Decreased pituitary sensitivity to glucocorticoids in endurance-trained men

OBJECTIVE: Muscular exercise induces hypothalamo-pituitary-adrenal (HPA) axis activation and when regularly repeated, as in endurance training, leads to HPA axis adaptation. To assess whether non-professional endurance-trained (ET) men with a substantial training load and no clinical or biological features of HPA axis overactivity can present subtle alterations of HPA axis sensitivity to glucocorticoid negative feedback, nine ET men were subjected to HPA axis testing using the dexamethasone-corticotrophin-releasing hormone (CRH) test. DESIGN: Nine endurance-trained men and eight healthy age-matched sedentary men were studied. Morning plasma cortisol and 24 h urinary free cortisol (UFC) were determined and a low dose dexamethasone suppression test (LDDST) was performed followed by CRH stimulation (dexamethasone-CRH test). RESULTS: After a day without physical exercise, at 0800 h, plasma ACTH and cortisol concentrations, and the 24 h UFC and UFC/urinary creatinine (UC) ratio were similar in ET and sedentary men. By contrast, clear differences between the groups were seen in cortisol and ACTH responses to the dexamethasone-CRH test. In eight ET subjects, after LDDST, basal ACTH and cortisol levels were similar to those of sedentary men, whereas one ET subject displayed a poor suppression of cortisol level (131 nmol/l). After injection of CRH, however, three of nine ET men's cortisol levels were not suppressed by dexamethasone but instead displayed significant CRH-induced increase (peak cortisol: 88, 125 and 362 nmol/l). No sedentary subject exhibited any increase in cortisol levels. CONCLUSION: Three of nine ET men with a mean maximum rate of O2 uptake (VO2, max) of 61 ml/kg per min, running 50-70 km per week, were resistant to glucocorticoid suppression during the combined dexamethasone-CRH test.     

The dexamethasone-suppressed corticotropin-releasing hormone stimulation test and the desmopressin test to distinguish Cushing's syndrome from pseudo-Cushing's states

OBJECTIVE: Cushing's syndrome (CS), when fully expressed, is easily diagnosed. Mild cases, however, may require careful distinction from pseudo-Cushing's states as may occur in depression, alcoholism, polycystic ovary disease and visceral obesity. The aim of the present study is a reappraisal of the diagnostic accuracy of the two tests most commonly used to differentiate CS from pseudo-Cushing's: corticotropin-releasing hormone (CRH) stimulation after low dose dexamethasone administration and desmopressin stimulation. DESIGN: The study population comprised 32 patients with CS and 23 with pseudo-Cushing's evaluated retrospectively. METHODS: Urinary free cortisol (UFC), serum cortisol at midnight and after low dose dexamethasone (1 mg overnight and 2 mg over two days) were measured. Further, patients were tested with dexamethasone + CRH and desmopressin and the diagnostic performances of the two tests were compared in the entire series as well as in patients with mild hypercortisolism only (i.e. UFC < 690 nmol/24 h). RESULTS: As expected, measurement of UFC, assessment of cortisol rhythmicity and inhibition after 1 mg/2 mg dexamethasone failed to clearly classify patients with pseudo-Cushing's. Administration of CRH following 2-mg dexamethasone achieved 100% sensitivity but 62.5% specificity. Conversely, desmopressin testing correctly classified all but two patients with pseudo-Cushing's (90% specificity) with 81.5% sensitivity. Diagnostic accuracy was comparable in the subgroup with mild hypercortisolism (21 CS, all 23 pseudo-Cushing's patients). Desmopressin offered an incremental diagnostic effectiveness of 35.8/million inhabitants compared with dexamethasone + CRH as a second-line test. CONCLUSIONS: Neither of the two tests guarantees absolute diagnostic accuracy. The specificity of dexamethasone + CRH is less brilliant than previously reported and appears to be inferior to desmopressin stimulation. The greatest diagnostic effectiveness results from the low-dose dexamethasone test combined with the desmopressin test. Skilful use of dynamic testing and balanced clinical judgement are necessary to distinguish between Cushing's syndrome and pseudo-Cushing's.     

