Dexamethasone Challenge Research Articles

Hypothalamic-Pituitary-Gut Axis Dysregulation in Irritable Bowel Syndrome: Plasma Cytokines as a Potential Biomarker?

Irritable bowel syndrome (IBS) is a functional disorder with an etiology that has been linked to both psychological stress and infection. The primary aim of this study was to examine the hypothalamic-pituitary-adrenal axis in patients with IBS and to relate such response to plasma cytokine profiles. A total of 151 subjects, 76 patients and 75 controls, were recruited. The patients with IBS were diagnosed according to Rome II criteria. Forty-nine patients and 48 matched controls had cytokine levels measured, and a subset of 21 patients and 21 controls also underwent a corticotropin-releasing hormone (CRH) stimulation test with plasma levels of adrenocorticotropic hormone (ACTH) and cortisol measured. The remaining 27 patients and 27 controls underwent a dexamethasone (1 mg) challenge. Cortisol and the proinflammatory cytokines interleukin (IL)-6 (together with its soluble receptor) and IL-8 were elevated in all IBS subgroups (diarrhea predominant, constipated, and alternators), although the elevation was most marked in the constipated subgroup. There was no alteration in the anti-inflammatory cytokine IL-10. Following CRH infusion, an exaggerated release of both ACTH and cortisol was observed in patients with IBS. There was a significant correlation between the ACTH response (deltaACTH) and the IL-6 levels. A similar relationship existed between the deltaACTH/deltacortisol ratio and the IL-6 levels. Dexamethasone suppression of cortisol was similar in patients and controls. IBS is characterized by an overactivation of the hypothalamic-pituitary-adrenal axis and a proinflammatory cytokine increase.

Social instability in female rats: The relationship between stress-related and anxiety-like consequences

It is generally believed that anxiety and depression develop in response to stressful events that chronically increase glucocorticoid production (which in turn affects various neurotransmitter systems). In contrast to depression, however, the relationship between chronic stress and anxiety is less clear, as anxiety patients often show normal glucocorticoid levels and respond normally to dexamethasone challenge. Here we report on the interaction between symptoms of chronic stress and anxiety in female rats by making use of the social instability model of anxiety. Subjects were exposed to alternating 24 h periods of isolation and moderate crowding for 14 days. Symptoms of chronic stress and anxiety-like behaviour in the social interaction test were evaluated on the 15th day, i.e. 1 day after the last crowding phase. Social instability resulted in decreased weight gain, and chronically elevated plasma glucocorticoid levels only in rats that showed high aggressiveness during the crowding phases. In contrast, anxiety-like behaviour was increased irrespective to crowding-related aggressiveness. Thus, the development of chronic stress symptoms and anxiety-like behaviour dissociated: the former was bound to crowding-induced aggressiveness (i.e. to a higher stress load), whereas the latter occurred also when such aggressiveness was low, and symptoms of chronic stress did not develop. This finding is consistent with human data, and suggests that stressful events lead to anxiety in both cases: when stressors do or do not lead to chronic stress responses. Studying the distinctive features of anxieties associated or not with chronic endocrine stress responses would enhance our understanding of this disorder.

Habituation to stress and dexamethasone suppression in rats with selective basal forebrain cholinergic lesions.

Previous studies suggest a role for basal forebrain cholinergic neurons in enhancing the inhibitory influence of the hippocampus and medial prefrontal cortex (mPFC) on glucocorticoid stress responses mediated by the hypothalamic-pituitary-adrenocortical (HPA) axis. An inhibitory action of the basal forebrain cholinergic (BFC) system may occur through facilitation of stress-related information processing and maintenance of glucocorticoid receptor (GR) expression and negative feedback signaling in these target regions. The current study investigated the possibility that BFC input to the hippocampus contributes to habituation of the glucocorticoid response following repeated exposure to a stressor. Cholinergic lesions were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band, and 3 weeks later rats were subjected to six daily sessions of restraint stress. Blood samples taken before, during and after acute stress revealed a significant increase in peak activation and protracted elevation of corticosterone in cholinergic lesioned rats. After 5 days of repeated stress, however, both groups habituated to the stressor, as indicated by similarly low corticosterone profiles throughout both the response and recovery period. Against that habituated background, rats were administered a dexamethasone challenge on day 6, so that feedback status could be examined. Dexamethasone-induced suppression of endogenous corticosterone before, during, and after stress was significantly attenuated in lesioned rats. The profile of dysfunction in glucocorticoid regulation after selective cholinergic lesions in young animals may be relevant to the adrenocortical hyperactivity and negative feedback deficits seen in conditions such as normal aging and Alzheimer's dementia, in which integrity of the basal forebrain cholinergic system is compromised.

