Constitutive activation of PKA catalytic subunit in adrenal Cushing's syndrome.

BACKGROUND: Corticotropin-independent Cushing's syndrome is caused by tumors or hyperplasia of the adrenal cortex. The molecular pathogenesis of cortisol-producing adrenal adenomas is not well understood. METHODS: We performed exome sequencing of tumor-tissue specimens from 10 patients with cortisol-producing adrenal adenomas and evaluated recurrent mutations in candidate genes in an additional 171 patients with adrenocortical tumors. We also performed genomewide copy-number analysis in 35 patients with cortisol-secreting bilateral adrenal hyperplasias. We studied the effects of these genetic defects both clinically and in vitro. RESULTS: Exome sequencing revealed somatic mutations in PRKACA, which encodes the catalytic subunit of cyclic AMP-dependent protein kinase (protein kinase A [PKA]), in 8 of 10 adenomas (c.617A→C in 7 and c.595_596insCAC in 1). Overall, PRKACA somatic mutations were identified in 22 of 59 unilateral adenomas (37%) from patients with overt Cushing's syndrome; these mutations were not detectable in 40 patients with subclinical hypercortisolism or in 82 patients with other adrenal tumors. Among 35 patients with cortisol-producing hyperplasias, 5 (including 2 first-degree relatives) carried a germline copy-number gain (duplication) of the genomic region on chromosome 19 that includes PRKACA. In vitro studies showed impaired inhibition of both PKA catalytic subunit mutants by the PKA regulatory subunit, whereas cells from patients with germline chromosomal gains showed increased protein levels of the PKA catalytic subunit; in both instances, basal PKA activity was increased. CONCLUSIONS: Genetic alterations of the catalytic subunit of PKA were found to be associated with human disease. Germline duplications of this gene resulted in bilateral adrenal hyperplasias, whereas somatic PRKACA mutations resulted in unilateral cortisol-producing adrenal adenomas. (Funded by the European Commission Seventh Framework Program and others.).

Copeptin Associates with Cause-Specific Mortality in Patients with Impaired Renal Function: Results from the LURIC and the 4D Study.

BACKGROUND: In chronic kidney disease (CKD) arginine vasopressin (AVP) cannot efficiently act via renal V2-receptors. AVP is upregulated leading to augmented activation of V1a- and V1b-receptors, which might contribute to the increase in cardiovascular and infectious complications in CKD. Here, we evaluate copeptin, a surrogate of AVP, and its association with cause specific mortality among patients within the whole spectrum of renal function. METHODS: Copeptin was measured in baseline samples from the LURIC (n = 3131 patients with coronary angiograms) and the 4D-Study (n = 1241 type 2 diabetic hemodialysis patients). Patients were stratified into 4 groups: estimated glomerular filtration rate (eGFR) ≥90 mL/min/1.73 m2, 60-89 mL/min/1.73 m2, <60 mL/min/1.73 m2, and hemodialysis. The association of copeptin with mortality was assessed by Cox proportional hazards regression during 9.9 years of median follow-up in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study and 4 years of median follow-up in the German Diabetes Dialysis Study (4D-Study). RESULTS: Median copeptin increased with decreasing eGFR: 5.6 [interquartile range (IQR), 3.1-8.1] pmol/L (eGFR ≥90 mL/min/1.73 m2), 6.7 (2.9-10.5) pmol/L (eGFR 60-89 mL/min/1.73 m2), 15.3 (6.7-23.9) pmol/L (eGFR <60 mL/min/1.73 m2), and 80.8 (51.2-122) pmol/L (hemodialysis), respectively. Per SD increase in copeptin, the risk of coronary, infectious, and all-cause mortality increased by 25, 30, and 15% [hazard ratios (HR), 1.25; 95% CI, 1.13-1.39; HR, 1.30; 95% CI, 0.98-1.71; and HR, 1.15; 95% CI, 1.05-1.25], respectively, in patients with eGFR 60-89 mL/min/1.73 m2. Except for coronary death, results were similar among patients with more advanced renal disease. No significant association was found in patients with normal renal function. CONCLUSIONS: Copeptin concentrations were independently associated with coronary, infectious, and all-cause mortality in patients with renal impairment. In patients with normal renal function no significant association was found.

