Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

What factors have impact on glucocorticoid replacement in adrenal insufficiency: a real-life study.

PURPOSE: The impact of patient's characteristics on glucocorticoid (GC) replacement therapy in adrenal insufficiency (AI) is poorly evaluated. Aims of this study were to assess the influence of sex and body weight on GC dosing and to describe the choice of GC in AI of different etiologies. METHODS: We retrospectively evaluated hydrocortisone (HC) equivalent total daily dose (HC-TDD) and per-kg-daily dose (HC-KDD) in 203 patients (104 primary AI [pAI], 99 secondary AI [sAI]) followed up for ≥ 12 months. They were treated with HC, modified-release HC (MRHC) or cortisone acetate (CA) and fludrocortisone acetate (FCA) in pAI. RESULTS: At baseline, CA was preferred both in pAI and sAI; at last visit, MRHC was most used in pAI (49%) and CA in sAI (73.7%). Comparing the last visit with baseline, in pAI, HC-TDD and HC-KDD were significantly lower (p = 0.04 and p = 0.006, respectively), while FCA doses increased during follow-up (p = 0.02). The reduction of HC-TDD and HC-KDD was particularly relevant for pAI women (p = 0.04 and p = 0.002, respectively). In sAI patients, no change of HC-KDD and HC-TDD was observed, and we found a correlation between weight and HC-TDD in males (r 0.35, p = 0.02). CONCLUSIONS: Our real-life study demonstrated the influence of etiology of AI on the type of GC used, a weight-based tailoring in sAI, a likely overdosage of GC treatment in pAI women at the start of treatment and the possibility to successfully increase FCA avoiding GC over-treatment. These observations could inform the usual clinical practice.

May an adrenal incidentaloma change its nature?

BACKGROUND: Up to 70% of adrenal masses detected in patients affected by extra-adrenal malignancy are metastatic lesions. Therefore, detection of an adrenal mass in patients with active or previous malignancy requires a careful differential diagnostic workup. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is increasingly being used to determine the malignant potential of adrenal lesions. CLINICAL CASE: We report the case of a 64-year-old man who had a single adrenal metastasis due to non-small-cell lung carcinoma developing on a pre-existing benign adrenal lesion. This metastasis occurred in a phase of perceived oncological remission and was detected thanks to 18F-FDG-PET/CT showing a focal adrenal uptake. Contrast-enhanced computed tomography (CT), performed as part of oncological follow-up, and MRI with chemical shift sequences did not lead to the correct diagnosis. The patient underwent laparoscopic adrenalectomy and the pathological evaluation confirmed a lung carcinoma metastasis. CONCLUSION: The present case highlights the peculiarity of the follow-up of adrenal masses in cancer patients and the primary role of 18F-FDG-PET/CT in the management of such patients.

New perspectives for mitotane treatment of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, mitotane is used in association with chemotherapy to treat the more aggressive forms, while mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.

Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence.

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.

Surgical remission of Cushing's syndrome reduces cardiovascular risk.

OBJECTIVE: Recent studies have questioned the reversibility of complications of Cushing's syndrome (CS) after successful surgical treatment. The aim of this study was to assess the outcome of patients with CS who achieved disease remission compared with those patients with persistent hypercortisolism and matched controls. DESIGN: A retrospective study of 75 patients with CS followed at an academic center. METHODS: Cardiovascular risk profile was evaluated in 51 patients with CS in remission (group 1) and 24 patients with persistent disease (group 2) and compared with 60 controls. Mortality of patients with CS was compared with the background population. RESULTS: In group 1, the frequency of cardiovascular risk factors dropped after disease remission even if it remained higher at the last follow-up than in the control group. In group 2, the frequency of cardiovascular risk factors remained unchanged during follow-up. The rate of cardiovascular and thromboembolic events was higher in group 2 than in group 1, as was the mortality rate (two deaths in group 1 and nine in group 2; ratio of two SMRs, 0.11; 95% CI, 0.011-0.512). Survival was significantly longer in group 1 than in group 2 (87 months, 80-98 vs 48 months, 38-62; P<0.0001). CONCLUSIONS: Successful surgical treatment of hypercortisolism significantly improves cardiovascular risk and may reduce the mortality rate. Patients with persistent disease have increased morbidity and mortality when compared with patients in remission.

