post-dexamethasone cortisol levels at the identical wake times, and (3) percentage of cortisol suppression. Control variables included age, gender, average daily alcohol use, night shift work, routine work environment stressors, and salivary dexamethasone levels. Zero order correlations showed that greater levels of PTSD symptoms, peritraumatic distress, and peritraumatic dissociation were associated with lower levels of pre-dexamethasone cortisol levels on awakening, but were not associated with the other two cortisol variables. A trend was also noted for older subjects to have lower pre-dexamethasone cortisol on awakening. When these four predictors were entered simultaneously in a regression analysis, only age and PTSD symptom severity significantly predicted pre-dexamethasone awakening cortisol levels. These results replicate previous research indicating a relationship between greater PTSD symptoms and lower levels of basal cortisol on awakening, and extend this finding to a previously unstudied non-treatment seeking population, urban police.

Glucocorticoid sensitivity is determined by a specific glucocorticoid receptor haplotype.

Differences in glucocorticoid (GC) sensitivity may underlie both common diseases (e.g. hypertension) and variability in response to treatment with GCs (e.g. asthma). We tested the potential involvement of the GC receptor (GR) gene in mediating GC sensitivity using haplotype analysis and a low-dose dexamethasone suppression test. Linkage disequilibrium across the GR gene was determined in 216 U.K. Caucasians, and 116 had a 0.25-mg overnight dexamethasone suppression test. Very strong linkage disequilibrium was observed across the GR gene with only four haplotypes accounting for 95% of those observed. Haplotype pattern mining and linear regression analyses independently identified a three-marker haplotype, across intron B, to be significantly associated with low postdexamethasone cortisol (P = 0.03). Carriage of this haplotype occurred in 41% of the individuals with low postdexamethasone cortisol vs. 23% in the combined other quartiles (odds ratio 2.4, 95% confidence interval 0.9-6.3, P = 0.05). This is the first comprehensive, haplotype based analysis of the GR gene. A three-point haplotype, within intron B, is associated with enhanced sensitivity to GCs. This haplotype may help predetermine variation in clinical response to GC therapy and also assist the understanding of diseases related to GC production.

The dexamethasone suppression test and DSM-III-R diagnoses in suicide attempters

Previous research on hypothalamic-pituitary adrenal (HPA) axis-activity in suicide attempter research has shown conflicting outcomes. The design of the present study was to test the influence of personality disorders and concominant axis I diagnoses on the dexamethasone suppression diagnostic test by use of multiple regression analyses. The sample consisted of 184 patients with a recent suicide attempt and 42 healthy controls. As expected, the lowest pre- and postdexamethasone cortisol levels were found in patients with personality disorders axis II, cluster B as compared to the other patients. The results remained significant when analysed for covariance with DSM-III-R axis I diagnoses, age or sex. Whether these low cortisol levels are due to previous experience of extreme stressful events or long-lasting burden, or whether they may be a consequence of biogenetic or psychological predisposal of interest, remains to be elucidated. Axis I comorbidity needs to be further examined.

Relationship between dexamethasone-inhibited lysozyme activity in peripheral mononuclear leukocytes and the cortisol and glucocorticoid receptor response to dexamethasone

The assessment of lysozyme activity in mononuclear leukocytes (MNLs) following the in vitro administration of dexamethasone (DEX) provides a measure of peripheral glucocorticoid sensitivity. The goal of the present study was to determine the relationship between the IC 50 of lysozyme activity following such challenge, and the cortisol response to oral administration of 0.50 mg DEX in 18 healthy subjects. The results demonstrated a robust association between the IC 50 and both cortisol decline and percent suppression of cortisol in response to low-dose DEX. However, this measure was uncorrelated with pre or post DEX cortisol levels or GR number. The high correlation between the inhibitory effect of DEX on lysozyme synthesis and two measures reflecting cortisol suppression in response to oral DEX reflects the similarities of GC responsiveness in both in vivo and in vitro models, and suggests that the in vitro assessment of lysozyme activity in MNLs may be useful in the study of neuropsychiatric or other clinical disorder.

Cortisol levels are positively correlated with hippocampal N-acetylaspartate

Background This study examined the relationship of hypothalamic–pituitary–adrenal measures and hippocampal N-acetylaspartate (NAA) in posttraumatic stress disorder (PTSD) patients and control subjects. Methods Eleven patients with combat-related PTSD and 11 control subjects were evaluated with magnetic resonance spectroscopy as well as by morning salivary cortisol samples before and after administration of low-dose dexamethasone (.5 mg). Results Left hippocampal NAA was strongly associated with both pre-dexamethasone cortisol levels ( n = 22, r = .53, p = .013) and post-dexamethasone cortisol levels ( n = 22, r = .63, p = .002). After accounting for clinical symptom severity and hippocampal volume, cortisol levels accounted for 21.9% of the variance ( F = 5.6, p = .004) in left hippocampal NAA and 12.6% of the variance ( F = 3.2, p = .035) in right hippocampal NAA. Conclusions This study shows a positive relationship between cortisol levels and hippocampal NAA in subjects without hypercortisolemia. Within the range of values seen in our subjects, cortisol may have a trophic effect on the hippocampus.