Combination chemotherapy in advanced adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

Prognostic value of aldosterone and cortisol in patients hospitalized for acutely decompensated chronic heart failure with and without mineralocorticoid receptor antagonism.

BACKGROUND: Serum aldosterone and cortisol independently predict an increased mortality risk in heart failure (HF), and mineralocorticoid receptor antagonism (MRA) improves survival. The prognostic relevance of aldosterone and cortisol with MRA is unclear. METHODS AND RESULTS: In this post hoc analysis of a prospective cohort, study serum levels of aldosterone and cortisol were measured at baseline in 842 patients with systolic HF. The mean age was 68 ± 12 years (27% female, 45% in New York Heart Association functional class III/IV, 43% with MRA; median follow-up 38 months [interquartile range 30-43 mo]). Crude mortality in the total cohort was 43% (patients with vs without MRA: 34% vs 41%; P = .052). In MRA-naïve patients, higher levels of both aldosterone and cortisol were predictive of increased mortality risk in multivariable Cox regression: hazard ratio (HR) with 95% confidence interval of highest vs lowest tertile for aldosterone: 1.51 [1.02-2.24] (P = .040); and for cortisol: 1.94 [1.28-2.93] (P = .002). In MRA-treated patients, aldosterone (highest vs lowest tertile: HR 1.65 [1.01-2.71]; P = .048) but not cortisol (HR 0.77 [0.44-1.27]; P = .33) was associated with all-cause mortality. Further subgroup analysis revealed that particularly patients with low cortisol and high aldosterone levels had the worst prognosis (HR 5.01 [2.22-11.3]; P < .001), compared with the reference of low cortisol and low aldosterone. Subjects with this profile had larger ventricles and more often coronary artery disease. CONCLUSIONS: In systolic HF, the prognostic value of aldosterone and cortisol levels differs in dependency of MRA intake. The pathophysiologic link between low cortisol, high aldosterone, and increased mortality risk in patients with MRA needs to be clarified.

Timelines in the management of adrenal crisis - targets, limits and reality.

OBJECTIVE: To evaluate current management timelines in adrenal crisis (AC) and to establish time targets and time limits for emergency treatment. DESIGN/PATIENTS: Patients from a prospective study who had reported an AC (n = 46) were contacted and asked about management of their AC. A survey among 24 European endocrinologists collected expert recommendations concerning time targets and time limits for contact-arrival time of emergency health professionals and presentation of emergency card-glucocorticoid (GC) injection time. RESULTS: Median time targets and time limits regarded by experts as adequate for contact-arrival time were 45 and 90 min, respectively, and for card-injection time 15 and 30 min, respectively. Thirty-seven of 46 patients could be interviewed. All patients were equipped with an emergency card but only 23 (62%) with an emergency kit. Seven patients (19%) were trained in GC self-injection. The median time interval between contacting a health professional and arrival was 20 min (range 2-2880 min); ≤45 min: n = 32 (86%), <90 min: n = 34 (92%). The median time interval between arrival and administration of GC was 30 min (range 2-2400 min); ≤15 min: n = 17 (46%), ≤30 min: n = 20 (54%). CONCLUSION: While the time between contacting health professionals and their arrival was within the limits set by experts, initiation of GC administration was delayed in 46% of patients. Thus, improved management of AC needs to focus on shortening the presentation of card-injection time. Given the current reality in the management of AC, promotion of self-injection of GC (s.c. or i.m.) is warranted.

Hypertension and hypertensive cardiomyopathy in patients with a relapse-free history of phaeochromocytoma.

