Corticotropin-releasing Hormone Test Research Articles

Human corticotropin releasing hormone test performance in the differential diagnosis between Cushing's disease and pseudo-Cushing state is enhanced by combined ACTH and cortisol analysis

Corticotropin releasing hormone (CRH) test does not reliably distinguish Cushing's disease (CD) from normality or pseudo-Cushing state (PC). We assessed whether this could be achieved with a novel approach while preserving the ability of the test to distinguish CD from ectopic ACTH syndrome (EAS). Design Retrospective/prospective study. We studied 51 subjects with CD, 7 with EAS, 26 with PC, and 31 controls (CT). Human CRH (hCRH) test was performed at 0830 h by measuring plasma ACTH and serum cortisol at -15, 0, 15, 30, 45, 60, 90, and 120 min. The area under the curve-ACTH exhibited a significant negative correlation with baseline serum cortisol in CT and PC, but not in CD or EAS patients. ACTH response to hCRH was blunted in PC compared with CT, whereas peak serum cortisol was higher in PC than in CT subjects. These findings suggested that ACTH-dependent Cushing's syndrome can be diagnosed by the presence of two hCRH test parameters and excluded if either or both are absent. Application of i) basal serum cortisol >12 microg/dl and peak plasma ACTH >54 pg/ml, or ii) peak serum cortisol >21 microg/dl and peak plasma ACTH >45 pg/ml, had 91.3% (95% confidence intervals (CI) 81-97.1) and 94.8% (CI 85.6-98.9) sensitivity and 98.2% (CI 90.6-99.9) and 91.2% (CI 80.7-97) specificity respectively, in diagnosing ACTH-dependent Cushing's syndrome. The >14% serum cortisol increase from mean baseline values to the mean of 15 and 30 min values in patients who were positive for the test completely discriminated between CD and EAS. Simultaneous plasma ACTH and serum cortisol analysis enables the hCRH test to distinguish CD from PC and from normality, while preserving its ability to discriminate CD from EAS.

Evaluation of Diagnostic Tests for ACTH-Dependent Cushing’s Syndrome

We evaluated the usefulness and accuracy of diagnostic tests for adrenocorticotropic hormone (ACTH)- dependent Cushing's syndrome, based on our experience of 88 cases, including 73 cases with Cushing's disease, and 15 cases with ectopic ACTH syndrome (EAS). In our study, 0.5 mg of dexamethasone failed to suppress the morning cortisol secretion in 100% of cases with Cushing's disease and EAS. Plasma ACTH levels were significantly increased by desmopressin (DDAVP) in 86% of cases with Cushing's disease, especially in microadenomas (90%), while these levels were not affected in normal subjects. In EAS, 44% responded to DDAVP. Plasma ACTH levels were increased in response to the human corticotropin-releasing hormone (CRH) test in 100% of microadenomas and 73% of macroadenomas with Cushing's disease, but only in 27% of cases with EAS. A high dose (8 mg) of dexamethasone suppressed the morning cortisol secretion in 89% of microadenomas with Cushing's disease, and in 82% of all cases with Cushing's disease, while it did in only 20% of cases with EAS. Taken together, the 0.5 mg dexamethasone suppression test (DST) and DDAVP test are considerably useful for the screening of ACTH-dependent Cushing's syndrome. The CRH test and 8 mg DST would be effective for the diagnosis of Cushing's diseases, because our study shows a sensitivity of 81% in cases with Cushing's disease when these tests are considered together. These data were submitted to prepare the diagnostic criteria for Cushing's disease, suggested by the working group of the Ministry of Health, Labour, and Welfare of Japan.

