Urinary free cortisol levels and dexamethasone suppression testing in organic affective disorder associated with hyperthyroidism

Eleven of 32 newly diagnosed untreated patients with hyperthyroidism met DSM-III criteria for organic affective syndrome. Thirty of these patients submitted 24-hour urine specimens for measurement of urinary free cortisol levels, and 31 were given a 1-mg dexamethasone suppression test (DST) before antihyperthyroidism therapy was started. There was no difference in the mean +/- SD urinary free cortisol excretion levels between depressed and nondepressed hyperthyroid patients. One nondepressed patient demonstrated nonsuppression (greater than 5 micrograms/dl) at 8:00 a.m. These results suggest that cortisol abnormalities as reflected by urinary free cortisol levels and DST findings are uncommon in patients with hyperthyroidism whether they are depressed or nondepressed.     

A new view on hypocortisolism

Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post-traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue. This overview will present data on the development, mechanisms and consequences of hypocortisolism on different bodily systems. We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic–pituitary–adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.     

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.     

Cortisol circadian rhythm alterations in psychotic major depression.

BACKGROUND: Increased hypothalamic-pituitary-adrenal axis activity is well described in psychotic depression with an emphasis on 24-hour, urinary free cortisol levels or dexamethasone suppression tests. There are limited data on cortisol levels during specific times of the day. METHODS: Patients with depression with (PMD) and without (NPMD) psychosis and healthy control subjects were studied using rating scales of depression and psychosis and measures of HPA activity, including overnight cortisol and adrenocorticotropin levels. We used analysis of variance to determine group differences and regression analyses to assess contributions of specific measures to cortisol levels. RESULTS: PMDs had higher cortisol during the evening hours than did NPMDs or control subjects, who did not differ from one another. Regression analyses suggest that depression and the combination of depressive and psychotic symptoms were important contributors to variance in evening cortisol. CONCLUSIONS: PMD is associated with increased cortisol levels during the quiescent hours. Enhanced cortisol activity, particularly a higher nadir, was related to depression severity and the interaction of depressive and psychotic symptoms. This increase suggests a defect in the action of the circadian timing system and HPA axis, creating a hormonal milieu similarly seen in early Cushing's syndrome and potentially an (im)balance of mineralocorticoid and glucocorticoid receptor activity.     

Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome

OBJECTIVE: The aim of this study was to obtain comprehensive information on basal hypothalamic-pituitary-adrenal (HPA) axis activity in chronic fatigue syndrome (CFS) patients who were not affected by medication or comorbid psychiatric disorder likely to influence the HPA axis. METHOD: Steroid analysis of urine collections from 0600 to 2100 h at 3-h intervals in CFS patients and in controls. RESULTS: Urinary free cortisol and cortisone concentrations showed a significant normal diurnal rhythm, but levels were lower across the cycle in CFS. In contrast, while urinary cortisol metabolites also showed a normal diurnal rhythm, levels were not significantly different between the CFS and controls at any time. Derived metabolite ratios were similar in both groups. CONCLUSION: This study provides further evidence for reduced basal HPA axis function in patients with CFS, based on lower free cortisol and cortisone levels, but this is not corroborated by cortisol metabolite data. The difference between these measures cannot be explained by an altered timing of the diurnal rhythm.     

Salivary cortisol patterns in vital exhaustion

OBJECTIVE: The syndrome of vital exhaustion (VE), a risk indicator for myocardial infarction, is characterized by excessive fatigue, irritability, and demoralization. Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is a potential pathogenic mechanism in fatigue syndromes, but little is known about HPA function in syndromal VE. METHOD: We assessed basal free cortisol levels and responses to a speech task and to morning awakening by collecting multiple saliva samples over 2 days from 29 VE men and 30 controls. RESULTS: VE subjects reported higher perceived stress, poorer sleep, and greater fatigue than controls. Basal cortisol levels were lower in VE subjects, especially in the evening, and were negatively associated with fatigue. Overall cortisol responses to the speech task were similar in VE and control groups, although VE subjects were less likely to show large (> or =2.76 nmol/l) responses. The cortisol response to awakening was associated with concurrent fatigue and poor sleep quality. CONCLUSION: These findings suggest a subtle HPA hypoactivity in VE, which may arise through chronic stress and associated sleep disturbances.     