BACKGROUND: In patients with a relapse-free history of phaeochromocytoma/paraganglioma (PCC/PGL), persistent hypertension has been reported, but has not been well characterized. METHODS: In 28 patients [mean age 54·5 (26-81) years] with a relapse-free history of PCC/PGLs, we prospectively analysed resting, supine blood pressure (BP), ambulatory BP, echocardiography, exercise testing, metabolic parameters and retrospectively collected data from the time of diagnosis (baseline). Echocardiographic measures were compared to healthy (n = 28) and hypertensive controls (n = 15). RESULTS: Median follow-up was 6 [1-16] years. Three patients had normal office and ambulatory BP and three patients had only increased office BP. Fifty-four per cent of patients had a blunted circadian rhythm. Comparing normal, hypertensive and PCC/PGL patients, we found significant differences in end-diastolic septal thickness (8·8 ± 0·2, 13·8 ± 0·4, 10·0 ± 0·3 mm, P < 0·05), septal basal thickness (9·0 ± 0·3, 15·9 ± 0·5, 11·2 ± 0·4 mm, P < 0·05) and left ventricular mass (143 ± 8, 255 ± 19, 169 ± 9 g, P < 0·05). In five patients, seven major cardiovascular events were observed. Compared to baseline, no significant difference was found in systolic (140 ± 35 vs 137 ± 18 mmHg) and diastolic (85 ± 18 vs 83 ± 10 mmHg) BP. An increase or a decrease in BP (>10 mmHg) was found in 36% and 39% of patients, respectively. The number of antihypertensive drugs had not changed [1 (0-3) vs 1 (0-4)]. Fewer patients received insulin (1 vs 3) or oral antiglycaemic drugs (2 vs 7). CONCLUSION: Our data indicate that hypertension persists after removal of PCG/PGL in a substantial proportion of patients. Hypertensive heart disease is common, and cardiovascular events are frequent in patients with a history of PCC/PGL.

A copeptin-based classification of the osmoregulatory defects in the syndrome of inappropriate antidiuresis.

Hyponatremia, the most frequent electrolyte disorder, is caused predominantly by the syndrome of inappropriate antidiuresis (SIAD). A comprehensive characterization of SIAD subtypes, defined by type of osmotic dysregulation, is lacking, but may aid in predicting therapeutic success. Here, we analyzed serial measurements of serum osmolality and serum sodium, plasma arginine vasopressin (AVP), and plasma copeptin concentrations from 50 patients with hyponatremia who underwent hypertonic saline infusion. A close correlation between copeptin concentrations and serum osmolality existed in 68 healthy controls, with a mean osmotic threshold±SD of 282±4 mOsM/kg H2O. Furthermore, saline-induced changes in copeptin concentrations correlated with changes in AVP concentrations in controls and patients. With use of copeptin concentration as a surrogate measure of AVP concentration, patients with SIAD could be grouped according to osmoregulatory defect: Ten percent of patients had grossly elevated copeptin concentrations independent of serum osmolality (type A); 14% had copeptin concentrations that increased linearly with rising serum osmolality but had abnormally low osmotic thresholds (type B); 44% had normal copeptin concentrations independent of osmolality (type C), and 12% had suppressed copeptin concentrations independent of osmolality (type D). A novel SIAD subtype discovered in 20% of patients was characterized by a linear decrease in copeptin concentrations with increasing serum osmolality (type E or "barostat reset"). In conclusion, a partial or complete loss of AVP osmoregulation occurs in patients with SIAD. Although the mechanisms underlying osmoregulatory defects in individual patients are presumably diverse, we hypothesize that treatment responses and patient outcomes will vary according to SIAD subtype.

Thyroid function, cardiovascular events, and mortality in diabetic hemodialysis patients.