Neuroendocrine stimulatory tests of hypothalamus–pituitary–adrenal axis in psoriasis and correlative implications with psychopathological and immune parameters

Psoriasis constitutes one of the most representative examples of psychosomatic disorders. The published work investigating the psychological parameters and the way they interact during the course of the disease is extensive, whereas only a few studies have focused on the neuroendocrine framework of psoriasis. In the present study, the objective was to investigate the neuroendocrine parameters of psoriasis and the way they interact with psychopathological and immune variables. Patients with psoriasis (n=24) and the same number of matched healthy controls underwent psychiatric evaluation with interviews and psychometric questionnaires. Both of the groups underwent the corticotropin-releasing hormone (CRH) test and the dexamethasone suppression test (DST) to investigate functional parameters of the hypothalamus-pituitary-adrenal (HPA) axis. The evaluation of immune variables included the estimation of the distribution of T-cell and natural killer lymphocytes. Levels of depressive and anxiety features were increased within subjects with psoriasis and they were significantly correlated with stressful life events and the extent of the disease. The adrenocorticotrophic hormone and cortisol levels increased after CRH infusion without significant differences between the two groups and the psoriatic subjects' cortisol suppression after DST was within normal range, though relatively blunted. No significant correlations were identified among neuroendocrine, psychopathological and immune parameters. No particular neuroendocrine profile has been identified among psoriatic patients and the hypothesized interaction with psychopathological and immune parameters was not replicated. Nevertheless, it is still premature to exclude the possibility that a subtle latent alteration of the HPA axis function might exist, in psoriasis, either stemming from the psychopathology or from the disease per se.

The combined low-dose dexamethasone suppression corticotropin-releasing hormone test as a tool to rule out Cushing's syndrome

It remains to be evaluated whether the combined low-dose dexamethasone suppression corticotropin-releasing hormone test (LDDST-CRH test) may add to the diagnostic approach of patients suspected to have Cushing's syndrome (CS). The aim of the present study was to evaluate whether the LDDST-CRH test may have a place in the diagnostic strategy of CS. Prospective evaluation of a consecutive series of patients with suspected CS from 2004 to 2006. All the subjects underwent the same screening protocol including 1 mg dexamethasone suppression test, 24-h urinary free cortisol (UFC), and midnight serum cortisol, followed by the LDDST-CRH test whose results were not used to establish a definitive diagnosis. Plasma dexamethasone concentration was measured 2 h after the last dose of dexamethasone. Patients qualified for CS when at least two screening tests were positive. Sixteen patients had CS while in the remaining 15 subjects CS was excluded. Even if not statistically significant, the sensitivity and the negative predictive value of the cortisol 15 min after CRH were better than the other tests; on the other hand, the test specificity was lower. All of the patients classified as indeterminate were correctly diagnosed by the LDDST-CRH test. Nevertheless, the repeated assessment of the screening tests and the active follow-up gave the same correct results. In all of the patients misclassified by the LDDST-CRH test, the plasma dexamethasone concentrations were in the normal range. Based on our findings, we suggest that the LDDST-CRH test may still find a place as a rule-out procedure in patients who present with indeterminate results after screening and may be unavailable to repeat testing during follow-up.

Role of Corticotropin-Releasing Hormone Testing in Assessment of Hypothalamic-Pituitary-Adrenal Axis Function in Infants with Congenital Central Hypothyroidism

The Dutch neonatal congenital hypothyroidism (CH) screening program detects infants with CH of central origin (CH-C). These infants have a high likelihood of multiple pituitary hormone deficiencies. ACTH deficiency especially poses an additional risk for brain damage and may be fatal. Our objective was to evaluate different tools for assessment of the integrity of the hypothalamus-pituitary-adrenocortex (HPA) axis in young infants, aiming for a strategy for reliable and timely diagnosis. This is a Dutch nationwide prospective study (enrollment 1994-1996). Patients were included if neonatal CH screening results were indicative of CH-C and HPA axis function could be tested within 6 months of birth. Nine male and three female infants with CH-C and four infants with false-positive screening results or transient hypothyroidism were included in the study. CRH test results, multiple cortisol plasma concentrations, and cortisol excretion in 24-h urine were measured. Six (50%) of the CH-C patients had abnormal CRH test results. Three of them had discordant test results: impaired increase of plasma cortisol in response to CRH, despite substantial increase of plasma ACTH. The other three infants, with concordant impaired responses of both ACTH and cortisol to CRH, had a very low urinary cortisol excretion in comparison with the subjects with normal CRH test results. The CRH test proves to be a fast and reliable tool in the assessment of HPA axis (dys)function. It enables timely diagnosis in (asymptomatic) neonates at risk for serious morbidity and mortality. The discordant response type, which has not been described before, may be an early phase of HPA axis dysfunction. Alternatively, patients with this response type may constitute a separate pathogenetic subset of HPA axis-deficient patients.