When not enough is too much: the role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders.

Previous theories have emphasized the role of excessive glucocorticoid activity in the pathology of chronic stress. Nevertheless, insufficient glucocorticoid signaling (resulting from decreased hormone bioavailability or reduced hormone sensitivity) may have equally devastating effects on bodily function. Such effects may be related in part to the role of glucocorticoids in restraining activation of the immune system and other components of the stress response, including the sympathetic nervous system (SNS) and corticotropin-releasing hormone (CRH). The literature on neuroendocrine function and glucocorticoid-relevant pathologies in stress-related neuropsychiatric disorders, including posttraumatic stress disorder and major depression, was reviewed. Although not occurring together, both hypocortisolism and reduced responsiveness to glucocorticoids (as determined by dexamethasone challenge tests) were reliably found. Stress-related neuropsychiatric disorders were also associated with immune system activation/inflammation, high SNS tone, and CRH hypersecretion, which are all consistent with insufficient glucocorticoid-mediated regulation of stress hyperresponsiveness. Finally, antidepressants, a mainstay in the treatment of stress-related disorders, were regularly associated with evidence of enhanced glucocorticoid signaling. Neuroendocrine data provide evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders. Impaired feedback regulation of relevant stress responses, especially immune activation/inflammation, may, in turn, contribute to stress-related pathology, including alterations in behavior, insulin sensitivity, bone metabolism, and acquired immune responses. From an evolutionary perspective, reduced glucocorticoid signaling, whether achieved at the level of the hormone or its receptor, may foster immune readiness and increase arousal. Emphasis on insufficient glucocorticoid signaling in stress-related pathology encourages development of therapeutic strategies to enhance glucocorticoid signaling pathways.

Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers.

Insulin resistance is observed in individuals with normal glucose tolerance. This indicates that increased insulin secretion can compensate for insulin resistance and that additional defects are involved in impaired glucose tolerance or type 2 diabetes. The objective of this study was to evaluate a procedure aimed at assessing the compensatory mechanisms to insulin resistance. Eight healthy nonobese female patients were studied on two occasions, before and after administration of 2 mg/d dexamethasone for 2 days during a two-step hyperglycemic clamp. Insulin secretion was assessed from plasma insulin concentrations. Insulin sensitivity was assessed from the ratio of whole-body glucose use (6,6 (2)H(2) glucose) to plasma insulin concentrations. This procedure is known to induce a reversible impairment of glucose tolerance and insulin resistance. In all subjects, dexamethasone induced a decrease in insulin sensitivity and a proportionate increase in first-phase insulin secretion and in insulin concentrations at both steps of glycemia. The resulting hyperinsulinemia allowed the restoration of normal whole-body glucose uptake and the suppression of plasma free fatty acids and triglycerides. In contrast, the suppression of endogenous glucose production was impaired after dexamethasone (p < 0.01). Increased insulin secretion fully compensates dexamethasone-induced insulin resistance in skeletal muscle and adipose tissue but not in the liver. This suggests that failure to overcome hepatic insulin resistance can impair glucose tolerance. The compensatory insulin secretion in response to insulin resistance can be assessed by means of a hyperglycemic clamp after a dexamethasone challenge.

Temporally sensitive trophic responsiveness of the adrenalectomized rat anterior pituitary to dexamethasone challenge: relationship between mitotic activity and apoptotic sensitivity.