BACKGROUND: In dialysis patients, the prevalence of thyroid disorders and their impact on specific cardiovascular (CV) events and mortality are largely unknown. The aim of the present study was to analyze whether subclinical thyroid disorders were associated with CV events and mortality. STUDY DESIGN: Prospective multicenter cohort study. SETTING & PARTICIPANTS: Thyroid status and clinical outcomes were explored in 1,000 diabetic hemodialysis patients from 178 centers in Germany. PREDICTOR: Thyroid status, defined by the following cutoff values: euthyroidism (thyrotropin [TSH], 0.30-4.0 mIU/L; free triiodothyronine [T3], 2.7-7.6 pmol/L; and free thyroxine [T4], 11.0-24.0 pmol/L), subclinical hyperthyroidism (TSH<0.3 mIU/L and free T3/free T4 within reference ranges), subclinical hypothyroidism (TSH, 4.1-15.0 mIU/L and free T3/free T4 within reference ranges), euthyroid sick syndrome (free T3<2.7 pmol/L and TSH/free T4 low or within reference ranges). OUTCOMES: During 4 years' follow-up, prespecified adjudicated end points were determined: sudden cardiac death, myocardial infarction, stroke, combined CV events, and overall mortality. Short-term effects within the first 12 months were contrasted to long-term effects (years 2-4). MEASUREMENTS: TSH, free T3, and free T4 levels at baseline. RESULTS: Euthyroidism was present in 78.1% of patients; subclinical hyperthyroidism, in 13.7%; and subclinical hypothyroidism, in 1.6%. Euthyroid sick syndrome was exhibited by 5.4% of patients. The adjusted short-term risk of sudden cardiac death was more than doubled (HR, 2.03; 95% CI, 0.94-4.36) in patients with subclinical hyperthyroidism, and similarly for patients with euthyroid sick syndrome (HR, 2.74; 95% CI, 0.94-7.98) compared with patients with euthyroidism. Short-term mortality was increased almost 3-fold for patients with euthyroid sick syndrome (HR, 2.97; 95% CI, 1.66-5.29), but this effect was not seen in the long term. Subclinical hypothyroidism was not associated with CV events or all-cause mortality. Risks of stroke and myocardial infarction were not affected meaningfully by thyroid disorders. LIMITATIONS: Observational study design. CONCLUSIONS: Sudden cardiac death may be influenced by subclinical hyperthyroidism and euthyroid sick syndrome in the short term. Furthermore, euthyroid sick syndrome is associated strongly with mortality in hemodialysis patients. Regular assessment of thyroid status may help estimate the cardiac risk of dialysis patients.

Rationale and design of the Mineralocorticoid Receptor Antagonists in End-Stage Renal Disease Study (MiREnDa).

BACKGROUND: End-stage renal disease (ESRD) patients exhibit an extraordinarily high annual mortality secondary to cardiac and vascular causes, particularly sudden cardiac death (SCD). Left ventricular (LV) hypertrophy is a frequent finding and constitutes an independent predictor of mortality risk in these patients. Mineralocorticoid receptor antagonists (MRAs) are cardioprotective in heart failure patients and effectively reduce LV mass, but are considered inappropriate in patients with severe renal impairment, given their potential to cause hyperkalaemia. Recent data from small clinical studies suggest that MRAs may be safe in patients undergoing regular haemodialysis, but cardiovascular (CV) protection in these patients is unclear. We here review the literature on CV effects of MRA in dialysis patients and report the design of the Mineralocorticoid Receptor antagonists in End-stage renal Disease (MiREnDa) trial. METHODS: The MiREnDa trial is a prospective randomized, placebo-controlled, double-blind, parallel group, multi-centre, intervention study investigating the effects of spironolactone (50 mg daily) compared with placebo in maintenance haemodialysis patients. The change in LV mass index (LVMI) as assessed by cardiac magnet resonance imaging (CMR) constitutes the primary efficacy end point. Secondary end points include changes in LV geometry and function, office and 24-h ambulatory blood pressure, cardiac arrhythmias, vascular function parameters, measures of heart failure and quality of life. Pre-dialysis potassium levels and the incidence of threatening hyperkalaemia (pre-dialysis potassium ≥6.5 mmol/L) constitute safety end points. CONCLUSIONS: MiREnDa will investigate CV efficacy and safety of spironolactone in haemodialysis patients [clinical trials.gov NCT01691053].

Clinical practice guideline on diagnosis and treatment of hyponatraemia.

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Suspected metastatic adrenocortical carcinoma revealing as pulmonary Kaposi sarcoma in adrenal Cushing's syndrome.