Corticotropin-Releasing-Hormon(CRH)-Test bei der Überwachung der Glucocorticoidtherapie

Suppression of endogenous cortisol production was assessed by a corticotropin-releasing hormone (CRH) test 24 hours after the last dose of the glucocorticoid in 48 patients (27 women and 21 men; mean age 48.9 [21-69] years) who had been taking fluocortolone for inflammatory rheumatic disease. Both during a few weeks of treatment (9 patients) and after a year (39 patients) complete suppression of endogenous cortisol production occurred in 17 patients, partial suppression in 17. This suppression did not unequivocally correlate with the dosage or duration of treatment, but there was a tendency towards it at higher dose levels (15-30 mg). Cortisol response to the CRH test was unremarkable in 14 patients. These results suggest that secondary adrenal insufficiency is to a considerable extent dependent on individual factors. Correspondingly the degree of suppression of the adrenal axis cannot be predicted for an individual patient without suitable testing.

Evaluation der hypothalamo-hypophysär-adrenalen Hormon-Achse bei Patienten mit chronisch-obstruktiver Atemwegserkrankung: Vergleich einer inhalativen mit einer systemischen Glucocorticoidtherapie

The action of inhalation and systemic treatment of chronic obstructive pulmonary disease by suppressing the hypothalamo-hypophyseal-adrenal axis was compared in patients with chronic obstructive pulmonary disease (COPD). Adrenocorticotropic hormone (ACTH) and cortisol concentrations were evaluated after a corticotropin-releasing-hormone (CRH)-test in 50 patients (aged 43 +/- 14 years) with chronic obstructive pulmonary disease (COPD) receiving inhalant glucocorticoid treatment (IGC), 61 patients (aged 54 +/- 11 years) with COPD on systemic glucocorticoid treatment (SGC) and 50 healthy volunteers (32 +/- 4 years). All 50 patients on IGC had normal CRH test results. 30 of 61 patients with SGC had decreased cortisol response (12 patients had no and 18 a reduced rise in cortisol). ACTH concentration was lower in patients on IGC than in the control group (basal ACTH 15.6 pg/ml and 24.5 pg/ml, respectively; after stimulation 40.3 vs 54.4 pg/ml, respectively). But systemic glucocorticoid treatment clearly caused suppression of basal (12.1 pg/ml) and stimulated (27.4 pg/ml) ACTH levels with correspondingly decreased cortisol levels (basal: 75.1 and 118.7 ng/ml [IGC], respectively, and after stimulation 128.5 and 225.9 ng/ml). Patients with COPD on inhalant glucocorticoid treatment have a clearly lower risk of adrenal cortical insufficiency than those on oral glucocorticoid treatment. But some suppression of ACTH secretion is demonstrable even in the former. Clinical significance of these findings seems unlikely. Development of adrenal cortical insufficiency need not be feared in patients treated with inhalant glucocorticoids.

Peri-operative glucocorticoid replacement therapy in transsphenoidal pituitary adenoma surgery: a prospective controlled study