The combined dexamethasone-CRH test before and after repetitive transcranial magnetic stimulation (rTMS) in major depression

Background: Hypothalamic-pituitary-adrenocortical (HPA) dysregulation assessed by the combined dexamethasone corticotropin releasing hormone test (DEX/CRH test) has been demonstrated to normalize after successful antidepressant pharmacotherapy. Here, we investigated whether repetitive transcranial magnetic stimulation (rTMS) also leads to a normalization of HPA system activity in depressed patients. Methods: Thirty-seven medication free patients suffering from a major depressive episode (DSM-IV) underwent a DEX/CRH test before and after 13 daily sessions of left prefrontal rTMS in an open trial. Results: There was an overshoot of CRH-induced cortisol release that was not affected by rTMS treatment. Postdexamethasone cortisol levels prior to CRH challenge decreased in responders after rTMS treatment, whereas no change of CRH-induced adrenocorticotropic hormone (ACTH) and cortisol release in responders or nonresponders was observed. Conclusions: The persisting HPA system hyperactivity after rTMS suggests a high risk for relapse and therefore argues for an immediate maintenance therapy in patients responding to this treatment.

Cortisol and ACTH Response to Oral Dexamethasone in Obesity and Effects of Sex, Body Fat Distribution, and Dexamethasone Concentrations: A Dose-Response Study

There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) < or = 25 kg/m(2)] and overweight or obese (BMI > 25 kg/m(2)) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear dose- response pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone concentrations were dose related (P < 0.001 for trend analysis) in all subjects, but the dose-related increase was significantly higher in normal-weight men than normal-weight women, whereas it was similar in obese subjects of both sexes. Stepwise multiple regression analysis revealed that both percent cortisol and percent ACTH variations were significantly and negatively influenced by dexamethasone levels, as well as by waist circumference values in men, and independently by BMI and waist circumference in women. However, in contrast to what has been found in men, a divergent contribution of BMI and waist circumference was found in women indicating that, with increasing waist values, a smaller suppression of the HPA axis was found with respect to that expected on the basis of BMI values. In conclusion, this study provides data of both physiological and physiopathological relevance. Overall, our data indicated that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in obese individuals, particularly when near-maximal doses are administered. However, this study demonstrated a highly significant effect of dexamethasone blood level concentrations on cortisol and ACTH suppression to low-dose dexamethasone tests. In addition, a significant effect of gender on postdexamethasone cortisol concentrations, suppression of the HPA axis, and dexamethasone levels were found, which may be dependent on related differences in both cortisol and dexamethasone metabolism. We showed that pituitary sensitivity to feedback inhibition by dexamethasone is preserved in obesity in both sexes even at low dosages. On the other hand, our data suggest that, at least in women, abdominal fat distribution may partially counteract the progressively greater suppressibility of the HPA axis that would be expected according to increasing BMI.

The natural history of incidentally discovered adrenocortical adenomas: a retrospective evaluation.

Adrenal adenoma is the most frequent lesion among adrenal incidentalomas. The present retrospective study was undertaken to investigate medium-term evolution of supposed or ascertained adrenocortical adenomas in a group of 53 subjects (16 males and 37 females, aged 31-83 yr), with bilateral (no.=8) or monolateral (no.=45) incidentally discovered adrenal masses (size 10-50 mm, median 25 mm), who were followed-up for 6-78 months (median 24 months). Diagnosis of adenoma was based on size and morphovolumetric aspect of the lesion at computed tomography (CT), scintigraphic pattern using NP59 as a tracer, and it was histologically confirmed in 7 patients. After an extensive hormonal investigation including morning (no.=53) and midnight (no.=28) serum cortisol, plasma ACTH (no.=50), serum DHEAS (no.=51), daily urinary free cortisol excretion (no.=52), post-dexamethasone (1 mg) cortisol (no.=42) and ACTH stimulation test for 17-hydroxyprogesterone (17-OHP) response (no.=48) at the time of diagnosis, patients were periodically re-evaluated for hormonal function and radiological aspect of the lesion(s) by CT. Seven patients underwent surgery 6-42 months after incidentaloma demonstration, with histological diagnosis of adrenal adenoma. During follow-up an increase in the size of the lesion was demonstrated in 22 patients (41.5%); the increase was greater than 10 mm in 8 cases. In 3 patients with unilateral mass, a contralateral lesion appeared 10-52 months after first demonstration. Six patients (11.3%) showed reduction or disappearance of the lesions. On the basis of the hormonal evaluation 3 patients were considered to have subclinical Cushing's syndrome and 10 patients exhibited 17-OHP hyperresponse to ACTH test consistent with partial 21 -hydroxylase deficiency. A significant difference in the size of the lesions was observed between patients with or without 17-OHP hyperresponse to ACTH test (31.1 1.9 vs 24.1 +/- 1.2 mm; p<0.01). No significant changes in the hormonal parameters were observed in the patients, when retested. In conclusion, although none of the patients of the present series exhibited evolution to hypersecretion or to aberrant growth, in more than 40% of patients an increase in the size of the mass was observed, even after a long period of "quiescence". This suggests that a radiological re-evaluation of lesions should be periodically undertaken.

Dexamethasone suppression test and suicide attempts in schizophrenic patients

The suicide attempts were assessed in 32 schizophrenic patients on whom the dexamethasone suppression test (DST) was done twice in the course of illness: in the years 1985–91 and 1996–97. In the 1985–91 period, both baseline and post-dexamethasone cortisol levels were significantly higher in the patients with previous suicide attempts and baseline cortisol was higher in the patients who were to make a future attempt. In 1996–97, DST non-suppression was shown in more than half of the patients with a history of suicide attempt and in none of those without such history: all cortisol levels were significantly higher in the patients with a history of suicide attempt. Although the mean intensity of depression was higher in the patients with a history of suicide attempt, no association between the intensity of depression and present or previous DST non-suppression status was found. It is suggested that the hyperactivity of the hypothalamic-pituitary-adrenal axis may constitute an element of diathesis for suicidal behavior in schizophrenic patients.