Predictors of morbidity and mortality in acromegaly: an Italian survey.

OBJECTIVE: To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients. DESIGN: Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months. RESULTS: A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 µg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87-1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34-2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality. CONCLUSIONS: Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.

Subclinical Cushing's syndrome: definition and management.

Subclinical Cushing's syndrome is an ill-defined endocrine disorder that may be observed in patients bearing an incidentally found adrenal adenoma. The concept of subclinical Cushing's syndrome stands on the presence of ACTH-independent cortisol secretion by an adrenal adenoma, that is not fully restrained by pituitary feed-back. A hypercortisolemic state of usually minimal intensity may ensue and eventually cause harm to the patients in terms of metabolic and vascular diseases, and bone fractures. However, the natural history of subclinical Cushing's syndrome remains largely unknown. The present review illustrates the currently used methods to ascertain the presence of subclinical Cushing's syndrome and the surrounding controversy. The management of subclinical Cushing's syndrome, that remains a highly debated issue, is also addressed and discussed. Most of the recommendations made in this chapter reflects the view and the clinical experience of the Authors and are not based on solid evidence.

AME position statement on adrenal incidentaloma.

OBJECTIVE: To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN: A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT: Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushing's syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT: Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Pros and cons of dexamethasone suppression test for screening of subclinical Cushing's syndrome in patients with adrenal incidentalomas.

The results of dexamethasone suppression tests (DST) in the screening of subclinical hypercortisolism are not readily comparable. Aim of the present study was to review the effectiveness of overnight 1-mg DST and 8-mg DST to look for functional autonomy of clinically inapparent adrenal adenomas. Sixty-eight consecutive patients with clinically inapparent adrenal adenomas were enrolled. All patients underwent 1-mg DST. The 8-mg DST was performed in the 11 patients who had post 1-mg DST cortisol >138 nmol/l and in 11 patients who had post 1-mg DST cortisol between 50 and 138 nmol/l. The a priori probability to have autonomous cortisol secretion was defined by the presence of at least two alterations of the hypothalamic-pituitary-adrenal axis among reduced ACTH concentrations, elevated urinary free cortisol (UFC) or elevated midnight serum cortisol. Cortisol levels >138 nmol/l after the 1-mg DST increases the post-test probability of adrenal functional autonomy to 55%, whereas cortisol levels <50 nmol/l reduce the post-test probability to 8%. Cortisol levels recorded after the 8-mg DST were nonsignificantly lower than after the 1-mg DST and all the patients with cortisol >138 nmol/l after the 1-mg DST maintained cortisol above this cut-point. The 1-mg DST should be considered as the more effective test to detect autonomous cortisol secretion by a clinically inapparent adrenal adenoma when cortisol levels are >138 nmol/l, while cortisol levels <50 nmol/l reduce remarkably the post-test probability of this event. The 8-mg DST seems to replicate by large the results of the 1-mg DST.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease.