Salivary cortisol measurement in normal-weight, obese and anorexic women: comparison with plasma cortisol.

OBJECTIVE: To compare salivary, plasma and urinary free cortisol (UFC) measurements in patients with anorexia nervosa, in whom an overdrive of the hypothalamic-pituitary-adrenal (HPA) axis is well established but information on salivary cortisol is lacking, in viscerally obese patients in whom subtle abnormalities of cortisol secretion and metabolism are postulated, and in normal-weight healthy women. PARTICIPANTS AND EXPERIMENTAL DESIGN: Measurement of salivary cortisol offers a convenient way to assess the concentrations of free, biologically active cortisol in plasma in different physiopathological settings. Forty-seven drug-free, newly diagnosed women with active restrictive anorexia nervosa, 30 restrictive anorexic women undergoing chronic psychopharmacological treatment, 47 women with mild-to-moderate visceral obesity, 103 women with severe central obesity and 63 normal-weight healthy women entered the study. Salivary and blood samples were collected at 0800 h, 1700 h and 2400 h, together with three consecutive 24-h urine specimens for UFC determination. In controls and patients with anorexia nervosa (n=83), salivary and plasma cortisol were also measured after a 1-mg overnight dexamethasone suppression test (DST). In patients with anorexia nervosa, mood was rated by the Hamilton scale for anxiety and depression. RESULTS: Untreated patients with anorexia nervosa showed increased plasma and salivary cortisol and UFC concentrations (all P<0.001 compared with controls), and decreased cortisol suppression after DST in plasma and saliva (P<0.0001 and P<0.005 respectively compared with controls). These alterations were less pronounced, although still statistically significant, in treated patients with anorexia nervosa. Salivary cortisol was highly correlated with paired plasma cortisol in the whole population and after splitting the participants by group (P<0.0001). However, for plasma cortisol values greater than 500 nmol/l (the corticosteroid-binding globulin saturation point), this parallelism was lost. Taking plasma cortisol as a reference, the level of agreement for post-dexamethasone salivary and plasma cortisol was 58.9% among suppressors and 77.8% among non-suppressors (chi2 test: P<0.01). Decreased 0800 h/2400 h cortisol ratios were observed in plasma and saliva in drug-free patients with anorexia nervosa (P<0.005 and P<0.05 respectively compared with controls), and in saliva in severely obese patients (P<0.05 compared with controls). Depression and anxiety scores were unrelated to cortisol concentrations in any compartment. CONCLUSIONS: Salivary cortisol measurement is a valuable and convenient alternative to plasma cortisol measurement. It enables demonstration of the overdrive of the HPA axis in anorexia nervosa and subtle perturbations of the cortisol diurnal rhythm in women with visceral obesity. With the establishment of more specific and widely acceptable cut-off values for dynamic testing, measurement of salivary cortisol could largely replace plasma cortisol measurement.     

Adrenal gland volume and dexamethasone-suppressed cortisol correlate with total daily salivary cortisol in African-American women

CONTEXT: Population-based studies of associations between subclinical hypercortisolism and risk for disease states, such as type 2 diabetes mellitus, have been difficult to assess because of imprecise measures of glucocorticoid exposure. Alternative measures (salivary cortisol and adrenal gland volume) have not been systematically compared with 24-h urine free cortisol (UFC) in a healthy population. OBJECTIVE: Our objectives were: 1) to determine whether 24-h UFC and total daily salivary cortisol correlated with each other, adrenal gland volume, and salivary cortisol after dexamethasone suppression and 2) to evaluate the association of adrenal gland volume with salivary cortisol after dexamethasone suppression. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 20 healthy, premenopausal African-American women aged 18-45 yr. MAIN OUTCOME MEASURES: Salivary cortisol was assessed at six time points throughout the day simultaneous with 24-h UFC collection. Adrenal gland volume was measured by computed tomography scan. Dexamethasone-suppressed salivary cortisol was measured at 0800 h after administration of 0.5 mg dexamethasone at 2300 h the prior evening. RESULTS: Dexamethasone-suppressed salivary cortisol levels correlated strongly with individual, timed salivary cortisol measurements, total daily salivary cortisol (rs=0.75; P=0.0001; n=20), and adrenal gland volume (rs=0.66; P=0.004; n=17). Total daily salivary cortisol and adrenal gland volume also correlated (rs=0.46; P=0.04; n=19). In contrast, 24-h UFC levels did not correlate with any of the other hypothalamic-pituitary-adrenal axis measures. CONCLUSION: A dexamethasone suppression test or adrenal gland volume may be alternative measures for characterizing subtle subclinical hypercortisolism in healthy adults.     

