Prevalence of Malignancies in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Aldosterone excess can cause DNA damage in vitro and in vivo. Single case reports have indicated a coincidence of PA with renal cell carcinoma and other tumors. However, the prevalence of benign and malignant neoplasms in patients with PA has not yet been studied. PATIENTS AND DESIGN: In the multicenter MEPHISTO study, the prevalence of benign and malignant tumors was investigated in 335 patients with confirmed PA. Matched hypertensive subjects from the population-based Study of Health in Pomerania cohort served as controls. RESULTS: Of the 335 PA patients, 119 (35.5%) had been diagnosed with a tumor at any time, and 30 had two or more neoplasms. Lifetime malignancy occurrence was reported in 9.6% of PA patients compared to 6.0% of hypertensive controls (P = .08). PA patients with a history of malignancy had higher baseline aldosterone levels at diagnosis of PA (P = .009), and a strong association between aldosterone levels and the prevalence of malignancies was observed (P = .03). In total, 157 neoplasms were identified in the PA patients; they were benign in 61% and malignant in 25% of the cases (14% of unknown dignity). Renal cell carcinoma was diagnosed in five patients (13% of all malignancies) and was not reported in controls CONCLUSION: Compared to hypertensive controls, the prevalence of malignancies was positively correlated with aldosterone levels, tended to be higher in PA patients, but did not differ significantly.

Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma.

CONTEXT: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head. OBJECTIVE: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. DESIGN/SETTING: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks. PATIENTS/INTERVENTIONS: Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail. MAIN OUTCOME MEASURE: The difference in median mitotane plasma levels between both treatment groups was measured. RESULTS: Despite a difference in mean cumulative dose (440 ± 142 g vs 272 ± 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 ± 494 mg/L · d vs 555 ± 168 mg/L · d (P = .080). CONCLUSIONS: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection.

CONTEXT: Mitotane plasma concentrations ≥ 14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. OBJECTIVE: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations ≥ 1 4 mg/l vs patients who did not. DESIGN AND SETTING: Retrospective analysis at six referral European centers. PATIENTS: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. MAIN OUTCOME MEASURES: RFS (primary) and overall survival (secondary). RESULTS: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; P=0.007), while the risk of death was not significantly altered (HR: 0.59, 0.26-1.34; P=0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. CONCLUSIONS: Mitotane concentrations ≥ 14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

Survivin in adrenocortical tumors - pathophysiological implications and therapeutic potential.

Treatment options for adrenocortical carcinoma (ACC) are very limited. In other solid tumors, small vaccination trials targeting the anti-apoptotic molecule survivin suggested immunological and clinical benefit in selected patients. Therefore, we investigated whether survivin might be a suitable target for immunotherapy in ACC. Survivin mRNA and protein expression was assessed in adrenal tissue specimens [by real-time-PCR in 29 ACC, 24 adrenocortical adenomas (ACA) and 12 normal adrenal glands; by immunohistochemistry in 167 ACCs, 15 ACA, and 5 normal adrenal glands]. Expression was correlated with clinical outcome using Kaplan-Meier and Cox regression analyses. The anti-apoptotic role of survivin was investigated in the SW13 ACC cell line using survivin siRNA. The presence of spontaneous survivin specific T-cells in peripheral blood was assessed by FACS dextramere staining in 29 ACC patients in comparison to healthy controls. Survivin mRNA in ACC was significantly overexpressed when compared with ACA or normal adrenal glands. Immunohistochemistry confirmed survivin protein expression in 97% of the ACCs. In 83% of samples, staining was moderate or high and clinical outcome in this subgroup showed a trend towards poorer prognosis [hazard ratio for death 2.28 (95% CI 0.99-5.28); p=0.053]. Survivin knockdown in SW-13 cell significantly increased the rate of apoptosis. Finally, spontaneous survivin-reactive T cells were detectable in 3 of 29 ACC patients. In conclusion, our data suggest that survivin could play an important role in the anti-apoptotic mechanisms in ACC and provide first hints that targeting survivin might be an interesting new therapeutic approach in this rare disease.

[A 47-year-old patient with paroxysmal arterial hypertension and gastric tumors]. / 47-jährige Patientin mit paroxysmaler arterieller Hypertonie und gastralen Raumforderungen.

Arterial hypertension caused by a paraganglioma is rare and approximately one third of all cases of paraganglioma occur as part of a hereditary syndrome. Among these the Carney-Stratakis syndrome is characterized by the occurrence of paraganglioma/pheochromocytoma and gastrointestinal stromal tumors caused by germline mutations of the succinate dehydrogenase subunit genes (B-D). We report the case of a 47-year-old female patient suffering from Carney-Stratakis syndrome with an endocrine active thoracic paraganglioma which was successfully resected with the assistance of a heart-lung machine and the gastric stromal tumors were removed in a second surgical intervention.

[German adrenocortical carcinoma registry. Surgical therapy results and follow-up treatment]. / Deutsches Nebennierenrindenkarzinom-Register. Chirurgische Therapieergebnisse und Nachbehandlung.