BACKGROUND: Kaposi sarcoma (KS) is a malignant disease most commonly diagnosed in the setting of a human immunodeficiency virus (HIV) infection and in patients receiving immunosuppressive treatment. Pulmonary KS has never been reported in association with endogenous Cushing's syndrome (CS). CASE PRESENTATION: A 60-year-old woman presented with symptoms and signs of CS. Adrenal CS was confirmed by standard biochemical evaluation. Imaging revealed a right adrenal lesion (diameter 3.5 cm) and multiple pulmonary nodules, suggesting a cortisol-secreting adrenal carcinoma with pulmonary metastases. The patient underwent right adrenalectomy with a pathohistological diagnosis of an adrenal adenoma. Subsequent thoracoscopic wedge resection of one lung lesion revealed pulmonary KS with positive immunostaining for human herpes virus 8 (HHV-8). HIV-serology was negative. Hydrocortisone replacement was initiated for secondary adrenal insufficiency after surgery. Post-operative follow up imaging showed complete remission of all KS-related pulmonary nodules solely after resolution of hypercortisolism. CONCLUSION: KS may occur in the setting of endogenous CS and may go into remission after cure of hypercortisolism without further specific treatment.

Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients.

BACKGROUND: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. METHODS AND RESULTS: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06-2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32-6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01-2.62). CONCLUSIONS: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials.

Bariatric surgery for morbid obesity in craniopharyngioma.

OBJECTIVE: To retrospectively analyse the effectiveness of bariatric surgery for hypothalamic obesity in patients with craniopharyngioma (CP). PATIENTS: Patients who developed morbid obesity after surgery for CP and who underwent laparoscopic gastric banding (LAGB), laparoscopic sleeve gastrectomy or gastric bypass were included (n = 9). Patients with common obesity who underwent bariatric surgery served as controls (LAGB n = 40, sleeve gastrectomy n = 49 and gastric bypass n = 54). RESULTS: CP was diagnosed during childhood or adolescence [median (range) 10 (1-21) years] and age at bariatric surgery was 17 [12-30] years. Six patients underwent gastric banding [median follow-up 5.5 years (range 1-9)], 4 had a sleeve gastrectomy [median follow-up 2 (0.4-4) years] and two patients had gastric bypass surgery (median follow-up 3 years). Three patients had more than one type of bariatric surgery. Different from controls, no weight loss was observed after LAGB or sleeve gastrectomy. The two patients who had gastric bypass surgery lost body weight comparable with controls. CONCLUSION: With LAGB and sleeve gastrectomy, no significant loss of body weight was achieved in young adult patients with craniopharyngioma-associated morbid obesity.

Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare malignancy with an unfavorable prognosis. The impact of a locoregional lymph node dissection (LND) has never been defined in this disease. We report the disease-specific outcome of patients treated with or without LND during primary adrenalectomy. METHODS: The medical records of patients followed by the German ACC Registry were retrospectively reviewed. Patients with incomplete resection or distant metastases were excluded. Only if the histologic analysis retrieved 5 or more lymph nodes, an intended LND was assumed (LND group). The predefined primary end point of the study was disease-specific survival. RESULTS: Of 283 included patients, 47 patients (16.6%) were treated with LND, whereas 236 patients (83.4%) underwent surgery without LND. Patients who underwent LND had a larger median tumor size (12.0 cm, range: 2.3-30 cm vs 10.0 cm, range: 4.0-39 cm, P = 0.007) and were more often treated by multivisceral resection (LND: 47.8% vs no-LND: 18.1%; P < 0.001). The other baseline characteristics (age, sex, endocrine activity, Weiss score, Ki-67 index, and adjuvant treatment) did not differ significantly. Median follow-up of all patients still alive was 40 months (range: 6-326). Multivariate analysis adjusted for age, tumor stage, multivisceral resection, adjuvant treatment, and lymph nodes status on preoperative imaging demonstrated a significantly reduced risk for tumor recurrence (hazard ratio: 0.65; 95% confidence interval: 0.43-0.98; P = 0.042) and for disease-related death (hazard ratio: 0.54; 95% confidence interval: 0.29-0.99; P = 0.049) in LND patients when compared with no-LND patients. CONCLUSIONS: Our retrospective data indicate that locoregional LND improves tumor staging and leads to a favorable oncologic outcome in patients with localized ACC.

Copeptin levels associate with cardiovascular events in patients with ESRD and type 2 diabetes mellitus.