Alcohol-induced pseudo-Cushing's disease: a study of prevalence with review of the literature

Alcohol-induced pseudo-Cushing's syndrome has been described in numerous case reports, yet the patients have been thoroughly evaluated in only a few cases and the prevalence of hypercortisolism in the alcoholic population is not known. We studied a group of 56 alcoholic men on admission to a detoxification ward using the overnight 1 mg dexamethasone suppression test as a screening test. Most (82%) had normal cortisol suppression, and of those who did not (18%), three of four who could be retested became normal within four days. A smaller group of 14 patients was evaluated with measurement of 24-hour urinary free cortisol, baseline plasma ACTH and serum cortisol measurements, and measurement of ACTH and cortisol after dexamethasone. One patient with sustained abnormal suppression of serum cortisol by dexamethasone (up to 18 days) also demonstrated a striking lack of suppression of plasma ACTH by dexamethasone, compared to the other alcoholics studied. The data obtained on this patient, as well as information obtained from published case reports, are consistent with the concept that alcohol-induced pseudo-Cushing's syndrome is a centrally mediated defect that occurs uncommonly in alcoholics.     

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management

Objective The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. Design Observational retrospective study in a single secondary/tertiary centre. Patients One hundred and seventy‐two patients with adrenal incidentalomas (41 with BI). Measurements Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA‐S), midnight F, 24‐h urine collection for cortisol (UFC), low‐dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F‐post‐LDDST>70 nmol/l and one more abnormality; several diverse cut‐offs were also examined. Results No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F‐post‐LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P < 0·001) and lower DHEA‐S (1·6 ± 1·5 vs 2·5 ± 2·3 μmol/l, P = 0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P < 0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F‐post‐LDDST (P = 0·008) and a decrease in midnight F (P = 0·015) levels. Conclusions Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management.     

Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients

OBJECTIVE: Subclinical hypercortisolism (SH) may play a role in several metabolic disorders, including diabetes. No data are available on the relative prevalence of SH in type 2 diabetes (T2D). In order to compare the prevalence of SH in T2D and matched non-diabetic control individuals, we performed a case-controlled, multicenter, 12-month study, enrolling 294 consecutive T2D inpatients (1.7% dropped out the study) with no evidence of clinical hypercortisolism and 189 consecutive age- and body mass index-matched non-diabetic inpatients (none of whom dropped out). DESIGN AND METHODS: Ascertained SH (ASH) was diagnosed in individuals (i) with plasma cortisol after 1 mg overnight dexamethasone suppression >1.8 microg/dl (50 nmol/l), (ii) with more than one of the following: (a) urinary free cortisol >60.0 microg/24 h (165.6 nmol/24 h), (b) plasma ACTH <10.0 pg/ml (2.2 pmol/l) or (c) plasma cortisol >7.5 microg/dl (207 nmol/l) at 24:00 h or >1.4 microg/dl (38.6 nmol/l) after dexamethasone-CRH (serum cortisol after corticotrophin-releasing hormone stimulus during dexamethasone administration) test, and (iii) in whom the source of glucocorticoid excess was suggested by imaging and by additional biochemical tests (for ACTH-dependent ASH). RESULTS: Prevalence of ASH was higher in diabetic individuals than in controls (9.4 versus 2.1%; adjusted odds ratio, 4.8; 95% confidence interval, 1.6-14.1; P = 0.004). In our population the proportion of T2D which is statistically attributable to ASH was approx. 7%. Among diabetic patients, the presence of severe diabetes (as defined by the coexistence of hypertension, dyslipidaemia and insulin treatment) was significantly associated with SH (adjusted odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P = 0.017). CONCLUSIONS: In hospitalized patients, SH is associated with T2D.     