Depending on timing and dose, exogenous glucocorticoids induce a wave of apoptosis in the adult rat anterior pituitary, a response that is enhanced by adrenalectomy. In this study, we show that the size of the glucocorticoid-sensitive apoptotic population progressively increases during the week following surgical adrenalectomy, plateaus for a further week, then spontaneously declines to levels seen in intact animals by 4 wk. Mitotic activity, in contrast, rises rapidly post adrenalectomy but returns to baseline within 2 wk. Increased mitotic activity precedes the increase in the population of cells that undergo glucocorticoid-induced apoptosis and the subsequent decline in mitotic activity precedes the decline in apoptotic sensitivity despite persistent elevation of hypothalamic CRH and pituitary proopiomelanocortin transcripts. If glucocorticoid exposure is delayed until 4 wk post adrenalectomy when the apoptotic response has returned to baseline, glucocorticoid withdrawal, by transiently increasing mitotic activity, again primes the formation of an expanded glucocorticoid-sensitive apoptotic cell population. These data suggest that apoptotic sensitivity is largely confined to cells that have recently entered the cell cycle. This observation is further corroborated by demonstrating an abrupt glucocorticoid-induced step-down in the bromodeoxyuridine-labeling index to basal levels in rats given daily injections of bromodeoxyuridine during the week following adrenalectomy.

Different effects of acute neonatal stressors and long-term postnatal handling on stress-induced changes in behavior and in ornithine decarboxylase activity of adult rats

A transient increase in brain polyamine (PA) metabolism, termed the PA–stress–response (PSR), is a common response to stressful stimuli. Previous studies have implicated the PSR as a component of the adaptive and/or maladaptive brain response to stressful events. Ample evidence indicates that stressful experiences during early life can alter normal developmental processes and may result in pathophysiological and behavioral changes in the adult. The aim of the present study, therefore, was to determine whether strong acute neonatal stressors (3 mg/kg dexamethasone, or 2 h restraint stress at day 7), as compared to mild long-term intermittent maternal separation and handling (15 min, twice a day between postnatal days 2 and 25), would lead in adult Wistar rats to different PSR and behavioral reactivity to novelty stress. Changes in ornithine decarboxylase (ODC) activity and in tissue PA concentrations served as markers of the PSR, and behavioral alterations in an open-field arena indicated the reactivity to novelty stress. Animals subjected to acute neonatal stressors, showed reduced behavioral reactivity in the open-field test, indicative of increased emotional reactivity to novelty. In these animals, the increase in ODC activity after dexamethasone challenge was attenuated in the brain, but exaggerated in the liver. In the thymus and adrenal gland of these animals, the basal enzyme activity was significantly increased, but a similar reduction was observed after dexamethasone challenge. In contrast, long-term postnatal handling led in adults to novelty-induced changes indicative of reduced emotional behavior, yet the alterations in ODC activity after dexamethasone challenge in these animals were similar to those in animals after acute stressors. The concentrations of tissue polyamines in adults were not affected by any of the postnatal stressors. The results justify the following conclusions: (1) Strong acute neonatal stressors can lead to increased emotional behavior in adults, while mild long-term intermittent handling, may result in adaptation and reduced emotionality. (2) Attenuated stress-induced increase of ODC activity in the brain, but exaggerated increased activity in the liver, may be implicated in altered emotional behavior reactivity to stressors.

Pharmacological characterization of central and peripheral type I and type II adrenal steroid receptors in the prairie vole, a glucocorticoid-resistant rodent.

The prairie vole (Microtus ochrogaster) has recently been shown to be glucocorticoid resistant; that is, the prairie vole adrenal axis is refractory to dexamethasone challenge, and highly elevated basal corticosterone titers occur without apparent pathophysiology. This study investigates the physiological correlates of glucocorticoid resistance in the prairie vole. We provide a detailed pharmacological characterization of intracellular type I and type II adrenal steroid receptors in peripheral tissues and the hippocampus of the prairie vole and the Sprague Dawley rat, a corticosensitive rodent. Adrenalectomy markedly reduces, but does not eliminate, circulating glucocorticoids in the prairie vole. Nonetheless, molecular, cellular, and physiological assays indicate adrenal insufficiency; salt appetite and dentate gyrus granule cell death are increased after adrenalectomy, suggesting vacancy of the high affinity type I subtype of central adrenal steroid receptor. Analysis of adrenal steroid receptor binding constants and selectivity for endogenous and synthetic steroids in the vole and rat indicated that the vole type I receptor is nearly identical to that of the rat in brain and periphery. However, voles demonstrated a 2-fold lower type I receptor binding density in colon and hippocampus compared with that in rats. The vole type II receptor bound the endogenous glucocorticoid corticosterone with an 8- to 10-fold lower affinity than the rat type II receptor and was expressed in lower densities in thymus and hippocampus. These data indicate physiological adaptations in the prairie vole adrenal axis consistent with other glucocorticoid-resistant species, such as the guinea pig and squirrel monkey.