We set out to prospectively study the peri-operative changes of the hypothalamic-pituitary-adrenal axis (HPA), and to test the hypothesis that the peri-operative corticoid replacement regimen used at the authors' institution in patients with impaired HPA undergoing transsphenoidal pituitary adenoma surgery is adequate. Thirty seven patients (21 females, 16 males, mean age 50.6 years) underwent transsphenoidal pituitary adenoma surgery (mean tumour diameter 20.6 mm, 13 tumours hormone-secreting). The HPA functions of these patients were classified as impaired (group A, n = 15) or preserved (group B, n = 22) according to the results of a pre-operative corticotrophin releasing-hormone test (CRHT). Eleven patients (9 female, 2 male, mean age 53.6 years) without pituitary adenomas and with a preserved HPA (as assessed by medical history and morning serum cortisol (MSC) measurements), undergoing decompressive surgery for degenerative lumbar disc disease, were also studied (group C). On the day of surgery, the patients of group A received 100 mg hydrocortisone (HC) replacement therapy, which was thereafter gradually tapered off in a standardised fashion. The patients of groups B and C were not treated with corticoids. Pre-operative, intra-operative and post-operative variables of these three patient groups were compared. The urinary free cortisol excretion (UFC) in group A declined from 6732 +/- 7683 microg/d on the day of surgery to 305 +/- 358 microg/d on the 10(th) post-operative day. In group B, the respective UFC values were 12,851 +/- 16,278 microg/d and 223 +/- 235 microg/d. In both of these groups, the mean UFC did not fall into the normal range during the first ten post-operative days. On none of the post-operative days, was there a significant difference between the UFC of groups A and B. The UFC values of group C dropped from 177 +/- 157 microg/d on the day of surgery to 87 +/- 61 microg/d on post-operative day six, reaching the normal range from the 2(nd) post-operative day onwards. All UFC values of group C were significantly lower than those of group A and B. None of the evaluated clinical, laboratory and MRI parameters, as disclosed by uni- and multivariate analysis, showed any significant influence on the peri-operative UFC values. The peri-operative UFC of pituitary adenoma patients with preserved HPA was very high, as compared to patients with degenerative lumbar disc disease. The present study showed for the first time, that the proposed regimen of peri-operative corticoid replacement therapy used in patients with pituitary adenomas and impaired HPA raised cortisol levels to match the physiological increase of UFC in patients with pituitary adenoma surgery and preserved HPA. However, although statistically not significant, the UFC of patients with pituitary adenomas and preserved HPA seemed considerably higher on the day of surgery than in patients with pituitary adenomas and HPA impairment. Although there is no evidence to make it mandatory, administration of 150 mg instead of 100 mg HC substitution on the day of pituitary adenoma surgery in patients with HPA impairment may be prudent.

CORTISOL IN SEVERELY BURNED PATIENTS

Thermal injuries of more than 20% of body surface area lead to conditions resembling a severe systemic inflammatory response syndrome, such as in septic shock. It has been shown that septic shock may lead to disturbances in cortisol metabolism and balance of the hypothalamic-pituitary-adrenal axis. To investigate whether such a disturbance also occurs in the very early stages of systemic inflammatory response syndrome in burned patients, we performed 20 corticotropin-releasing hormone tests on day 1 after admission to our unit. In 7 of 20 patients, a disturbance of cortisol secretion could be demonstrated. Four patients developed adrenal insufficiency. The correlation between the abbreviated burn severity index and the risk of developing adrenal insufficiency was significant (P = 0.008). We observed a higher mortality rate in adrenally insufficient patients; however, because of the small patient number, we were not able to prove this observation with a statistical significant correlation (P = 0.11). Our findings indicate that temporary adrenal insufficiency occurs in the early stages of severe injury. Further investigations will have to be performed to clarify whether such patients benefit from cortisol replacement.

The Dexamethasone-Suppressed Corticotropin-Releasing Hormone Test for the Diagnosis of Cushing’s Syndrome: What Have We Learned in 14 Years?

The Dexamethasone-Suppressed Corticotropin-Releasing Hormone Test for the Diagnosis of Cushing’s Syndrome: What Have We Learned in 14 Years?

HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis is one of the most prominent neurobiological findings in major depressive disorder (MDD). The relationship of regional brain metabolism to HPA axis dysfunction in depressed patients, however, is still unclear. In this study, to examine the clinical pharmacotherapeutic effects on HPA axis function and brain metabolism in MDD patients, we performed the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test on 24 antidepressant-free patients with MDD a few days after positron emission tomography (PET) with a radiotracer, [ 18F]-fluorodeoxyglucose (FDG). Moreover, 10 patients who responded to pharmacotherapy were re-tested. 75% of unmedicated MDD patients exhibited a heightened cortisol response to the DEX/CRH test, and thus were defined as non-suppressors. Non-suppressors showed a marked hypometabolism in the medial prefrontal cortex as compared with suppressors. After successful pharmacotherapy, enhanced cortisol responsiveness normalized. Prior to treatment of the unmedicated MDD, a significant hypometabolism in various frontal regions and a significant hypermetabolism in the right hippocampus and parahippocampal gyrus were observed compared with controls. Metabolic activity in treatment responders showed a normalizing pattern in almost all the areas that had been characterized by metabolic abnormality at baseline except for the medial prefrontal cortex. These results indicate that depressed patients remitted with antidepressant treatment were accompanied by resolution of HPA dysregulation and alteration of regional glucose metabolism in the prefrontal cortical, limbic and paralimbic regions.

The usefulness of combined biochemical tests in the diagnosis of Cushing’s disease with negative pituitary magnetic resonance imaging

The etiological diagnosis of ACTH-dependent Cushing's syndrome is often a problem. In fact, no endocrine or radiological examination can conclusively distinguish the ectopic from the pituitary source of disease. The aim of our study was to evaluate the role of stimulation and suppression endocrine tests in the diagnostic and therapeutic approach of patients with Cushing's disease (CD) and negative pituitary magnetic resonance imaging (MRI), considering their post-surgical outcome in comparison with patients with CD and positive MRI. We retrospectively analyzed 31 patients (25 women and 6 men, median age 40 +/- 15 years) with a confirmed diagnosis of CD who underwent transsphenoidal pituitary surgery by the same neurosurgeon between 2001 and 2005. Preoperative endocrine assessment included corticotropin-releasing hormone (CRH), desmopressin (dDAVP), and overnight 8 mg dexamethasone suppression tests (8-DST) in all patients. Fifteen patients had a normal pituitary MRI and sixteen had a clearly evident pituitary microadenoma. Bilateral inferior petrosal sinus sampling (BIPSS) was performed in patients with discordant biochemical results or with signs and symptoms highly suggestive of an ectopic source of ACTH. Post-surgical median follow-up was 38.4 +/- 22.0 months. Among patients with negative MRI, 60% had concordant positive endocrine tests and underwent neurosurgery without other examinations. BIPSS was performed in three other patients prompted by discordant endocrine tests (negative dDAVP) and in two patients with clinical suspicion of ectopic disease. Among patients with positive MRI, 87% underwent neurosurgery without BIPSS that was performed in two patients because of negative concomitant response to dDAVP and CRH tests. A pituitary adenoma, confirmed by pathological examination, was found in 40 and 81% of patients with negative and positive MRI respectively (P<0.05), corticotroph hyperplasia resulted more frequent in the group with negative MRI. Remission rate was not different between patients with negative and positive MRI (73 and 75% respectively; P=0.61) and between patients with negative MRI who did not undergo BIPSS and patients with positive MRI (P=0.56). The recurrence rate was also similar between groups (P=0.64), but higher, although not statistically different (P=0.07) in patients with corticotroph hyperplasia at histology. An accurate evaluation of presurgical endocrine tests results enabled us to reduce the number of BIPSS in patients with a negative MRI without any fallout on their post-surgical outcome. In the hands of an expert pituitary surgeon, the outcome after surgeryand the subsequent recurrence rate are much the same in patients with negative or positive MRI.