In ESRD, the neurohormone arginine vasopressin (AVP) may act primarily through V1a and V1b receptors, which promote vasoconstriction, myocardial hypertrophy, and release of adrenocorticotropic hormone. The preanalytical instability of AVP limits the investigation of whether this hormone associates with cardiovascular events, but the stable glycopeptide copeptin may serve as a surrogate because it is co-secreted with AVP from the posterior pituitary. Here, we studied whether copeptin predicts cardiovascular risk and mortality in ESRD. We measured copeptin at baseline in 1241 hemodialysis patients with type 2 diabetes participating in the German Diabetes and Dialysis Study. The median copeptin level was 81 pmol/L (interquartile range, 81 to 122 pmol/L). In Cox regression analyses, compared with patients with copeptin levels in the lowest quartile (≤51 pmol/L), patients with copeptin levels in the highest quartile (>122 pmol/L) had a 3.5-fold increased risk for stroke (HR, 3.48; 95% CI: 1.71 to 7.09), a 73% higher risk for sudden death (HR, 1.73; 95% CI: 1.01 to 2.95), a 42% higher risk for combined cardiovascular events (HR, 1.42; 95% CI: 1.06 to 1.90), and a 48% higher risk for all-cause mortality (HR, 1.48; 95% CI: 1.15 to 1.90). In contrast, we did not detect significant associations between copeptin levels and risks for myocardial infarction or death caused by congestive heart failure. In conclusion, copeptin levels strongly associate with stroke, sudden death, combined cardiovascular events, and mortality in hemodialysis patients with type 2 diabetes. Whether vasopressin receptor antagonists will improve these outcomes requires further studies.

Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma.

Mitotane [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2-dichloroethane, (o,p'-DDD)] is the only drug approved for the treatment for adrenocortical carcinoma (ACC) and has also been used for various forms of glucocorticoid excess. Through still largely unknown mechanisms, mitotane inhibits adrenal steroid synthesis and adrenocortical cell proliferation. Mitotane increases hepatic metabolism of cortisol, and an increased replacement dose of glucocorticoids is standard of care during mitotane treatment. Recently, sunitinib, a multityrosine kinase inhibitor (TKI), has been found to be rapidly metabolized by CYP3A4 during mitotane treatment, indicating clinically relevant drug interactions with mitotane. We here summarize the current evidence concerning mitotane-induced changes in hepatic monooxygenase expression, list drugs potentially affected by mitotane-related CYP3A4 induction and suggest alternatives. For example, using standard doses of macrolide antibiotics is unlikely to reach sufficient plasma levels, making fluoroquinolones in many cases a superior choice. Similarly, statins such as simvastatin are metabolized by CYP3A4, whereas others like pravastatin are not. Importantly, in the past, several clinical trials using cytotoxic drugs but also targeted therapies in ACC yielded disappointing results. This lack of antineoplastic activity may be explained in part by insufficient drug exposure owing to enhanced drug metabolism induced by mitotane. Thus, induction of CYP3A4 by mitotane needs to be considered in the design of future clinical trials in ACC.

Quality of life is less impaired in adults with congenital adrenal hyperplasia because of 21-hydroxylase deficiency than in patients with primary adrenal insufficiency.

OBJECTIVE: Current replacement regimens fail to restore well-being in patients with primary adrenal insufficiency (PAI). Data on health-related quality of life (HRQoL) in patients with congenital adrenal hyperplasia (CAH) are scarce, inconsistent and largely restricted to women. The objective of the study therefore was to study HRQoL in CAH because of 21-hydroxylase deficiency in comparison with PAI and healthy controls. DESIGN/PATIENTS: In a cross-sectional study, 81 German CAH patients from two tertiary care centres (45 women, 36 men; 71 classical, 10 nonclassical, age 18-65 years) completed three validated self-assessment questionnaires [Short Form-36 (SF-36), Giessen Subjective Complaints List (GBB-24), Hospital Anxiety and Depression Scale (HADS)]. Results were compared to sex- and age-matched controls from questionnaire-specific German reference cohorts and German PAI patients. RESULTS: Congenital adrenal hyperplasia patients had impaired HRQoL in three of five GBB-24 scores whereas SF-36 and HADS scores did not differ from controls. PAI patients showed impairment in more dimensions of the applied tests and, in women, significantly worse scores in several dimensions compared to CAH patients (physical functioning, vitality, social functioning, mental health dimensions of the SF-36, P<0·05 and HADS anxiety score, P<0·05). CONCLUSIONS: HRQoL in CAH is only mildly impaired and significantly less than in PAI patients. Differences between PAI and CAH in HRQoL suggest relevant modulating factors of HRQoL other than hormone replacement therapy itself.