Urinary free cortisol levels in obsessive-compulsive disorder

Seventeen obsessive-compulsive disorder (OCD) patients and 25 normal control subjects submitted 24-hour urine samples for measurement of urinary free cortisol (UFC). Thirteen of the 17 OCD patients submitted a second 24-hour urine collection after a 10-week trial of either clomipramine (n = 6) or placebo (n = 7). At baseline, the OCD patients had significantly higher UFC levels than the control group. After 10 weeks of clomipramine or placebo, however, the UFC levels for both OCD groups decreased and were comparable with those of the control group. Obsessive-compulsive symptomatology, as assessed by the Yale-Brown and the NIMH Global Obsessive-Compulsive Scales, improved in the clomipramine group but did not improve in the placebo group. There was a relationship between UFC levels and depressive symptoms.     

Phenylethylamine metabolism in Tourette's syndrome

Beta-phenylethylamine, phenylalanine, and phenylacetic acid were examined in 24-hour urine samples and/or plasma samples obtained from 28 medication-free patients with Tourette's syndrome and 20 control subjects matched for age and education. Statistical analyses revealed that Tourette patients had lower plasma phenylalanine and urinary free beta-phenylethylamine compared with the controls, but did not differ on urinary total levels of phenylacetic acid. Fifty percent of the Tourette patients had a urinary beta-phenylethylamine level that was lower than the lowest control subject. In addition, urinary beta-phenylethylamine levels were inversely related to several scores from the Tourette Syndrome Global Scale. These data suggest that abnormalities in synthesis or metabolism of beta-phenylethylamine may be involved in the etiology of some patients with Tourette's syndrome.     

The low-dose dexamethasone suppression test in fibromyalgia

OBJECTIVE: Fibromyalgia syndrome (FMS) has been associated with decreased cortisol secretion. Patients with posttraumatic stress disorder (PTSD) exhibit similar hypocortisolism in the context of increased negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis. Because trauma and PTSD have been associated with fibromyalgia, we evaluated whether patients with fibromyalgia demonstrate increased HPA feedback sensitivity. METHOD: Baseline blood samples were obtained at 0800 h, and 0.5 mg of dexamethasone was administered to 15 female patients with FMS and 20 normal controls at 2300 h. Adrenocorticotropin (ACTH), cortisol, and dexamethasone levels were measured at 0800 h after dexamethasone intake. RESULTS: There were no group differences in mean ACTH or cortisol levels or in ACTH/cortisol ratio at baseline. After dexamethasone intake, patients with FMS exhibited more pronounced suppression of cortisol but not of ACTH, as well as increased ACTH/cortisol ratios compared with controls. Percent cortisol suppression was associated with pain and fatigue, while ACTH/cortisol ratio and dexamethasone availability were associated with stress and anxiety measures. CONCLUSION: Our results suggest increased sensitivity to glucocorticoid feedback, manifested at the adrenal level, in FMS.     

Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder

Background: Limited studies of hypothalamic-pituitary-adrenal axis regulation in posttraumatic stress disorder have been performed in premenopausal women. We therefore undertook a study of hypothalamic-pituitary-adrenal axis regulation in this population.

Methods: Outpatient posttraumatic stress disorder subjects were compared with healthy, age- and weight-matched nontraumatized subjects. Subjects were free from psychotropic medications, alcohol and other illicit substances for at least 4 weeks before study. Menstrual cycle phase was determined by monitoring the LH surge and plasma progesterone levels. Corticotropin releasing factor and adrenocorticotropin stimulation tests, as well as 24-hour urinary-free cortisol measurements were performed.