The value of corticotropin-releasing hormone (CRH) test for differential diagnosis of Cushing’s syndrome

Diagnosis and differential diagnosis of Cushing's syndrome (CS) remain considerable challenge in endocrinology. For more than 20 years, CRH has been widely used as differential diagnostic test. Following the CRH administration, the majority of patients with ACTH secreting pituitary adenoma show a significant rise of plasma cortisol and ACTH, whereas those with ectopic ACTH secretion characteristically do not. The aim of our study was to assess the value of CRF test for differential diagnosis of CS using the ROC (receiver operating characteristic) curve method. A total of 30 patients with CS verified by pathological examination and postoperative testing were evaluated. CRH test was performed within diagnostic procedures. ACTH secreting pituitary adenoma was found in 18, ectopic ACTH secretion in 3 and cortisol secreting adrenal adenoma in 9 of all patients with CS. Cortisol and ACTH were determined -15.0, 15, 30, 45, 60, 90 and 120 min. after i.v. administration of 100 microg of ovine CRH. Cortisol and ACTH were determined by commercial RIA. Statistical data processing was done by ROC curve analysis. Due to small number, the patients with ectopic ACTH secretion were excluded from test evaluation by ROC curve method. In evaluated subgroups, basal cortisol was (1147.3 +/- 464.3 vs. 1589.8 +/- 296.3 vs. 839.2 +/- 405.6 nmol/L); maximal stimulated cortisol (1680.3 +/- 735.5 vs. 1749.0 +/- 386.6 vs. 906.1 +/- 335.0 nmol/L); and maximal increase as a percent of basal cortisol (49.1 +/- 36.9 vs. 9.0 +/- 7.6 vs. 16.7 +/- 37.3%). Consequently, basal ACTH was (100.9 +/- 85.0 vs. 138.0 +/- 123.7 vs. 4.8 +/- 4.3 pg/mL) and maximal stimulated ACTH (203.8 +/- 160.1 vs. 288.0 +/- 189.5 vs. 7.4 +/- 9.2 pg/mL). For cortisol, determination area under ROC curve was 0.815 +/- 0.083 (CI 95% 0.652-0.978). For cortisol increase cut-off level of 20%, test sensitivity was 83%, with specificity of 78%. For ACTH, determination area under ROC curve was 0.637 +/- 0.142 (CI 95% 0.359-0.916). For ACTH increase cut-off level of 30%, test sensitivity was 70%, with specificity of 57%. Determination of cortisol and ACTH levels in CRH test remains reliable tool in differential diagnosis of Cushing's syndrome.

Persistent Cognitive Impairment in Depression: The Role of Psychopathology and Altered Hypothalamic-Pituitary-Adrenocortical (HPA) System Regulation

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) system and cognitive impairment are consistent findings in depression. This study examines the associations between HPA system regulation, cognitive functioning, and psychopathology in depressed inpatients on admission and at discharge. The HPA system dysregulation was evaluated with the dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test. Cognitive assessment included speed of information processing, divided and selective attention, as well as short-term and working memory. Psychopathology was evaluated with the Hamilton Rating Scale for Depression (HAMD). Data from 75 depressed inpatients are reported, 51 (68%) of them achieved remission. Despite a significant reduction of depressive symptoms between admission and discharge, a high rate of patients remained cognitively impaired. Selective attention improved significantly in remitters and nonremitters, while speed of information processing increased only in remitters. The cortisol response to the DEX/CRH test decreased significantly only in remitters, which was uncorrelated with cognitive performance. In nonremitters, severity of depression was significantly correlated with information processing time while improvement in short-term memory was negatively associated with the cortisol response at discharge. Our data support the assumption that psychopathological symptoms and the HPA system dysregulation can be dissociated in their impact on cognitive functioning in depressed patients.

Combined Dexamethasone/Corticotropin Releasing Hormone Test Predicts Treatment Response in Major Depression–A Potential Biomarker?

Exaggerated corticotropin (ACTH) and cortisol response to the combined dexamethasone (DEX)/corticotropin releasing hormone (CRH) test, indicating impaired regulation of the hypothalamus-pituitary-adrenocortical (HPA) system, is frequently observed in depression. In the present study, we examined whether change in HPA system function during the first weeks of hospitalization predicts response to antidepressant treatment in major depression and thus constitutes a potential biomarker. We conducted the DEX/CRH test in 50 inpatients suffering from severe major depression, once after study inclusion and a second time 2 to 3 weeks later while under continuous antidepressant treatment. We found increased ACTH and cortisol responses to the first DEX/CRH test compared with healthy control subjects. In the second DEX/CRH test 2 to 3 weeks later, 36 of the 50 patients showed an attenuated cortisol response, while 14 patients did not display improvement or exhibited even aggravation of the altered HPA system function. Improved HPA system regulation in the second DEX/CRH test was associated with beneficial treatment response after 5 weeks and a higher remission rate at the end of hospitalization. The results suggest that change in HPA system regulation assessed with repeated DEX/CRH tests is a potential biomarker that may predict clinical outcome at follow-up. There is consensus that the drug development process could be improved, once reliable biomarkers become available that help to allow a judgement regarding the efficacy of a novel drug candidate. The combined DEX/CRH test seems to be a promising candidate for such a biomarker.