Bone metabolic disruption that occurs in bone metastatic prostate cancer could lead to disturbances of calcium metabolism. The prognostic role of either hypocalcemia or hypercalcemia was assessed in a consecutive series of hormone-refractory bone metastatic prostate cancer patients. Serum calcium was measured in 192 patients. The presence of hypocalcemia and hypercalcemia was related with baseline biochemical and clinical characteristics and the role of these two calcium disturbances in predicting prognosis and adverse skeletal-related events (SREs) was assessed. As compared to normocalcemic patients, hypocalcemic patients (n=51) had higher tumor load in bone (P=0.005), higher plasma chromogranin A (CgA, P=0.01), serum alkaline phosphatase (P=0.01), urinary N-telopeptide (NTX, P=0.002) and lower hemoglobin values (P=0.01), while hypercalcemic patients (n=16) had higher plasma CgA (P=0.001) and serum lactate dehydrogenase values (P=0.001), higher bone pain (P=0.003) and a lower frequency of pure osteoblastic lesions (P=0.001). Hypercalcemia was significantly associated with poor prognosis: hazard ratio (HR), 1.9 (95% confidence Interval (CI) 1.2-3.3) and higher risk to develop SREs HR, 2.5 (95% CI 1.2-5.2, P=0.01), while hypocalcemia was not associated with poor prognosis. The prognostic role of hypercalcemia was maintained in multivariate analysis after adjusting for validated prognostic parameters: HR, 2.72 (95% CI 1.1-6.8, P=0.03). These data suggest that serum calcium levels should be taken into account in the clinical decision-making process of bone metastatic prostate cancer patients. Patients with asymptomatic hypercalcemia could benefit of a strict follow-up and an immediate bisphosphonate treatment. Further prospective clinical trials are needed to confirm this finding.

Adrenal pseudocyst mimicking cancer: a case report.

Adrenal cysts are infrequently observed, since less than 500 cases have been reported in Western literature. Adrenal cysts are conventionally divided into four categories: epithelial, parasitic, endothelial, and hemorrhagic. They are characterized by different etiological and pathological features. Some authors suggest that endothelial and hemorrhagic cysts are related and may represent a spectrum of lesions. We report herein the case of an adrenal hemorrhagic pseudocyst that simulated adrenocortical cancer and argue on the clinical clues for a differential diagnosis with other adrenal tumors.

Prevalence of adrenal incidentaloma in a contemporary computerized tomography series.

Adrenal incidentalomas, defined as masses discovered incidentally during imaging investigation of non-adrenal disorders, have become a rather common finding in clinical practice. The prevalence is not well characterized and varies among studies. The aim of the present study was to perform a prospective evaluation of the prevalence of adrenal incidentalomas among subjects undergoing computerized tomography (CT) scan of the chest in a screening program of lung cancer (Tic TAC study) in Piedmont, a region of Northwestern Italy. This evaluation included 520 subjects (382 males and 138 females, aged between 55-82 yr), referred to our hospital from April to December 2001. Twenty-three patients with adrenal masses were identified: 21 adrenal adenomas, 1 myelolipoma, and 1 metastasis of lung cancer. Therefore, the overall prevalence of adrenal lesions was 4.4%, and that of benign adrenal masses was 4.2%. This prevalence is higher than those found in previous CT scan series reported in the literature, probably because of the use of high-resolution CT scanning technology. Another factor that influenced our results is that subject age is skewed towards the decades characterized by a greater occurrence of adrenal masses. The outcome of this study confirms that we are presently able to identify incidentally discovered adrenal masses more often than in early years and that the prevalence of adrenal incidentalomas on CT images is approaching that of autopsy series. The present study provides a reliable estimate of the prevalence of adrenal incidentaloma with currently used CT scanners. Notwithstanding that our subjects were at increased risk of lung cancer, the rate of adrenal metastases was low. We think that the present results can be generalized even if we may disclose the lack of histological diagnosis.

Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing's syndrome.

