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Atherosclerotic cardiovascular events are one of the common causes of mortality in patients with Cushing's syndrome (CS). Atherogenic dyslipidemia is more common among South Asian Indians as compared to other ethnicities and is likely to worsen among patients with CS. This retrospective study was done over 5 years at a single institute to evaluate the pattern of lipid abnormalities in subjects with CS and the changes in lipid parameters after surgical control of hypercortisolemia. The study was done in two parts. In the first part, records of patients with CS diagnosed over 3 years were retrospectively reviewed. Hormonal and metabolic parameters including fasting plasma glucose (FPG), post prandial plasma glucose (PPPG), HbA1c, serum lipids, serum cortisol and plasma ACTH were recorded. In the second part, lipid parameters were rechecked among patients who underwent surgery and a median follow up of 4±2 months after remission. Out of the 126 patients diagnosed with endogenous CS over 3 years, 100 patients were eligible for inclusion in the study. At baseline, sixty five (65%) patients had dyslipidemia as defined by the NCEP-ATPIII criteria. 47 out of 63 (74.6%) subjects achieved remission after surgical management of CS. 32 (68.1%) of these patients had dyslipidemia prior to surgery. After excluding 1 death, 26 of 46 (56.5%) subjects had dyslipidemia after the follow up period. Lipid abnormalities are common among South Asian Indian subjects with endogenous CS and the pattern persists in most of them, 3 months after surgical correction of hypercortisolism. [ABSTRACT FROM AUTHOR]

Summary: Objective: Hypercortisolism in Cushing's syndrome (CS) is associated with impaired health‐related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT‐CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR‐CS). Methods: Data from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ‐5D questionnaires at baseline and/or following treatment were analysed. Results: At baseline, HRQoL did not differ between PIT‐CS (n = 293) and ADR‐CS (n = 120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT‐CS and ADR‐CS was 41 ± 18 and 44 ± 20, respectively (P = .7). At long‐time follow‐up (>1 year after treatment) total CushingQoL score was however lower in PIT‐CS than ADR‐CS (56 ± 20 vs 62 ± 23; P = .045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow‐up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P < .001), and older age at diagnosis with worse total score (P = .01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow‐up (P < .001). Conclusion: PIT‐CS patients had poorer HRQoL than ADR‐CS at long‐term follow‐up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology. [ABSTRACT FROM AUTHOR]

Objective: Data on the incidence, mortality, and causes of death in patients with Cushing's syndrome (CS) are scarce, due to the rarity of CS. The aim of the study was to analyze mortality in a large cohort of patients of all etiologies and to determine the cause of death. Design: This was a retrospective study of patients with CS, treated over a period of 45 years in the main tertiary referral center in Bulgaria. Methods: Three hundred and eighty-six patients with CS of all etiologies were included. The main outcome measures were the standardized mortality ratio (SMR) and the cause of death. Results: Mean (GS.D.) age at diagnosis was 38G13 years; 84% of patientswerewomen; mean follow-up was 85 months (range: 0-494 months). The SMR in the CS cohort was 4.05 (95% CI 2.50-5.80) (P!0.0001). The following subgroups did not have a significantly increased SMR: patients with Cushing's disease SMR - 1.88 (95% CI 0.69-4.08), adrenal adenomas 1.67 (95% CI 0.20-6.02), and ACTH-independent bilateral adrenal hyperplasia 1.14 (95% CI 0.21-6.34). Patients with adrenal carcinomas, ectopic CS, and those with CS of undetermined etiology had significantly increased SMR: 48.00 (95% CI 30.75-71.42), 13.33 (95% CI 0.00-24.59), and 4.00 (95% CI 0.48-14.45) respectively (P!0.0001). The significant predictors for mortalitywere active disease at death, age, male sex, etiology of the disease, and the overall duration of active disease. The major causes of death were vascular events (40%) - cardiovascular 29%, and cerebrovascular 11% - followed by infections (12%). Conclusions: Patients with CS have increased mortality due to vascular events and infections. [ABSTRACT FROM AUTHOR]