The role of corticotrophin-releasing hormone in the diagnosis of Cushing’s syndrome

Background: Corticotrophin-releasing hormone (CRH) was identified by Vale and co-workers in 1981 and has since been used extensively in the diagnosis of ACTH-dependent Cushing’s syndrome (CS). It was hoped that the CRH test would discriminate between pituitary and ectopic ACTH secretion. In adults, a rise from basal to peak plasma cortisol of ≥20% and ACTH of ≥50% is consistent with Cushing’s disease (CD). Methods: Twenty-seven paediatric patients, with CD (mean age ± s.d. 13.1 ± 3.2; range 6.4–17.8 years) were investigated in our centre between 1982 and 2005. Results: During the CRH test, all patients showed an increase in cortisol of &gt;20% (range 106–554%). In one patient with ectopic ACTH syndrome, there was no increase in cortisol after CRH. In six paediatric patients with CS due to primary adrenal hyperplasia, no patient showed an increase in cortisol after CRH of &gt;1%. Conclusions: A further suggested use of CRH is to increase the sensitivity of the central to peripheral and interpetrosal ratios of ACTH during inferior petrosal sinus catheterisation (IPSS). Bilateral IPSS with human CRH (hCRH) has been performed in our unit in 21 children with CD, as part of the preoperative preparation prior to transsphenoidal surgery (TSS). Its principal role was to identify the site of the microadenoma. Sixteen of 21 patients (76%) who underwent IPSS with hCRH were cured following TSS. In our view, the CRH test is of value during IPSS by clarifying the position of the microadenoma and in this way contributed to the overall outcome of TSS in paediatric patients with CD.

Ectopic ACTH syndrome: our experience with 25 cases

Ectopic ACTH syndrome (EAS) occurs in about 5-10% of all patients with ACTH-dependent hypercortisolism with most of them caused by intrathoracic neoplasms. It may be associated with overt malignancies or with occult and indolent tumors. We assessed the accuracy of dynamic tests, inferior petrosal sinus sampling (IPSS) using desmopressin, and imaging in the work-up diagnosis of EAS. Tumor markers, imaging, and outcome data from 25 patients (13F/12M) aged 18-72 years. High dexamethasone suppression test (HDDST), desmopressin test, GHRP-6 test, corticotropin-releasing hormone (CRH) test, IPSS, computed tomography (CT), magnetic resonance imaging (MRI), and (111)In-pentetreotide scintigraphy were revised. In 5 out of 20 patients HDDST was positive. In 13 patients who underwent desmopressin test, ACTH- and cortisol-positive responses were seen in six and five patients respectively. GHRP-6 test was positive in two out of three cases. Two patients underwent CRH test with negative response. In the seven patients submitted to IPSS using desmopressin in six of them, none had ACTH gradients. CT was positive in 15 out of 21 patients and MRI in 8 out of 17 cases. (111)In-pentetreotide scintigraphy was positive in three out of five patients. Fourteen patients had intrathoracic tumors, five had pheochromocytomas, three had pancreatic tumors, one had a glomic tumor, and had three occult tumors. Six out of 11 patients with metastasis died and 3 others without metastasis died. IPSS with desmopressin was helpful for differential diagnosis. Patients initially harboring occult carcinoids may also exhibit severe hypercortisolism and those harboring tymic carcinoids had poor prognoses when compared with bronchial carcinoids and pheocromocytomas.