Either exogenous or endogenous glucocorticoid excess is an established cause of osteoporosis and fractures. Glucocorticoids exert their negative effects on bone through mechanisms that are not yet completely elucidated; however, as many as 50% of patients with Cushing's syndrome suffer from osteoporosis. Bone loss induced by glucocorticoids is potentially reversible after resolution of glucocorticoid excess. It is presently unknown if Cushing's disease (CD) sustained by a pituitary ACTH-producing adenoma and adrenal-dependent Cushing's syndrome (ACS) sustained by an adrenocortical adenoma have a different potential of inducing osteopenia. The aim of the present study was to retrospectively analyze bone mineral density (BMD) in 26 patients with CD (4 men, 22 women, aged 14-79 years), 12 patients with ACS (4 men, 8 women, aged 32-79 years) and 38 healthy subjects carefully matched for sex, age and body mass index (BMI). Measurement of BMD was performed by dual-energy X-ray absorptiometry (DXA) using the Hologic QDR 4500 W instrument. Data were analyzed using absolute BMD values (g/cm2), T-score and Z-score referred to the manufacturer's normative data for the lumbar spine and to the NHANES III dataset for the hip. The patients with CD and ACS were comparable for age, BMI, estimated duration of disease, urinary free cortisol (UFC) levels, midnight serum cortisol and gonadal function. The analysis of variance demonstrated that lumbar bone densitometric parameters were significantly different among the three groups. They were more reduced in patients with ACS (BMD, 0.76+/-0.03 g/cm2; T-score, -2.78+/-0.28; Z-score, -2.25+/-0.30) while patients with CD (BMD, 0.87+/-0.02 g/cm2; T-score, -1.74+/-0.24; Z-score, -0.99+/-0.32) showed DXA values between the first group and controls (BMD, 1.02+/-0.02 g/cm2; T-score, -0.35+/-0.19; Z-score, 0.33+/-0.16). The difference in BMD at the spine remained statistically significant ( P=0.04) after adjustment for the non-significant differences in age, UFC and fat mass between CD and ACS. Conversely, femoral bone densitometric parameters were not significantly different between patients with ACS and CD, even if they were more reduced than in controls. In patients with ACS, we observed a reduction of DHEA-S levels, expressed as standard score ( Z-score) values referred to a group of 180 healthy subjects stratified by sex and different age groups (<40 years, between 40 and 60 years, >60 years) to circumvent the pronounced effect of gender and age on such hormone (ACS DHEA-S Z-score -0.88+/-1.4 versus CD DHEA-S Z-score 2.25+/-2.35, P=0.0001). DHEA-S Z-score values were significantly correlated with lumbar BMD ( r=0.41, P=0.02) and femoral BMD ( r=0.43, P=0.01). DHEA-S Z-score values were also significantly correlated with osteocalcin levels ( r=0.45, P=0.01). Our data suggest that bone loss is greater in ACS than in CD. A plausible explanation comes from the reduced DHEA-S level in ACS since DHEA-S has well known anabolic actions on bone. However, this hypothesis needs to be confirmed in large, prospective series of patients with Cushing's syndrome of different etiology.

Autocrine down-regulation of glucocorticoid receptors by interleukin-11 in human osteoblast-like cell lines.

It has recently been suggested that interleukin (IL)-11 plays a role in the pathogenesis of glucocorticoid (GC)-induced osteoporosis. IL-11 belongs to the gp130 cytokine family, which includes also IL-6. We have previously investigated GC-IL-6 interplay, showing that GC inhibits IL-6 release and IL-6 up-regulates GC receptor (GR) numbers in the human osteoblast-like cell lines Saos-2 and MG-63, which constitutively have an opposite pattern of expression for GR, IL-11, IL-6, alkaline phosphatase and osteoprotegerin (OPG). The aim of this study was to investigate GC-IL-11 interplay in the same two cell lines. First, cells were incubated with cortisol (0.01-1 microM) for 20 h in the presence and in the absence of a known IL-11 secretagogue (IL-1beta); cell media were assayed for IL-11 by ELISA. Secondly, cells were incubated with IL-11 (0.1-100 ng/ml) or specific anti-IL-11 monoclonal antibody for 20 h, and then assayed for GR by a radioligand binding assay. Similar to IL-6, both constitutive and IL-1beta-inducible IL-11 release were dose-dependently inhibited by cortisol (P<0.01); at variance with IL-6, exogenous IL-11 dose-dependently decreased GR numbers in MG-63 cells (P<0.05), while anti-IL-11 antibody significantly increased GR numbers in both cell lines (P<0.05). IL-11-induced reduction of GR in MG-63 cells was confirmed by Western blot analysis. While exerting opposite effects on GR numbers, neither IL-6 nor IL-11 significantly modified GC-dependent inhibition of OPG release. Our data indicate that even physiological concentrations of cortisol negatively modulate IL-11 secretion and demonstrate, for the first time, an inhibitory effect of the cytokine on GR. Thus, the concept of autocrine-paracrine loops that modulate GC action and involve gp130 cytokines is corroborated. These loops could have clinical relevance for the dynamics of bone loss in patients given GC and having high concentrations of these cytokines in the bone microenvironment.