Cushing’s syndrome (CS) is characterized by pathologically elevated free glucocorticoid levels. Endogenous hypercortisolism is usually due to ACTH-secreting pituitary corticotropic adenomas and less often due to ectopic ACTH-secreting neuroendocrine neoplasms or ACTH-independent adrenal cortisol hypersecretion. CS is a serious chronic disease leading to a several-fold increase in cardiovascular morbidity and mortality. Multiple genetic alterations have been described in the setting of sporadic corticotropinoma formation. Changes in the expression profiles have been demonstrated in growth factors and their receptors, cell-cycle regulators and in various genes related to hormonal gene transcription, synthesis and secretion. Sporadic adrenal adenomas and carcinomas may demonstrate dysfunction in genes such as TP53 among others. Cushing’s disease can be an inherited condition also. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenomas (FIPA) together account for 5% of pituitary adenomas. Cushing’s disease occurs infrequently in an inherited setting in both of these conditions. To date only 2 cases of Cushing’s disease have been described in association with mutations in AIP. One case of Cushing’s disease has been reported as part of MEN4, a rare MEN1-like syndrome due to mutation in the CDKN1B gene. Carney complex (CNC) due to PRKAR1A mutations in most cases is associated with CS, mainly as a cause of bilateral adrenal hyperplasia. The cAMP signaling pathway is affected in this setting. In recent times the involvement of genes such as PDE11A, PDE8B and others have expanded the spectrum of the genetic pathophysiology of CS. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Germline mutations of the aryl hydrocarbon receptor (AHR)-interacting protein (AIP) gene confer a predisposition to pituitary adenomas (PA), usually in the setting of familial isolated PA. To provide further insights into the possible role of AIP in pituitary tumour pathogenesis, the expression of AIP and AHR was determined by real-time RT-PCR and/or immunohistochemistry (IHC) in a large series of PA (n=103), including 17 with AIP mutations (AIP(mut)). Variable levels of AIP and AHR transcripts were detected in all PA, with a low AHR expression (P<0.0001 versus AIP). Cytoplasmic AIP and AHR were detected by IHC in 84.0 and 38.6% of PA respectively, and significantly correlated with each other (P=0.006). Nuclear AHR was detected in a minority of PA (19.7%). The highest AIP expression was observed in somatotrophinomas and non-secreting (NS) PA, and multivariate analysis in somatotrophinomas showed a significantly lower AIP immunostaining in invasive versus non-invasive cases (P=0.019). AIP expression was commonly low in other secreting PA. AIP immunostaining was abolished in a minority of AIP(mut) PA, with a frequent loss of cytoplasmic AHR and no evidence of nuclear AHR. In contrast, AIP overexpression in a subset of NS PA could be accompanied by nuclear AHR immunopositivity. We conclude that down-regulation of AIP and AHR may be involved in the aggressiveness of somatotrophinomas. Overall, IHC is a poorly sensitive tool for the screening of AIP mutations. Data obtained on AHR expression suggest that AHR signalling may be differentially affected according to PA phenotype. [ABSTRACT FROM AUTHOR]

The aim of the present study is to evaluate the measurement of midnight salivary cortisol as a method of screening for Cushing’s syndrome (CS). Here we tested the performance of a highly sensitive electrochemiluminescence immunoassay (ECLIA) for midnight salivary cortisol measurement in an extensive clinical study (n=104). Three groups were investigated: 30 patients with CS, 34 with obesity and 40 healthy normal weight controls. All of them collected saliva samples at 24:00 h and urine samples over the same day (24 hour period). An electrochemiluminescence immunoassay was used to measure salivary cortisol. Mean midnight salivary cortisol in healthy volunteers, obese patients and patients with CS was 8.33 ± 3.62, 8.13 ± 4.47 and 33.11 ± 21.68 nmol/l, respectively. No significant difference was found between midnight salivary cortisol in healthy and obese subjects (P>0.05). In contrast, salivary cortisol at midnight was significantly higher in patients with CS (P<0.001) as compared to both other groups. The cut-off point of 14.2 nmol/l yielded a sensitivity of 93.3% and a specificity of 94.2% (AUCROC=0.984 ± 0.01(0.965-1.000). A strong positive correlation between midnight salivary cortisol and urinary free cortisol has been found in the CS group (r=0.686, P<0.0001). Our results demonstrate that measurement of midnight salivary cortisol could be successfully used as a first-line screening method for CS. Our data approve ECLIA as a simple, reliable and timesaving method for the assessment of salivary cortisol. Automated measurement of midnight salivary cortisol by ECLIA would facilitate the routine practice in the screening for CS. [ABSTRACT FROM AUTHOR]