Dexamethasone-corticotropin Releasing Hormone Test Research Articles

The dexamethasone corticotropin releasing hormone test in healthy and depressed women with and without childhood adversity

BackgroundAlterations of the hypothalamic-pituitary-adrenal (HPA) axis are a prominent finding in patients with major depressive disorder (MDD). Inconsistencies regarding a hyper- or hypoactive HPA axis may be explained by the moderating effect of childhood adverse experiences (ACE) which are associated with both HPA axis dysfunction and MDD in adulthood. We aimed to systematically disentangle the effects of ACE and MDD on HPA axis by comparing healthy women with and without childhood adversity and women with MDD with and without ACE. MethodsThe dexamethasone/corticotropin-releasing hormone (DEX/CRH) test was administered in 35 women with MDD and ACE as determined by a clinical interview (SCID, Early Trauma Inventory), 51 women with MDD without ACE, 21 women with ACE but no current or lifetime MDD and 37 healthy women without either MDD or ACE. ResultsThere were no group differences in age, smoking, body mass index, and intake of oral contraceptives. Free salivary cortisol responses were not significantly different between the four groups. ConclusionsThis study shows no evidence for a dysregulation of the HPA axis as measured by the DEX/CRH test in depressed women with and without childhood adversity as compared to mentally healthy women with or without early life stress. Our results do not support the assumption of distinct neuroendocrine endophenotypes in MDD with regard to ACE.

A Comorbid Major Depression in Patients with Panic Disorder Affects the HPA Axis Response in the DEX-CRH Test

Panic disorder (PD) has been associated with an altered reactivity of the hypothalamic-pituitary-adrenocortical (HPA) system in the dexamethasone-corticotropin-releasing-hormone (DEX-CRH) test. Recent findings showed that the duration of the PD and the severity of psychopathology are prominent moderators of the HPA-axis reactivity under hormonal stress induction. As major depression (MD) often occurs as comorbidity in patients with PD, a secondary MD might influence the reactivity of HPA-axis in the DEX-CRH test. For this study, the DEX-CRH test was implemented to observe the adreno-corticotropin-hormone (ACTH) and the cortisol release. The sample included 20 patients diagnosed with PD (mean age = 32.20 years, SD = 9.98), 20 patients with PD and comorbid MD (mean age = 37.63 years, SD = 11.31) in a Structured Clinical Interview (SCID), and 20 healthy controls (mean age = 31.97 years, SD = 10.53) matched by age and gender. The ACTH and the cortisol release increased significantly in all three groups due to the CRH injection (p < .001). The two anxiety patient groups differed in the cortisol response pattern, however, not in the ACTH. Patients with pure PD showed a lower CRH-induced cortisol release than healthy controls (p < .038) and patients with a comorbid major depression (p = .001); the latter showed the highest cortisol release in DEX-CRH test. Duration (AUCg: r = .353, p = .030; AUCi: r = .339, p = .037) and severity of psychopathology (AUCg: r = .496, p = .026; AUCi: r = .463, p = .040) significantly correlated with the cortisol release. Patients with/without comorbid MD showed some dissociation between the central and the peripheral HPA-axis functionality under the DEX-CRH test. Furthermore, it seems that a secondary depressive disorder is the decisive factor in explaining an increased reactivity of HPA-axis in patients with PD.

Dissociation between ACTH and cortisol response in DEX–CRH test in patients with panic disorder