Prolactin response to low-dose dexamethasone challenge in combat-exposed veterans with and without posttraumatic stress disorder and normal controls

The prolactin and cortisol responses to dexamethasone (0.5 mg) were studied in combat veterans with (n = 18) and without (n = 12) posttraumatic stress disorder (PTSD) and normal controls (n = 18). Both veteran groups demonstrated greater prolactin suppression than the normals. In contrast, only veterans with PTSD showed an enhanced cortisol suppression in response to dexamethasone. These findings suggest that the prolactin response to dexamethasone may reflect a feature of combat exposure rather than PTSD per se.

Source localization of androgen excess in adolescent girls.

Functional ovarian hyperandrogenism (FOH) is characterized by an abnormal ovarian response to challenge with the GnRH analogs nafarelin and leuprolide acetate, similar to that observed in women with well defined polycystic ovary syndrome, regardless of whether elevated LH levels or polycystic ovaries are present. We studied an unselected group of 42 hyperandrogenic adolescents (age range, 14-22 yr; mean, 18.1 +/- 2.5 yr) 1) to determine FOH incidence through the assessment of ovarian-steroidogenic response to a single dose of leuprolide acetate, 2) to assess the clinical characteristics of patients according to their responses to GnRH analog stimulation, and 3) to evaluate adrenal steroidogenic function and its relation to ovarian hyperandrogenism in patients with either normal or abnormal responses to leuprolide acetate challenge. All patients underwent leuprolide acetate and ACTH testing, dexamethasone and ovarian suppression tests, and pelvic ultrasonography. Twenty-four (58%) patients had supranormal plasma 17-hydroxyprogesterone (17-OHP) responses to leuprolide acetate characteristic of FOH, and in 18, the 17-OHP response was similar to that of controls (n = 24; age, 17.1 +/- 2.3 yr). Seven patients (5 with FOH and 2 with normal responses to leuprolide acetate) had an abnormal response to ACTH, but only 1 had conclusive evidence of 21-hydroxylase deficiency. In 16 patients, the response to both stimulation tests was normal. Only 13 (54%) of the 24 FOH patients had polycystic ovaries on ultrasonography, and in 11 (46%), basal plasma LH levels were elevated. In FOH patients, reduction in testosterone and androstenedione plasma levels was significantly greater after ovarian suppression than after dexamethasone challenge (P < 0.0005 and P < 0.02, respectively). Peak plasma 17-OHP levels postleoprolide acetate simulation correlated with dexamethasone-suppressed plasma testosterone concentrations, dexamethasone-suppressed plasma androstenedione levels, and the free androgen index postdexamethasone treatment (r = 0.4, P = 0.01; r+ 0.4, P < 0.05; and r = 0.41, P = 0.007, respectively), Plasma sex hormone-binding globulin levels after dexamethasone administration correlated negatively with the baseline free androgen index (r = -.0.67; P < 0.0001). Considering our diagnostic criteria, 26 (62%) of our collective of 42 patients had abnormal responses to one or both stimulation tests, whereas 16 (37%) had normal response. FOH is the most common cause in (58%) of androgen excess in adolescence. Short term leuprolide acetate stimulation is a reliable tool fro identification of the ovary as the source of their hyperandrogenism.

Glucocorticoids down-regulate beta 1-adrenergic-receptor expression by suppressing transcription of the receptor gene.

The expression of beta 2-adrenergic receptors is up-regulated by glucocorticoids. In contrast, beta 1-adrenergic receptors display glucocorticoid-induced down-regulation. In rat C6 glioma cells, which express both of these subtypes of beta-adrenergic receptors, the synthetic glucocorticoid dexamethasone stimulates no change in the total beta-adrenergic receptor content, but rather shifts the beta 1:beta 2 ratio from 80:20 to 50:50. Radioligand binding and immunoblotting demonstrate a sharp decline in beta 1-adrenergic receptor expression. Metabolic labelling of cells with [35S]-methionine in tandem with immunoprecipitation by beta 1-adrenergic-receptor-specific antibodies reveals a sharp decline in the synthesis of the receptor within 48 h for cells challenged with glucocorticoid. Steady-state levels of beta 1-adrenergic-receptor mRNA declined from 0.47 to 0.26 amol/microgram of total cellular RNA within 2 h of dexamethasone challenge, as measured by DNA-excess solution hybridization. The stability of receptor mRNA was not influenced by glucocorticoid; the half-lives of the beta 1- and beta 2-subtype mRNAs were 1.7 and 1.5 h respectively. Nuclear run-on assays revealed the basis for the down-regulation of receptor expression, i.e. a sharp decline in the relative rate of transcription for the beta 1-adrenergic-receptor gene in nuclei from dexamethasone-treated as compared with vehicle-treated cells. These data demonstrate transcriptional suppression as a molecular explanation for glucocorticoid-induced down-regulation of beta 1-adrenergic receptors.