The DEX/CRH neuroendocrine test and the prediction of depressive relapse in remitted depressed outpatients

Hypothalamo–pituitary–adrenal (HPA) system dysfunction is the most characteristic biological alteration found in a majority of depressed patients. Accumulating evidence suggests that the combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) test is highly sensitive to detect HPA system abnormalities. The aim of this study was to evaluate whether the DEX/CRH test has a predictive value for the risk of depressive relapse in outpatients who are in clinical remission from a major depressive episode. Thirty-eight depressed outpatients (23 women, 15 men) in remission (MADRS score ⩽8) underwent the DEX/CRH test and were followed up for 12 months regarding the occurrence of a new depressive episode. In parallel we recruited 24 controls (13 men and 11 women). The main result is a statistically significant difference concerning the delta and AUC numbers for cortisol plasmatic values between the group of patients who relapsed during the 1-year follow-up and control subjects, but not between the group of patients with prolonged remission and controls. These results suggest that in outpatients who are in clinical remission from a major depressive episode, high delta and AUC values in the DEX/CRH test compared to controls subjects can be associated with a higher risk of relapse.

Temperament and hypothalamic–pituitary–adrenal axis function in healthy adults

Traits such as behavioral inhibition and neuroticism have been linked to the development of mood and anxiety disorders. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, a manifestation of the stress response, is often seen in major depression and has also been demonstrated in animals and humans with inhibited temperaments. A recent study found HPA hyperactivity in adults with high levels of neuroticism. The present study investigated associations of temperament and HPA function in 31 healthy adults. Subjects completed diagnostic interviews, questionnaires, and the dexamethasone-/corticotropin-releasing hormone (Dex/CRH) test. Temperament was assessed using the Tridimensional Personality Questionnaire (TPQ). Novelty Seeking was inversely related to plasma cortisol concentrations in the Dex/CRH test. Harm Avoidance and Reward Dependence were not significantly associated with cortisol responses in the Dex/CRH test. The results were not accounted for by psychiatric symptoms or a history of stress or childhood maltreatment. These findings are consistent with previous reports associating temperament factors with HPA axis hyperactivity. Further work is needed to replicate these observations and determine whether HPA axis dysfunction might account for some of the previously reported association of personality factors with mood and anxiety disorders.

Corticotrope hypersecretion coupled with cortisol hypo-responsiveness to stimuli is present in patients with autoimmune endocrine diseases: evidence for subclinical primary hypoadrenalism?

In autoimmune polyglandular syndrome types 1, 2, and 4 primary adrenal insufficiency is present, but its diagnosis is often late. We investigated the function of the hypothalamic-pituitary-adrenal axis in a group of patients with autoimmune diseases (AP) without any symptoms and signs of hypoadrenalism. In 10 AP and 12 normal subjects (NS), we studied cortisol (F), aldosterone (A), and DHEA responses to 0.06 microg adrenocorticotropin (ACTH) (1-24) followed by 250 microg, ACTH and F responses to human corticotropin-releasing hormone (hCRH; 100 microg) and insulin tolerance test (ITT) (0.1 UI/kg). Basal F, A, DHEA, as well as urinary free cortisol and plasma renin activity levels in AP and NS were similar, whereas ACTH levels in AP were higher (P<0.05) than in NS. NS showed F, A, and DHEA response to both consecutive ACTH doses. In AP, the F, A, and DHEA responses to 250 microg ACTH were similar to those in NS, whereas the 0.06 microg ACTH dose did not elicit any significant response. The ACTH responses to hCRH and ITT in AP were higher (P<0.05) than in NS. The F response to hCRH in AP was lower (P<0.05) than in NS, whereas the F response to ITT in AP did not significantly differ from NS. Enhancement of both basal and stimulated corticotrope secretion coupled with reduced adrenal sensitivity to low ACTH dose is present in AP patients without symptoms and signs of hypoadrenalism. This functional picture suggests that normal adrenal secretion is maintained due to corticotrope hyperfunction, suggesting the existence of some subclinical primary hypoadrenalism.