Results: Corticotropin releasing factor test: Baseline adrenocorticotropic hormone and cortisol levels did not differ between the 12 PTSD and 11 comparison subjects, but the posttraumatic stress disorder group had greater adrenocorticotropic hormone and cortisol responses to corticotropin releasing factor, as well as a later cortisol peak. Adrenocorticotropic hormone test: Baseline cortisol levels did not differ between the 10 posttraumatic stress disorder subjects and seven controls, but the posttraumatic stress disorder group showed greater cortisol responses to adrenocorticotropic hormone. Peak cortisol responses to corticotropin releasing factor and adrenocorticotropic hormone were correlated with each other and with 24-hour urinary-free cortisol excretion.

Conclusions: Pituitary and adrenal hyperreactivity to exogenous corticotropin releasing factor and adrenocorticotropic hormone is demonstrated in premenopausal women with chronic posttraumatic stress disorder. Cortisol hyperreactivity thus may play a role in the pathophysiology of posttraumatic stress disorder in women.     

Urinary free cortisol excretion in elderly persons with minor and major depression

Several studies have found that cortisol hypersecretion may occur in severely depressed patients, characterized by melancholic features. On the other hand, illness chronicity seems to be related to low, rather than high, cortisol levels. This study aims to trace factors associated with 24-h urinary free cortisol levels in a sample of 23 elderly persons with major or minor depression and 21 non-depressed control subjects. Depressive episodes were subdivided according to severity and chronicity (i.e. length and recurrence). None of the depressed persons showed unusually high 24-h cortisol levels, and cortisol excretion was not elevated as compared with that in the control group, regardless of subtype of depression. The results suggest, however, that hyposecretion of cortisol may be a feature of chronic depressive episodes, especially in males.     

Central and peripheral ACTH and cortisol levels in anorexia nervosa and bulimia

To explore the relationship of central and peripheral adrenocorticotropic hormone (ACTH, or corticotropin) levels to hypothalamo-pituitary-adrenal axis dysfunction in patients with eating disorders, levels of cerebrospinal fluid (CSF) and plasma ACTH, cortisol, and 24-hour urinary free cortisol were measured in 16 patients with anorexia nervosa (60% +/- 1.1% of ideal body weight), 14 patients with bulimia (93.2% +/- 4.6% of ideal body weight), and 11 healthy age-matched women volunteers. The CSF, plasma, and urinary free cortisol levels were elevated in underweight anorexic patients and showed declines following weight recovery. Cortisol-binding globulin levels were similar in anorexics and controls. In contrast, underweight anorexics showed low CSF ACTH levels that returned to normal following weight recovery, and their plasma ACTH levels were normal. On hospital admission, bulimic patients demonstrated normal ACTH and cortisol levels. After their abstinence from binge-purge episodes, the CSF ACTH levels decreased significantly. Positive relationships were found among CSF, plasma, and urinary cortisol levels, and inverse relationships were seen between cortisol measures and CSF ACTH levels in patients with eating disorders. Secretion of ACTH into the CSF may respond to feedback by cortisol or, alternatively, may be suppressed by the hypersecretion of corticotropin-releasing hormone, leading to the depletion of the pro-opiomelanocortin molecule.     

The dexamethasone suppression test and pituitary-adrenocortical function

The dexamethasone suppression test (DST) as now commonly carried out in psychiatric settings yields "abnormal" results in many conditions including the healthy state. To determine whether the DST accurately identifies patients with physiologically meaningful increases in pituitary-adrenocortical activity, we compared DST results to baseline urinary cortisol level. Thirty-four psychiatric inpatients underwent a 24-hour urine collection and then a DST using 1 or 2 mg of dexamethasone. With the common 1-mg DST, 24-hour urinary cortisol levels in nonsuppressors and suppressors did not differ. With the 2-mg DST, however, nonsuppressors had significantly higher urinary cortisol levels than suppressors, and all nonsuppressors had urinary cortisol levels above the normal range. Thus, the 1-mg DST may not identify the heuristically important subgroup of psychiatric patients who have a pathophysiologically meaningful alteration in pituitary-adrenal regulation.     

Glucocorticoid level and neuropsychiatric symptoms in homosexual men with HIV infection.