Screening for Cushing's syndrome in obese women with and without polycystic ovary syndrome

Obesity and insulin resistance, menstrual abnormalities and clinical and biochemical signs of hyperandrogenism are common features in women with polycystic ovary syndrome (PCOS) and Cushing's syndrome (CS). Further, an overdrive of the pituitary-adrenal axis has been documented in PCOS and this condition is often present in women with CS. For this reason, screening for hypercortisolism is often needed in obese women with polycystic ovaries. The aim of this study was to compare the diagnostic value of different screening tests for CS in a population of obese premenopausal women with PCOS and without PCOS (OB) and in a group of patients with CS. We reviewed retrospectively the case records of 117 obese women of reproductive age (60 PCOS and 57 OB, BMI 25.1-70.1, 13-45 yr) who were screened for CS at our Institution in the years 1995-2001 and turned out to be free of the disease. Data were compared with those of 58 premenopausal obese women with active CS (BMI 25.1-50.2 kg/m2, 18-45 yr). Screening for CS was performed by urinary free cortisol (UFC) (three consecutive 24-h urine collections), cortisol circadian rhythm (blood samples taken at 08:00-17:00-24:00 h), and 1 mg overnight dexamethasone suppression test (DST). A 24:00 h plasma cortisol (MNC) of 207 nmol/l, a UFC of 221 nmol/day and plasma cortisol after DST of 50 nmol/l and 138 nmol/l were taken as cut-off values for the diagnosis of CS. As expected, patients with CS showed elevated basal and post-dexamethasone plasma cortisol and UFC levels (p < 0.001 vs OB and PCOS). PCOS had higher UFC (p < 0.005) but not MNC and post-DST plasma cortisol levels compared to OB. DST showed the greatest specificity and diagnostic accuracy in differentiating CS from PCOS and OB (both p < 0.05 vs MNC and UFC, according to the 138 nmol/l criterion) while MNC and UFC displayed a similar discriminatory value. However, by using a lower threshold (50 nmol/l) as response criterion, there were no diagnostic differences between DST and the other tests. Specificity and diagnostic accuracy of UFC measurement was lower in PCOS than in OB (both p < 0.05) whilst there were no differences between groups for DST and MNC. Similarly, the area under the ROC curve relative to DST, giving an estimate of the inherent diagnostic accuracy of the test, was slightly greater than those of MNC and UFC (z = 0.694 and z = 0.833 for DST vs MNC and UFC, respectively, both p = NS). These results indicate that the 1-mg DST and MNC are unaffected by the presence of PCOS and can be safely used to screen for CS premenopausal obese women with PCOS, while caution should be exercised in interpreting mildly elevated UFC levels in these patients.     

A single sleeping midnight cortisol has 100% sensitivity for the diagnosis of Cushing's syndrome