Negative and depressive symptoms in suicidal schizophrenics

The aim of this study was to determine the value of positive, negative and depressive symptoms, and of the dexamethasone suppression test (DST), in differentiating schizophrenics with and without a history of suicide. Fifty-seven hospitalized patients with schizophrenia were assessed at the end of a neuroleptic free interval with the Brief Psychiatric Rating Scale (BPRS), the Hamilton Rating Scale for Depression (HRSD), and with a dexamethasone challenge. Suicide attempters were significantly more likely to meet criteria for major depression than nonattempters. Scores on the HRSD differentiated the two groups whereas the sums of positive and negative symptom items from the BPRS did not. DST a.m. and p.m. cortisol values differentiated suicide attempters from nonattempters and HRSD scores correlated significantly with cortisol levels. This study confirms the importance of depressive symptoms in schizophrenic patients with a history of suicide. Assessment of the hypothalamic-pituitary-adrenal axis in schizophrenia may also provide useful information.

Lithium exerts a time-dependent and tissue-selective attenuation of the dexamethasone-induced polyamine response in rat brain and liver

It has previously been shown that chronic, but not acute, lithium treatment indirectly prevents the dexamethasone-induced increase in brain polyamine-metabolizing enzymes. In the present study we determined the effects of lithium treatment on changes in cellular polyamines, 6 h after dexamethasone challenge (3 mg/kg intraperitoneally). The findings demonstrate that chronic lithium (daily intraperitoneal 2.5 mmol/kg injections for 2 weeks) treatment completely prevents the accumulation of putrescine, in parallel to its prevention of the dexamethasone-induced increase in ornithine decar☐ylase activity. A partial attenuation of this polyamine response was also observed in the liver. Only minor and inconsistent changes were observed in the concentrations of the polyamines, spermidine and spermine. Acute lithium treatment (a single injection at times ranging from 1 to 24 h prior to dexamethasone challenge) did not attenuate the dexamethasone-induced increases in brain putrescine concentration nor in ornithine decar☐ylase activity. It is suggested that prevention of the stress-induced polyamine response in the brain may be an important mechanism through which prophylactic lithium may exert its beneficial effect in manic-depressive illness.

Post-dexamethasone cortisol levels and computerized tomographic findings in manic patients.

The relations of post-dexamethasone cortisol levels to computerized tomography (CT) scan findings of lateral and third ventricle size and cortical sulcal prominence rated separately for frontal and parieto-occipital distributions were examined in 15 manic patients. Failure to suppress endogenous cortisol after a dexamethasone challenge was associated with larger third ventricles, but not to any of the other CT scan measures.

Modulation of the plasminogen activation system in murine macrophages

We have dissected the state of fibrinolytic balance in the C57/BL mouse macrophages, by means of immunotrap assays and zymography. We have monitored the individual changes of plasminogen activator (PA) and plasminogen activator inhibitor (PAI) activities of cellular lysates and secretions of these macrophages, after they were stimulated by various exogenous agents. The resident peritoneal macrophages were found to have very little PA but high level of PAI, and are therefore highly anti-fibrinolytic in nature. Upon stimulation by thioglycollate, PA activity increased and PAI activity decreased, thus raising the fibrinolytic balance in these macrophages. Upon incubation of resident or thioglycollate-activated macrophages by lipopolysaccharide (LPS), the PA level was depressed while the PAI level was increased, resulting in a large drop in the total fibrinolytic balance of the activated cells. When resident or thioglycollate-activated macrophages were incubated with the anti-inflammatory agent dexamethasone, the drug depressed both the expressions of PA and PAI, in the lysate and conditioned medium of both cell types. Thus cell-bound or secreted forms of macrophage PA and PAI activities were either increased or decreased in response to thioglycollate, LPS or dexamethasone challenge. The changes in PA and PAI resulted in different state of fibrinolytic balance in macrophages, and could be related to the different functions of these macrophages at different stages of their development.