Panic disorder (PD) has been associated with the altered circadian rhythm of the hypothalamic-pituitary-adrenocortical (HPA) axis. The findings regarding the stress-specific functioning of the HPA-system are inconsistent. It is also unclear whether the HPA-system response after the Corticotropin-Releasing-Hormone (CRH) challenge becomes altered. For this study, the dexamethasone-corticotropin-releasing-hormone (DEX-CRH) test was implemented to assess the HPA-axis reactivity indicated by the plasma adreno-corticotropin-hormone (ACTH) and the cortisol release. The sample included 32 patients diagnosed with PD in a Structured Clinical Interview (SCID). Fourteen male and eighteen female patients, [mean age = 33.50 years, SD = 12.76] were matched with 32 healthy controls by age and gender. Moreover, a sample of patients with unipolar depression (n = 21, ten females) was examined as a clinical control group. In healthy controls as well as in patients with PD and patients with unipolar depression, the ACTH and the cortisol response increased significantly due to the CRH injection after dexamethasone pre-treatment. There were differences between the healthy controls and the patients with PD in the plasma cortisol response pattern, however, not in the ACTH. The patients with PD showed a decreased CRH-induced plasma cortisol response. A median-split gave evidence that patients suffering from PD longer than two years showed a remarkably higher HPA-axis reactivity under CRH-injection than patients suffering from PD two years or less. These findings provide strong evidence that patients with PD show some dissociation between ACTH and cortisol response under the DEX-CRH test with strong indicators that the length of the duration of the psychopathology is a risk factor for an increased reactivity of the HPA-axis in patients with PD.

Escitalopram and Neuroendocrine Response in Healthy First-Degree Relatives to Depressed Patients – A Randomized Placebo-Controlled Trial

IntroductionThe mechanisms by which selective serotonin re-uptake inhibitors (SSRI) act in depressed patients remain unknown. The serotonergic neurotransmitter system and the hypothalamic-pituitary-adrenal (HPA) system may interact. The aim of the AGENDA trial was to investigate whether long-term intervention with SSRI versus placebo affects the cortisol response in the dexamethasone corticotropin-releasing hormone (DEX-CRH) test in healthy first-degree relatives to patients with major depressive disorder (MDD).MethodsEighty healthy first-degree relatives to patients with MDD were randomized to escitalopram 10 mg versus matching placebo daily for four weeks. The primary outcome measure was the intervention difference in the change of the total area under the curve (CorAUCtotal) for plasma cortisol in the DEX-CRH test at entry to after four weeks of intervention.ResultsChange in CorAUCtotal showed no statistically significant difference between the escitalopram and the placebo group, p = 0.47. There were large intra- and inter-individual differences in the results of the DEX-CRH test. There was statistically significant negative correlation between the plasma escitalopram concentration and change in CorAUCtotal, rho = −0.41, p = 0.01. Post-hoc analyses showed a statistically significant interaction between age and intervention group and change in log CorAUCtotal.ConclusionThe present trial does not support an effect of escitalopram 10 mg daily compared with placebo on the HPA-axis in healthy first-degree relatives to patients with MDD. Increasing levels of escitalopram tended to decrease the HPA-response in the DEX-CRH test and this effect increased with age.Trial RegistrationClinicalTrials.gov [NCT00386841

Concomitant Medication Use Can Confound Interpretation of the Combined Dexamethasone-Corticotropin Releasing Hormone Test in Cushing's Syndrome

Concomitant Medication Use Can Confound Interpretation of the Combined Dexamethasone-Corticotropin Releasing Hormone Test in Cushing's Syndrome

Concomitant Medication Use Can Confound Interpretation of the Combined Dexamethasone-Corticotropin Releasing Hormone Test in Cushing’s Syndrome