OBJECTIVE The diagnosis of Cushing's syndrome remains a major challenge in clinical endocrinology. Various screening tests are commonly used to support a biochemical diagnosis in the context of clinical suspicion. The aim of this study was to compare the sensitivity in the diagnosis of Cushing's syndrome of a single in-patient sleeping midnight cortisol to a standard 48-hour in-patient low-dose dexamethasone suppression test (LDDST) during the same admission. DESIGN A retrospective analysis was performed on 150 patients Investigated in our department between the years 1970 and 1994 with a confirmed diagnosis of Cushing's syndrome. PATIENTS One hundred and fifty patients with a diagnosis of Cushing's syndrome were analysed: 110 with Cushing's disease; 12 with tumours with ectopic ACTH secretion; 8 with ACTH dependent Cushing's syndrome of so far undetermined origin; 17 with cortisol secreting adrenal tumours; 3 with adrenocortical nodular hyper-plasia. Twenty normal volunteers and nine patients with non-endocrine conditions were also investigated as controls. MEASUREMENTS Plasma cortisol was measured by radioimmunoassay (RIA) in the 122 patients presenting after 1980, and by fluorimetry prlor to this date. RESULTS In all the control subjects the sleeping midnight cortisol was < 50 nmol/l, below the lowest standard of the routine In-house RIA. In every patient with Cushing's syndrome the sleeping midnight cortisol was detectable with a value greater than 50 nmol/l, with a range of 70–2000 nmol/l. In contrast, in three cases, all of whom had proven Cushing's disease on histology, there was uncharacteristic complete suppression of plasma cortisol to < 50 nmol/l following the LDDST. CONCLUSION In this series of 150 cases, a single in-patient sleeping midnight cortisol above 50 nmol/l had a 100% sensitivity for the diagnosis of Cushing's syndrome, clearly different from normal subjects. in contrast, the low-dose dexamethasone suppression test had a sensitivity of 98% even when the drug was administered as an in-patient. We recommend that a low-dose dexamethasone suppression test should not be used alone for confirmation of Cushing's syndrome since it may miss 2% of cases.     

Diagnosis and differential diagnosis of Cushing's syndrome.

The clinical recognition of Cushing's syndrome and its biochemical confirmation is a challenging problem. The best diagnostic approach to patients with suspected Cushing's syndrome is still evolving. The traditional diagnostic approach of urine free cortisol and low-dose dexamethasone suppression testing may be inadequate when the degree of hypercortisolism is mild. Late-night salivary cortisol determinations may evolve as the simplest means of screening patients for suspected hypercortisolism. Repeated measurements of cortisol secretion (urine free cortisol or late-night salivary cortisol) over an extended period of time may be necessary to provide diagnostic certainty. The dexamethasone-CRH test is a reasonable approach in patients with equivocal data. The introduction of reliable, sensitive, and specific plasma ACTH measurements, the use of IPSS for ACTH with CRH stimulation, and the improved techniques of pituitary and adrenal imaging have made the differential diagnosis of Cushing's syndrome relatively straightforward (see Fig. 2). Clinicians who have never missed the diagnosis of Cushing's syndrome or have never been fooled by attempting to establish its cause should refer their patients with suspected hypercortisolism to someone who has.     

Apparent free cortisol concentrations in patients with anorexia nervosa at different stages of the disease

We have measured the total cortisol concentration (TC) and the apparent free cortisol concentration (AFCC) in plasma samples of 17 patients with anorexia nervosa (AN) at different stages of the disease, in basal conditions and after suppression test. We measured free cortisol values directly by a RIA method in dialyzed plasma samples after an equilibrium dialysis system. We have found significantly elevated TC and AFCC values in basal conditions and after suppression test only in the group of patients in the severe stage of the disease. In addition, a significant (p less than 0.05) correlation existed between percent loss of ideal body weight TC and AFCC values after suppression test. Our results suggest that the hypothalamus-pituitary-adrenal axis may be grossly impaired only in the severe stage of AN.     

The continuous 7-hour intravenous dexamethasone suppression test in the differential diagnosis of ACTH-dependent Cushing''s syndrome