The limited value of the desmopressin test in the diagnostic approach to Cushing's syndrome.

OBJECTIVE: The desmopressin test is generally regarded as an alternative to the CRH test but it is unclear whether desmopressin is as effective as CRH in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, a precise assessment of the operating characteristics of the desmopressin test in comparison with the CRH test has not been reported. The aim of the present study was to make a comparative evaluation of desmopressin and CRH tests in a consecutive cohort of patients with ACTH-dependent Cushing's syndrome and in a group of healthy subjects. DESIGN AND SUBJECTS: We studied 34 patients with Cushing's disease (CD) and nine patients with ectopic ACTH syndrome (EAS). The control group included 30 healthy subjects. Estimates of sensitivity and specificity were determined for a value of ACTH percent increment (Delta%) > 35% and for a Delta % > 50%, following either desmopressin or CRH, to differentiate CD from EAS. The sensitivity and specificity of a composite rule requiring an ACTH net increment (Delta) > 4.5 pmol/l at both values of Delta % was also calculated. When evaluating cortisol responses, the criteria were Delta % > 20% and Delta > 193 nmol/l. Moreover, to allow comparison of individual end points of the desmopressin and CRH tests at multiple levels of Delta % or Delta either for ACTH or cortisol without the bias of predetermined criteria, univariate curves of the receiver operating characteristics (ROC) were constructed by plotting the sensitivity against 1 - specificity at each level. RESULTS: In the patients with CD, the frequency of ACTH response was of 90% after both tests while the figures for cortisol were 73% after CRH and 77% after desmopressin, respectively. In the 15 patients who underwent both tests the magnitude of ACTH and cortisol responses induced by the 2 stimuli were fully comparable. In the patients with EAS a (false) positive ACTH response was found in 2/9 cases (22%) after the CRH test and in 2/5 patients (40%) after the desmopressin test. In the healthy subjects the CRH test was performed in 25 cases and the desmopressin test in 15 cases. The frequency of ACTH response was 52% following CRH and 13% following desmopressin. In the 10 healthy subjects who underwent both tests the ACTH response was significantly greater after CRH than desmopressin. The area under the ROC curve for the ACTH Delta % was significantly different than that occurring by chance following CRH but not desmopressin. The point on the ROC curve closest to 1 corresponded to an ACTH Delta % of 47% (sensitivity 87% and specificity 89%). However, a criterion of 100 % specificity would require an increase in the threshold for the ACTH Delta % to 259%. ROC analysis validated also the use of the ACTH Delta as a method to assess the response to CRH, but not after desmopressin. However, the diagnostic performance of this parameter was reduced in comparison to that of the ACTH Delta %, since the best cut-off for the Delta (6.2 pmol/l) had inferior specificity (79%). The operating characteristics of CRH and desmopressin were worse when considering cortisol responses. CONCLUSIONS: The present data suggest that the CRH test is more reliable than the desmopressin test in determining the aetiology of Cushing's syndrome. The desmopressin test resulted in a high frequency of false positive results in patients with ectopic ACTH secondary to carcinoid tumours. This finding may be due to the capability of these tumours to express the V3 vasopressin receptor through which desmopressin acts. However, the clinical endocrinologist may be confronted with some disturbing cases which are misdiagnosed because it is almost impossible to set a diagnostic criterion providing complete specificity in the differentiation of (occult) ectopic Cushing's syndrome using either CRH or desmopressin tests.