The ability of combined dexamethasone-corticotropin releasing hormone (Dex-CRH) testing to distinguish pseudo-Cushing's syndrome (PCS) from Cushing's syndrome is controversial. One factor potentially impairing diagnostic efficacy is the concomitant use of commonly prescribed medications that may alter dexamethasone metabolism. Our objective was to assess the diagnostic accuracy of the Dex-CRH test and evaluate the potential impact of concomitant drugs. The study was a retrospective one. Participants included 101 patients [60 Cushing's disease (CD); 41 PCS] who underwent 112 Dex-CRH tests. Patients were divided into two groups, depending on use of medications potentially interfering with dexamethasone metabolism: 58 tests were classified as No Meds (32 CD; 26 PCS) and 54 as Meds (34 CD; 20 PCS). The latter group was further subdivided into patients taking one medication vs. those taking multiple medications. Diagnostic accuracy of different serum cortisol and ACTH thresholds at baseline and 15 min after CRH injection was assessed. The specificity of a baseline post-low-dose-dexamethasone-suppressed test cortisol lower than 1.4 microg/dl (38 nmol/liter) was significantly higher in the No Meds vs. the Meds group (P = 0.014). Sensitivity and specificity using a post-CRH cortisol cutoff of 1.4 microg/dl (38 nmol/liter) were 93.1% (95% confidence interval = 88.4-97.8) and 92.3% (95% confidence interval = 87-97.6) in the No Meds group. The specificity of a cortisol lower than 1.4 microg/dl (38 nmol/l) at 15 min after CRH was significantly higher in patients taking only one medication vs. those on multidrug treatment (P < 0.05). Medications commonly prescribed in hypercortisolemic patients undergoing Dex-CRH testing may contribute to the variable diagnostic accuracy of this test. Prospective studies to address this issue are needed.

Changes of Sleep Architecture, Spectral Composition of Sleep EEG, the Nocturnal Secretion of Cortisol, ACTH, GH, Prolactin, Melatonin, Ghrelin, and Leptin, and the DEX-CRH Test in Depressed Patients during Treatment with Mirtazapine

The noradrenergic and specific serotoninergic antidepressant mirtazapine improves sleep, modulates hormone secretion including blunting of hypothalamic-pituitary-adrenocortical (HPA) activity, and may prompt increased appetite and weight gain. The simultaneous investigation of sleep electroencephalogram (EEG) and hormone secretion during antidepressive treatment helps to further elucidate these effects. We examined sleep EEG (for later conventional and quantitative analyses) and the nocturnal concentrations of cortisol, adrenocorticotropin (ACTH), growth hormone (GH), prolactin, melatonin and the key factors of energy balance, ghrelin, and leptin before and after 28 days of treatment of depressed patients (seven women, three men, mean age 39.9+/-4.2 years) with mirtazapine. In addition, a sleep EEG was recorded at day 2 and the dexamethasone-corticotropin-releasing hormone (DEX-CRH) test was performed to assess HPA activity at days -3 and 26. Psychometry and mirtazapine plasma concentrations were measured weekly. Already at day 2, sleep continuity was improved. This effect persisted at day 28, when slow-wave sleep, low-delta, theta and alpha activity, leptin and (0300-0700) melatonin increased, and cortisol and ghrelin decreased. ACTH and prolactin remained unchanged. The first two specimens of GH collected after the start of quantitative EEG analysis were reduced at day 28. The DEX-CRH test showed, at day 26, a blunting of the overshoot of ACTH and cortisol found at day -3. The Hamilton Depression score decreased from 32.1+/-7.3 to 15.5+/-6.7 between days -1 and 28. A weight gain of approximately 3 kg was observed. This unique profile of changes is compatible with the action of mirtazapine at 5-HT-2 receptors, at presynaptic adrenergic alpha 2 receptors, at the HPA system, and on ghrelin and leptin.

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.

Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis.

Hypothalamo-pituitary-adrenal (HPA) dysregulation has recently been demonstrated in multiple sclerosis (MS) by means of combined dexamethasone corticotropin-releasing hormone (Dex-CRH) suppression tests. Authors found a correlation with course of disease and to a lesser extent with depressive symptoms. In this study, we aimed to further evaluate whether HPA disturbances in MS are correlated with cognitive impairment, disability status, and fatigue. Dex-CRH tests were performed in a total of 40 patients and 11 healthy controls. Concomitantly, cognitive impairment was evaluated using the symbol digit modalities test and fatigue was assessed by different fatigue severity scales. When comparing patient subpopulations to healthy subjects, Dex-CRH stimulation tests indicated an HPA hyperactivity in primary and secondary progressive MS, while relapsing-remitting patients had response patterns similar to controls. However, results were only significant for one of the six analysed parameters, i.e. area under the curve calculations of ACTH stimulation. Within the patient sample, clear-cut differences emerged between groups of different cognitive impairment, being significant for all ACTH response parameters. Our results suggest an HPA hyperactivation related to increased cognitive impairment. Indicators of HPA axis activation further correlated substantially with neurologic disability, but only moderately with duration of disease and even less with depressive symptoms and fatigue. We conclude that the observed dysregulation is more likely a secondary effect of the extent of brain damage rather than primarily involved in the pathogenesis of MS.