OBJECTIVE: A recent report showing disappointingly low sensitivity and specificity for the oral high dose dexamethasone test in the differential diagnosis of Cushing's syndrome prompted us to re-evaluate the results obtained in our centre using the continuous 7-hour intravenous dexamethasone suppression test for this purpose. PATIENTS: 105 patients with ACTH-dependent Cushing's syndrome were included in this study; 78 with Cushing's disease, 8 with ectopic ACTH-secreting tumours and 19 were classified as 'of unknown aetiology'. RESULTS: In 74/78 (94.9%) of patients with Cushing's disease and in 3/8 (37.5%) patients with the ectopic ACTH syndrome, a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values was achieved in the continuous 7-hour intravenous dexamethasone suppression test. Using a plasma cortisol decrease > 190 nmol/l at 7 h as compared to baseline values as the cut-off value, the sensitivity and specificity of the continuous 7-hour intravenous dexamethasone suppression test for the diagnosis of Cushing's disease in patients with ACTH-dependent Cushing's syndrome were 94.9% and 62.5%, respectively. CONCLUSIONS: In patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease > 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test, additional localizing investigations such as bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy should be performed when no clearly discernible pituitary adenoma is observed on MRI studies. Patients with ACTH-dependent Cushing's syndrome with a plasma cortisol decrease < 190 nmol/l at 7 h in the continuous 7-hour intravenous dexamethasone suppression test should also undergo bilateral simultaneous inferior petrosal sinus sampling and/or pentetreotide scintigraphy to demonstrate the presence of a nonpituitary source of ACTH overproduction.     

Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome

CONTEXT: The low-dose dexamethasone suppression test (LDDST) is widely used in confirming a diagnosis of Cushing's syndrome. CRH administration at the end of an LDDST has been reported to improve the diagnostic accuracy of this test. OBJECTIVE: Our objective was to assess whether CRH administration after a standard LDDST (LDDST-CRH test) improves diagnostic accuracy in Cushing's syndrome. DESIGN, SETTING, AND PARTICIPANTS: Thirty-six individuals with a clinical suspicion of Cushing's syndrome each completed a standard LDDST and an LDDST-CRH test at Hammersmith Hospitals NHS Trust, London. The LDDST involved administration of 0.5 mg oral dexamethasone given 6-hourly for 48 h. Serum cortisol was measured 6 h after the last dose of dexamethasone, with a value of 50 nmol/liter or below excluding Cushing's syndrome. Immediately after this, the LDDST-CRH test commenced with administration of a ninth dose of 0.5 mg dexamethasone. Exactly 2 h later, 100 mug human-sequence CRH was administered. Serum cortisol was measured 15 min after the CRH injection, with a value of less than 38 nmol/liter also excluding Cushing's syndrome. MAIN OUTCOME MEASURE: Diagnosis or exclusion of Cushing's syndrome was the main outcome measure. RESULTS: Twelve subjects were diagnosed with Cushing's syndrome (eight Cushing's disease and four primary adrenal). The sensitivity of the LDDST in diagnosing Cushing's syndrome was 100%, with a specificity of 88%. In contrast, although the sensitivity of the LDDST-CRH test was also 100%, specificity was reduced at 67%. These results give a positive predictive value of 80% for the LDDST and 60% for the LDDST-CRH test. CONCLUSION: This small study suggests that the addition of CRH to the LDDST does not improve the diagnostic accuracy of the standard LDDST in Cushing's syndrome.     

Rapid escape of cortisol from suppression in response to i.v. dexamethasone in anorexia nervosa

The suppressive effect of dexamethasone (Dex) on plasma cortisol and beta-lipotrophin (beta LPH) was investigated in patients with anorexia nervosa. Dex was given either orally, 1 mg at 2400 h, with blood sampling at 0800 h on the days before and after Dex, or by i.v. infusion starting at 1100 h (1 mg/h) for 4 h with sampling at 0800, 1100, 1500, 2000 and 2400 h and at 0800 h the following day. The plasma cortisol and beta LPH levels during oral or i.v. Dex administration were compared between patients and normally menstruating women of normal weight. The results showed that Dex administration depressed cortisol significantly (P less than 0.0001) during oral or i.v. infusion in most patients, without, however, suppressing it entirely as is the case in normal women. Moreover, during i.v. Dex infusion, the concentrations of cortisol escaped suppression and were higher than in normal women (less than 50 nmol/l) by 0800 h on the day following infusion. In the patients who were reinvestigated after re-feeding and weight gain (n = 9), a normal suppression of cortisol in response to i.v. Dex infusion was observed in only five cases and a slight failure to suppress, although concentrations were lower than before refeeding, was still evident in four. We concluded that, in anorexia nervosa, cortisol concentration rapidly escapes suppression by Dex administration, and that this escape is not related to the degree of starvation.     