Multiple HPA profiles in endogenous depression: Effect of age and sex on cortisol and beta-endorphin

We have previously shown that a number of depressed patients demonstrated a failure to suppress corticotrophic secretion, as measured by β-Endorphin/β-Lipotropin (β-End/β-LPH levels), following dexamethasone challenge. The current study is an extension and replication of these findings, as well as an analysis of some of the biological variables which may contribute to the variance in β-End/β-LPH nonsuppression. We continue to observe a high rate of β-End/β-LPH nonsuppression in depressed patients following dexamethasone; this escape at the pituitary level is even observed in a number of patients who demonstrate normal cortisol suppression. Advancing age, particularly in women, led to higher baseline cortisol, lower baseline β-End/β-LPH, and a greater likelihood of being a nonsuppressor on one or both measures.

Relationship of object loss during development to hypothalamic-pituitary-adrenal axis function during major affective illness later in life

Although many studies have attempted to determine whether early object loss influences the risk of developing major affective illness in adulthood, there are few empirical data relating early loss to subsequent hypothalamic-pituitary-adrenal (HPA) axis dysfunction in adulthood. Forty-five psychiatric inpatients admitted for an active major affective illness, all of whom had a previous history of a significant permanent object loss (by death only), were studied retrospectively in this preliminary investigation to examine whether the type and timing of object loss experienced earlier in life would discriminate affectively ill patients who exhibit HPA dysfunction. Several loss variables were found to be statistically significant predictors of cortisol responses following glucocorticoid challenge. A median split of the distribution was used to classify patients into early loss (⩽ 19 years) and late loss (⩾ 20 years) groups. Analyses for all subjects, early and late loss combined, showed that late loss was associated with higher 11 p.m. cortisol levels. Within the early loss group, however, age of first loss was the most significant predictor of 4 p.m. cortisol levels after dexamethasone challenge. Consistent with the hypothesis that childhood object loss may be associated with long-term alterations in HPA axis function, younger age of loss correlated significantly with higher 4 p.m. cortisol responses. These preliminary data suggest that future prospective investigation of the neurobiological as well as psychosocial consequences of various types of early loss warrant further study.

Cortisol, ACTH, and beta-endorphin after dexamethasone administration in Parkinson's dementia

The dexamethasone suppression test (DST) has been suggested as an effective tool for differentiating between depression and dementia. After administering 1 mg dexamethasone, we measured cortisol, ACTH, and beta-endorphin levels in 32 nondepressed patients with idiopathic Parkinson's disease (PD) (14 also with dementia) and 20 healthy, age-matched controls. Four of the 20 controls, 9 of the 18 with PD alone, and 8 of the 14 with PD and dementia were dexamethasone nonsuppressors (cortisol value ≥ 5 μg/100 ml). Plasma ACTH and beta-endorphin responded in a coupled way to dexamethasone challenge. Higher basal levels of both peptides were found among PD patients (demented and nondemented), nonresponders to DST. Thus, the DST does not appear to be effective in differentiating between depression and dementia in PD. In addition, PD nonsuppressors showed higher basal values of plasma ACTH, beta-endorphin, and cortisol (similar to patients with major depression). This suggests that although the depression is clinically undetectable, both disorders may share some pathophysiological features at the hypothalamic hypophyseal adrenal level.

Acute Administration of Corticoids: A New and Peculiar Stimulus of Growth Hormone Secretion in Man*

It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.

Prediction of serum cortisol response to dexamethasone in normal volunteers: a multivariate approach.

Dexamethasone (DEX, 0.5 mg orally at 11 PM) challenge was used for the assessment of hypothalamic-pituitary-adrenal (HPA) activity in 20 normal volunteers. Age and pre-DEX serum cortisol levels were theè evaluated as predictors of postDEX serum cortisol levels using step-wise multiple regression analysis. Both age and preDEX serum cortisol levels were significant predictors of postDEX serum cortisol levels. It is suggested that the adjustment for age and preDEX serum cortisol level could be useful for the interpretation of abnormal postDEX levels.