Classic and Recent Etiologies of Cushing??s Syndrome

Endogenous Cushing's syndrome can result from excess adrenocorticotropic hormone (ACTH; corticotropin) production by a pituitary adenoma (Cushing's disease) or by ectopic tumors secreting ACTH or corticotro- pin-releasing hormone (CRH). ACTH-independent Cushing's syndrome is caused by adrenocortical tumors or hyperplasias. Initial diagnosis is performed using 24-hour urinary free cortisol, low-dose dexamethasone tests, salivary cortisol, or night-time plasma cortisol values. A dexamethasone CRH test can discriminate between Cushing's syndrome and pseudo-Cushing's syndrome. If ACTH is elevated, combinations of high-dose dexamethasone tests, CRH/desmopressin tests, and pituitary magnetic resonance imaging can indicate a pituitary source. Discrimination from an ectopic ACTH tumor often requires inferior petrosal sinus sampling to confirm the ACTH source. If ACTH is low, adrenal computed tomography scan will identify the adrenal lesion(s) implicated. Some cortisol-producing adrenal tumors or, more frequently, bilateral macronodular hyperplasias, are under the control of aberrant membrane hormone receptors, or altered activity of eutopic receptors. The initial therapy of choice for patients with Cushing's disease is the selective transsphenoidal removal of the corticotroph adenoma; this induces remission in approximately 80% of patients, but long-term relapse occurs in up to 30% of these cases. The choice of second-line therapy remains controversial. Repeat surgery can be successful when residual tumor is detectable on magnetic resonance imaging, but carries a high risk of hypopituitarism. Bilateral adrenalectomy may be a better choice in patients without visible residual tumors, particularly in women desiring fertility. Radiotherapy combined with ketoconazole or radiosurgery was recently found effective, but longer-term evaluation of hypopituitarism and brain function is required. Current studies do not support the systematic use of prophylactic radiotherapy after bilateral adrenalectomy to decrease the risk of Nelson's syndrome; however, as soon as the residual tumor progresses, surgery and radiotherapy should be initiated. Various drugs which inhibit steroid synthesis (ketoconazole, metyrapone, aminoglutethimide, mitotane) are often effective for rapidly controlling hypercortisolism either in preparation for surgery, after unsuccessful removal of the etiologic tumor, or while awaiting the full effect of radiotherapy or more definitive therapy. Surgery is usually the treatment of choice for removal of cortisol-secreting adrenal tumors or ectopic ACTH/CRH-secreting tumors. The identification of aberrant adrenal receptors has recently allowed normalization of cortisol secretion by specific ligand receptor antagonists in limited cases of Cushing's syndrome secondary to bilateral macronodular adrenal hyperplasia. The long-term follow-up of patients treated for Cushing's syndrome should include the adequate replacement of glucocorticoids and other hormones, treatment of osteoporosis, and detection of long-term relapse of Cushing's syndrome.