OBJECTIVE: There is a controversial literature suggesting that stress, anxiety, and depression are harmful to the immune system and therefore to health. Preclinical studies indicate that activation of the hypothalamic-pituitary-adrenal (HPA) axis by stress may be responsible for immunocompromise. The goal of this study was to assess this phenomenon in human immunodeficiency virus (HIV) infection. METHOD: Homosexual men in the community who did not meet modified Centers for Disease Control criteria for acquired immune deficiency syndrome (AIDS) were recruited for the study; 113 of the men were HIV positive and 77 were HIV negative. Very few of the men studied suffered from depression or anxiety disorder at the time of the first assessment. Twenty-four-hour urinary free cortisol levels were obtained from the 112 HIV-positive and 75 HIV-negative men whose 24-hour urine volumes were 500 ml or more. Cortisol levels were correlated with measures of medical, immunological, neurological, and psychiatric status. RESULTS: Small but significant correlations between 24-hour urinary free cortisol and medical status, level of depression, and level of anxiety were found in the HIV-positive group. There was no relationship between cortisol level and the number of CD4+ or CD8+ T lymphocytes or the CD4-CD8 ratio. CONCLUSIONS: Although HPA activation may be associated with stress in cases of HIV infection, it does not seem to be associated with further loss of CD4+ T lymphocytes. Subjects with HIV infection with the most evidence of medical complications may also be the most anxious and depressed.     

The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders

Representing a challenge for current concepts of stress research, a number of studies have now provided convincing evidence that the adrenal gland is hypoactive in some stress-related states. The phenomenon of hypocortisolism has mainly been described for patients, who experienced a traumatic event and subsequently developed post-traumatic stress disorder (PTSD). However, as presented in this review, hypocortisolism does not merely represent a specific correlate of PTSD, since similar findings have been reported for healthy individuals living under conditions of chronic stress as well as for patients with several bodily disorders. These include chronic fatigue syndrome, fibromyalgia, other somatoform disorders, rheumatoid arthritis, and asthma, and many of these disorders have been related to stress. Although hypocortisolism appears to be a frequent and widespread phenomenon, the nature of the underlying mechanisms and the homology of these mechanisms within and across clinical groups remain speculative. Potential mechanisms include dysregulations on several levels of the hypothalamic-pituitary adrenal axis. In addition, factors such as genetic vulnerability, previous stress experience, coping and personality styles may determine the manifestation of this neuroendocrine abnormality. Several authors proposed theoretical concepts on the development or physiological meaning of hypocortisolism. Based on the reviewed findings, we propose that a persistent lack of cortisol availability in traumatized or chronically stressed individuals may promote an increased vulnerability for the development of stress-related bodily disorders. This pathophysiological model may have important implications for the prevention, diagnosis and treatment of the classical psychosomatic disorders.     

Differential diagnosis and pathophysiology of Cushing's syndrome and primary affective disorder

Most patients with major depression have increased 24-hour urinary free cortisol and cortisol nonsuppression after dexamethasone administration, which are cornerstones of a diagnosis of Cushing's syndrome. Similarly, Cushing's syndrome patients often suffer from major psychiatric syndromes, most often depression. These similarities between the two conditions sometimes make it difficult to differentiate them and have led some investigators to suggest they are two points on a spectrum of endocrinologic dysfunction. This article reviews the literature comparing Cushing's syndrome and primary affective disorder and presents two cases that illustrate just how closely these diseases may resemble one another.     

Deficits in hippocampus-mediated Pavlovian conditioning in endogenous hypercortisolism.

BACKGROUND: Elevated endogenous levels of corticosteroids cause neural dysfunction and loss, especially within the hippocampus, as well as cognitive impairment in hippocampus-mediated tasks. Because Cushing's syndrome patients suffer from hypercortisolism, they represent a unique opportunity to study the impact of elevated glucocorticoids on cognitive functions. The aim of this study was to examine the performance of Cushing's syndrome patients on trace eyeblink conditioning, a cross-species, hippocampal-mediated test of learning and memory. METHODS: Eleven Cushing's syndrome patients and 11 healthy control subjects participated in an eyeblink trace conditioning test (1000-msec trace) and a task of declarative memory for words. Salivary cortisol was collected in both the patients and the control subjects, and urinary free cortisol was collected in the patients only. RESULTS: The patients exhibited fewer conditional responses and remembered fewer words, compared with the control subjects. Cortisol levels correlated with immediate and delayed declarative memory only. Conditional response correlated with delayed recall after controlling for the magnitude of unconditional response. CONCLUSIONS: The integrity of the hippocampus seems to be compromised in Cushing's syndrome patients. Trace eyeblink conditioning might be useful both as a clinical tool to examine changes in hippocampus function in Cushing's disease patients and as a translational tool of research on the impact of chronic exposure of glucocorticoids.     