Androgen deficiency in heart failure.

Androgen deficiency is a hormonal disorder that is frequently observed in advanced chronic conditions. A reduction of androgen blood levels may be cause or consequence of the disease, or both. Typical symptoms, such as fatigue or muscle weakness, may be particularly aggravated in heart failure, and disease severity may be indirectly affected by low levels of androgen. Recently, androgen replacement therapy has been suggested as a new treatment option of heart failure symptoms, and placebo-controlled pilot trials showed a modest improvement of physical performance. However, testosterone replacement in elderly patients is not without risks, and the benefit-risk ratio for such adjunct treatment is unclear. This review focuses on the general effects of androgens on the cardiovascular system and outlines expected benefits and suspected side effects of testosterone replacement therapy in patients with heart failure.

Adjuvant mitotane treatment for adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma is a rare neoplasm characterized by a high risk of recurrence after radical resection. Whether the use of mitotane is beneficial as an adjuvant treatment has been controversial. Our aim was to evaluate the efficacy of adjuvant mitotane in prolonging recurrence-free survival. METHODS: We performed a retrospective analysis involving 177 patients with adrenocortical cancer who had undergone radical surgery at 8 centers in Italy and 47 centers in Germany between 1985 and 2005. Adjuvant mitotane was administered to 47 Italian patients after radical surgery (mitotane group), whereas 55 Italian patients and 75 German patients (control groups 1 and 2, respectively) did not receive adjuvant treatment after surgery. RESULTS: Baseline features in the mitotane group and the control group from Italy were similar; the German patients were significantly older (P=0.03) and had more stage I or II adrenocortical carcinomas (P=0.02) than did patients in the mitotane group. Recurrence-free survival was significantly prolonged in the mitotane group, as compared with the two control groups (median recurrence-free survival, 42 months, as compared with 10 months in control group 1 and 25 months in control group 2). Hazard ratios for recurrence were 2.91 (95% confidence interval [CI], 1.77 to 4.78; P<0.001) and 1.97 (95% CI, 1.21 to 3.20; P=0.005), respectively. Multivariate analysis indicated that mitotane treatment had a significant advantage for recurrence-free survival. Adverse events associated with mitotane were mainly of grade 1 or 2, but temporary dose reduction was needed in 13% of patients. CONCLUSIONS: Adjuvant mitotane may prolong recurrence-free survival in patients with radically resected adrenocortical carcinoma.

Epidermal growth factor receptor in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome.

Adrenocortical carcinoma is a rare but highly malignant neoplasm with still limited treatment options. Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in many solid tumors, but its expression in adrenocortical carcinoma has been studied only in a limited number of cases. Therefore, we analyzed the expression of EGFR in 169 adrenocortical carcinoma samples and compared it with 31 adrenocortical adenomas. Additionally, in 30 cases of adrenocortical carcinoma, exons 18-21 of the EGFR gene were cloned and sequenced. EGFR expression was found in 128 of 169 adrenocortical carcinoma samples (76%), and in 60 of these samples (=36%) strong membrane staining was detected. However, there was no significant correlation with clinical outcome. In addition, all 30 sequenced cases revealed unmutated EGFR genes. In contrast, only 1 out of 31 adrenocortical adenomas weakly expressed the EGFR (3%). In summary, EGFR was overexpressed in more than three-quarters of adrenocortical carcinoma cases of this series. However, no mutations of the EGFR gene were found and EGFR expression was not of prognostic relevance. As EGFR is hardly expressed in adrenocortical adenomas, our results suggest that its expression in adrenocortical tumors indicates a malignant phenotype, which may be used in the differential diagnosis between adrenocortical adenomas and carcinomas.