Contingent negative variation and Dex-CRH test in patients with major depression

E€ects of corticosteroid secretion on cognitive information processing have been reported in studies with animals (Vicedomini et al., 1990; Oitzl and de Kloet, 1992; Sandi and Rose, 1994), healthy human subjects (Wolkowitz et al., 1990, 1997), patients with Cushing's syndrome (Whelan et al., 1980) or treated with corticosteroids (Ling et al., 1981; Varney et al., 1984). In depression hypothalamic pituitary adrenal (HPA) axis dysregulation is the major neuroendocrine ®nding (Holsboer and Barden, 1996) and cognitive impairment is frequently observed (Weingartner, 1982; Veiel, 1997), however, only a limited number of studies addressed the relationship between HPA axis dysregulation and cognitive dysfunction in depression. Findings of these studies suggest an association between cognitive impairment assessed by neuropsychological tests and nonsuppression of cortisol in the dexamethasone suppression test (DST) (Siegel et al., 1989, Wolkowitz et al., 1990). The contingent negative variation (CNV), an event related potential, provides a tool to evaluate the central neurophysiological activity underlying cognitive processes of attention (McCallum and Walter 1968). In addition, CNV amplitudes were inversely correlated with severity of depression (Papart et al., 1990). Furthermore, nonsuppression in DST was associated with alterations of CNV amplitude and latency in depressed patients (Timsit-Berthier et al., 1986). In a recent study by our group (Heimberg et al., 1999) a complex CNV paradigm was applied which included a variation in the intensity of attention. Compared to healthy controls, depressed patients presented with a slightly decreased CNV in the target, but a substantial CNV in the nontarget-condition, which was not observed in healthy subjects (Heimberg et al., 1999). In eight inpatients of this study [6 females, 2 males, age: 51.8 11.3 years (mean S.D.)] a combined dexamethasone-corticotropin releasing hormone (Dex-CRH) test (Holsboer et al., 1987), which provides an increased sensitivity compared to the DST (Heuser et al., 1994) was additionally performed. All patients were in an acute phase of major depression (between the ®rst and second week after admission to the depression unit) and were treated with a monotherapy of 200 mg trimipramine for at least 5 days before the examination of the CNV and seven days before the Dex-CRH test. Severity of depression was assessed by Hamilton Rating Scale of Depression (HDRS, Hamilton, 1967). The CNV paradigm, a choice-reaction task, which included a preceding warning period of one second, consisted of a series of 72 ®gures of three complex ®gures presented tachistoscopicly. One third of the series consisted of three identical ®gures (response-relevant condition=RR) and had to be con®rmed by button press immediately after the presentation of the third identical condition (target condition). In the two further thirds of the series either two of the ®gures were identical or all ®gures di€ered (response irrelevant condition=RI). In the response-irrelevant condition (RI) no button press was required. Therefore, both conditions (RRand RI-condition) di€er to a large extent in the requirement of attentional demanding processes. CNV prior to the second ®gure served as the baseline. Monopolar EEG was recorded with the electrode positions Fz, Cz, Pz and two connected electrodes at the mastoid position as reference. Maximal amplitude of CNV was measured between 1200 and 1500 ms after onset of the second ®gure (S1) and before the third ®gure (S2); for further details see Heimberg et al. (1999). In depressed patients (HDRS-score, 21.6 5.9) CRH stimulated cortisol in the Dex-CRH test was increased by trend compared to healthy controls matched by age

Dysregulation of the hypothalamic-pituitary-adrenocortical system in panic disorder

The responsiveness of the hypothalamic-pituitary-adrenocortical (HPA) system was investigated with the combined dexamethasone-corticotropin-releasing hormone (DEX-CRH) challenge test in 13 patients with "pure" panic disorder. After DEX pretreatment, this group of patients had higher CRH-induced adrenocorticotrophic hormone (ACTH) and cortisol levels than the control group, but lower than a reference group of depressed patients. The panic disorder patients were also in a middle position in the ratio of suppressors to nonsuppressors on the dexamethasone suppression test (DST) and in the ratio of normal to abnormal results on the DEX-CRH test. Our results using the combined DEX-CRH test, which is known to be much more sensitive than the original DST, support the hypothesis that HPA system functioning is altered in panic disorder patients and that this dysregulation is directly involved in the pathogenesis of the disorder.