Dexamethasone infusion testing in the diagnosis of Cushing's syndrome

Cushing's syndrome and its various aetiologies is a markedly difficult diagnosis to make given its subtle signs, sometime cyclical nature, and the lack of a single definitive diagnostic test. Although a great variety of diagnostic tests have been developed to assist in the diagnosis, even with the best clinical acumen, biochemistry and medical imaging the diagnosis can remain elusive. The long low and high dose oral dexamethasone suppression test is cumbersome, costly and often requiring an extended inpatient stay. The utility of the dexamethasone suppression test would be greatly enhanced if it could be performed as a short outpatient procedure. In this study we sought to confirm and refine the clinical utility of the high dose 4 mg intravenous dexamethasone suppression test as an alternative diagnostic test for Cushing's syndrome. There were a total of 31 subjects: 8 patients with proven pituitary Cushing's disease, 3 with primary adrenal tumors, 10 with pseudo-Cushing's syndrome and 10 healthy controls. All subjects with pseudo-Cushing's syndrome suppress serum cortisol at +5 and at +24 hours. In subjects with pituitary Cushing's disease, 7 out of 8 (88%) had serum cortisol suppressed at +5 hours but rebounded at +24 hours to at least 70% of the original serum level. Primary adrenal tumors showed a pattern of non-suppression throughout. The 4 mg intravenous dexamethasone suppression test is excellent in ruling out pseudo-Cushing's syndrome. This test is much simpler and more convenient than the oral dexamethasone suppression test in confirming clinical suspicion of pituitary Cushing's disease.     

Effects of the opiate agonist loperamide on pituitary-adrenal function in patients with suspected hypercortisolism

In the present work the possible use of loperamide, an opiate agonist, in the dynamic evaluation of patients with suspected hypercortisolism was investigated. The effects of loperamide on plasma ACTH and cortisol levels were evaluated in normal subjects and in 58 patients with suspected Cushing's syndrome. The results were compared to those obtained after the overnight dexamethasone suppression test. In normal subjects plasma ACTH and cortisol levels were significantly (p less than 0.005) suppressed by both loperamide (16 mg po) and dexamethasone (1 mg po). In 17 patients, in whom the diagnosis of Cushing's syndrome was confirmed by subsequent investigations, neither loperamide or dexamethasone inhibited cortisol (from a baseline of 606 +/- 55 nmol/L) to a nadir of 502 +/- 43 nmol/L and 539 +/- 50 nmol/L, respectively) and ACTH concentration (from a basal level of 70.1 +/- 11.8 pg/ml to a nadir of 46.0 +/- 8.6 pg/ml and 54.3 +/- 7.5 pg/ml, respectively). In 34 patients, in whom the suspect of hypercortisolism was ruled out, either loperamide or dexamethasone suppressed the pituitary-adrenal axis: cortisol and ACTH levels significantly fell from 417 +/- 24 nmol/L and 28.3 +/- 3.5 pg/ml to 60 +/- 6 nmol/L and 14.4 +/- 1.4 pg/ml after loperamide and to 26 +/- 4 nmol and 16.4 +/- 1.7 pg/ml after dexamethasone. In 7 patients discordant responses were observed. In 3 patients treated with antiepileptic drugs ACTH and cortisol levels were inhibited by loperamide, but not by dexamethasone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing's syndrome

Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing's syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial. To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing's syndrome. There were 80 patients with Cushing's disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing's disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001). This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing's syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.     