Low platelet-poor plasma concentrations of serotonin in patients with combat-related posttraumatic stress disorder.

BACKGROUND: Combat-related posttraumatic stress disorder (CR-PTSD) is associated with a dysregulation of various neurotransmitter systems. METHODS: We assessed levels of platelet-poor plasma (PPP) norepinephrine (NE), and serotonin (5-HT), and 24-hour urinary excretion of NE, dopamine (DA), and homovanillic acid (HVA) in 17 male outpatients with untreated chronic CR-PTSD (age, 33.1 +/- 7.4 years) and 10 normal control subjects (age, 35.8 +/- 2.7 years). RESULTS: Compared with the control subjects, the PTSD patients showed significantly lower PPP 5-HT levels, elevated PPP NE levels, and significantly higher mean 24-hour urinary excretion of all three catecholamines (NE, DA, and HVA). The 24-hour urinary HVA values of the CR-PTSD patients correlated significantly and positively with the total Impact of Event Scale scores and the avoidance symptoms cluster scores, and the PPP 5-HT levels correlated negatively with the Hamilton Anxiety Rating Scale scores. The PPP NE/5-HT ratio was significantly higher in the study group than in the control subjects. CONCLUSIONS: We believe this combined enhanced noradrenergic activity and diminished 5-HT activity may be relevant to the neurobiology of CR-PTSD.     

Lymphocyte glucocorticoid receptor number in posttraumatic stress disorder

OBJECTIVE: The authors' objective was to investigate the possibility that glucocorticoid receptor changes may be involved in the dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in posttraumatic stress disorder (PTSD). METHOD: They measured the number of lymphocyte cytosolic glucocorticoid receptors and plasma cortisol concentrations in 15 consecutively admitted male combat Vietnam veterans with PTSD and in a normal comparison group of 11 subjects. RESULTS: Both the patients and the normal comparison subjects showed a morning-to-afternoon decline in glucocorticoid receptor concentrations, paralleling the normal diurnal decline in cortisol levels. The number of glucocorticoid receptors was 63% greater in the morning and 26% greater in the afternoon in the patients with PTSD than in the normal subjects. No group differences in cortisol levels were observed, nor were glucocorticoid receptor number and cortisol levels correlated. The number of morning glucocorticoid receptors was positively correlated with symptoms of PTSD and anxiety. CONCLUSIONS: These results provide further evidence for a dysregulation of the HPA axis in PTSD. The finding that patients with PTSD had a substantially greater number of lymphocyte glucocorticoid receptors than normal comparison subjects is consistent with the authors' previous observations of low 24-hour urinary cortisol excretion in subjects with PTSD. Furthermore, the receptor changes observed are opposite of those reported in major depressive disorder. The present data, along with other findings of HPA abnormalities in PTSD, support the possibility of a greater negative feedback sensitivity at one or more levels of the HPA axis.     

Melatonin and cortisol secretion in patients with primary obsessive-compulsive disorder.

Plasma levels of melatonin and cortisol were measured over a 24-hour period in seven patients with primary obsessive-compulsive disorder (OCD) and seven matched healthy control subjects. In OCD patients, the 24-hour secretion of melatonin was reduced as compared with that in healthy control subjects, whereas its circadian rhythm was preserved. In addition, in OCD patients, the overall secretion of cortisol was higher than that in control subjects, but there was no change in the circadian pattern of cortisol secretion. No correlation was found between clinical parameters and hormone levels.