Pitfalls in the diagnosis of Cushing's syndrome

Among endocrine disorders, Cushing's syndrome (CS) is certainly one of the most challenging to endocrinologists due to the difficulties that often appear during investigation. The diagnosis of CS involves two steps: confirmation of hypercortisolism and determination of its etiology. Biochemical confirmation of the hypercortisolaemic state must be established before any attempt at differential diagnosis. Failure to do so will result in misdiagnosis, inappropriate treatment, and poor management. It should also be kept in mind that hypercortisolism may occur in some patients with depression, alcoholism, anorexia nervosa, generalized resistance to glucocorticoids, and in late pregnancy. Moreover, exogenous or iatrogenic hypercortisolism should always be excluded. The three most useful tests to confirm hypercortisolism are the measurement of 24-h urinary free cortisol levels, low-dose dexamethasone-suppression tests, and determination of midnight serum cortisol or late-night salivary cortisol. However, none of these tests is perfect, each one has different sensitivities and specificities, and several are usually needed to provide a better diagnostic accuracy. The greatest challenge in the investigation of CS involves the differentiation between Cushing's disease and ectopic ACTH syndrome. This task requires the measurement of plasma ACTH levels, non-invasive dynamic tests (high-dose dexamethasone suppression test and stimulation tests with CRH or desmopressin), and imaging studies. None of these tests had 100% specificity and their use in combination is usually necessary. Bilateral inferior petrosal sinus sampling is mainly indicated when non-invasive tests do not allow a diagnostic definition. In the present paper, the most important pitfalls in the investigation of CS are reviewed.     

Reevaluation of the combined dexamethasone suppression-corticotropin-releasing hormone test for differentiation of mild cushing's disease from pseudo-Cushing's syndrome

CONTEXT: The diagnostic accuracy of the combined dexamethasone suppression test (DST)-CRH test for the differential diagnosis between Cushing's disease (CD) and pseudo-Cushing syndrome (PCS) has recently been debated. OBJECTIVE: Our objective was to reevaluate the performance of the DST-CRH test to differentiate CD from PCS and compare it with that of midnight plasma cortisol measurement. SETTING: The study took place at three specialized tertiary care university hospitals. DESIGN: Fourteen patients with PCS and 17 patients with CD matched for 24-h urinary free cortisol were retrospectively studied. MAIN OUTCOME MEASURE: Diagnosis or exclusion of CD was the main outcome measure. RESULTS: A 55 nmol/liter cortisol concentration after dexamethasone (DST) yielded 94% sensitivity, 86% specificity, and 90% diagnostic accuracy. Using the historical 38 nmol/liter threshold for plasma cortisol 15 min after CRH administration, the DST-CRH test achieved 100% sensitivity, 50% specificity, and 77% diagnostic accuracy. Increasing the threshold to 110 nmol/liter improved the specificity and diagnostic accuracy to 86 and 93.5%, respectively. However, diagnostic accuracy was not significantly different from that of the DST. A midnight plasma cortisol concentration of more than 256 nmol/liter was consistent with the diagnosis of CD with 100% sensitivity, specificity, and diagnostic accuracy. CONCLUSION: The diagnostic performance of the DST-CRH test for the differential diagnosis between PCS and mild CD was lower than previously reported. Although the specificity of the test is improved using a revised cortisol threshold, its diagnostic accuracy is not better than that of the standard DST. Our study supports the preferential use of the DST and midnight plasma cortisol measurement as first-line diagnostic tests in equivocal cases.     

Pseudo-Cushing syndrome. Physiopathologic aspects and differential diagnosis

Pseudo-Cushing Syndromes (PCS) are a heterogeneous group of disorders, including alcoholism and depression, that share many of the clinical and biochemical features of Cushing's Syndrome (CS). It has been suggested that hypercortisolism of PCS may be the result of increased hypothalamic corticotropin-releasing hormone secretion in the context of a hypothalamic-pituitary-adrenal axis that is otherwise normally constituted. The substantial overlap in clinical features and daily urinary free cortisol levels between several patients with CS and those with PCS can make the differential diagnosis difficult. The most accurate tests in the distinction of CS from alcohol-induced PCS are dexamethasone-CRH and a midnight serum cortisol measurement. In depressed patients, the insulin tolerance test may be useful, although some overlap may exist. This brief review summarises the principal pathophysiological events of PCS and provides a useful strategy for differential diagnosis.