Adrenocortical carcinoma (ACC) is a highly aggressive endocrine disease with an incidence of 1-2 cases per million population per year. Due to the low incidence of ACC knowledge concerning the surgical management is mainly based on retrospective studies or recommendations of isolated experts. Cancer databases, such as the German ACC registry are prerequisite to collect and evaluate clinical data from a large number of patients. For non-metastatic tumor stages, complete tumor resection is the only treatment with curative intent. Open surgery remains the recommended approach for ACC. However, in small tumors with uncertain malignancy a laparoscopic resection by an expert surgeon can be considered. A loco-regional lymphadenectomy should be part of the primary surgical treatment of ACC. Tumor recurrence is common even after an apparently complete primary resection. Therefore, based on the individual risk (tumor size, resection status, proliferation index) adjuvant mitotane treatment is recommended in most patients. Patients with low-risk should be included in the ADIUVO trial. In case of tumor relapse indications for a reoperation should be strongly considered, especially when the time interval since the primary surgery is long (> 12 months) and a complete resection of the recurrent disease seems to be feasible.

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.

[Current TNM classification systems for adrenocortical carcinoma]. / Aktuelle TNM-Klassifikationssysteme für das Nebennierenkarzinom.

Adrenocortical carcinoma (ACC) is a rare malignancy and often difficult to diagnose. It was only in 2003 that the UICC proposed the first TNM classification for ACC. However, an analysis based on data from the German ACC Registry revealed several shortcomings of this classification; in particular, the outcome of patients with UICC stage II and III was not significantly different. Therefore, the European Network for the Study of Adrenal Tumours (ENSAT) developed a revised staging system, the superiority of which was recently confirmed in an independent American cohort. In the ENSAT classification, stage I (tumors ≤ 5 cm) and II (tumors < 5 cm) are non-infiltrating tumors without positive lymph nodes and distant metastases. Stage III is defined by the presence of positive lymph nodes, infiltration of surrounding tissue, or venous tumor thrombus. Stage IV is restricted to patients with distant metastasis. Since the ENSAT classification better reflects patient prognosis than the UICC classification, its use for future clinical and research purposes is recommended. Furthermore, exact documentation of the resection status is essential for optimal decisions on treatment.

Prevention of hypertensive crises in rats induced by acute and chronic norepinephrine excess.

Calcium Channel Blockers (CCBs), competitive α-adrenoceptor blockers, and phenoxybenzamine (POB) are used for preoperative treatment of pheochromocytomas. We analyzed the protection from hypertensive crisis provided by these drugs during acute and chronic norepinephrine excess. To ensure adaptive changes during chronic norepinephrine (NE) excess, we continuously exposed male Wistar rats to NE for 3 weeks (osmotic pumps). Afterwards, blood pressure (BP) was continuously measured while NE boli (0-1000 µg/kg, i. v.) were administered before and after antihypertensive treatment in anesthetized and catheterized rats. A single dose of urapidil (10 mg/kg), nitrendipine (600 µg/kg) and POB (10 mg/kg) lowered BP from 212 ± 12 mmHg by 52 ± 7%, 31 ± 9%, and 50 ± 6%, respectively. With NE boli a maximum BP of 235 ± 29, 240 ± 30 and 138 ± 3 mmHg was measured in urapidil, nitrendipine, and POB treated animals (p<0.05). The number of hypertensive episodes (delta BP >30 mmHg) was 3 (3), 1.5 (0-3), and 0 (0-1) (p<0.05). Because of inferiority, urapidil was excluded from further testing. Chronically NE exposed rats were treated with POB (10 mg/kg/d), nifedipine (10 mg/kg/d), or vehicle for 7 days. Marked BP elevations were observed at baseline (167 ± 7, 210 ± 7 , and 217 ± 7 mmHg, p<0.01) and maximum blood pressure was 220 ± 32, 282 ± 26, and 268 ± 40 mmHg (p<0.001) with NE boli. Further stabilization was achieved combining POB pretreatment with a continuous nifedipine infusion, which effectively prevented BP elevations during NE excess. POB was the most effective drug used in monotherapy, but BP stabilization was superior using a combination of POB pretreatment with a continuous nifedipine infusion in this model.

The syndrome of inappropriate secretion of antidiuretic hormone: diagnostic and therapeutic advances.

Hyponatremia is the most common electrolyte disorder and its presence predicts poor prognosis. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is among the most frequent causes of hyponatremia and is caused by a variety of disorders and pathomechanisms, mostly related to malignancy, pulmonary, or neurologic disorders. The introduction of small molecule vasopressin receptor-2 (VR2) antagonists, so called vaptans, into clinical medicine for the treatment of SIADH makes a reliable diagnosis of SIADH mandatory. This requires structured assessment of essential and supplemental criteria of SIADH, an approach that is currently frequently neglected in clinical routine. Hypertonic saline remains the gold standard in the initial treatment of symptomatic SIADH with severe neurological deficits. However, correction of hyponatremia needs to be slow (<10-12 mmol/l within the first 24 h, and <18 mmol/l within the first 48 h, respectively) to avoid osmotic myelinolysis. Fluid restriction and demeclocyclin have been the most widely used treatments for chronic hyponatremia in SIADH. However, fluid restriction suffers from poor long-term acceptance and demeclocyclin lacks broad availability and has been associated with safety concerns. In controlled clinical trials vaptans have been shown to be efficacious both during short-term and long-term administration (up to 12 months) for mild to moderate SIADH with an acceptable safety profile. However, clinical experience with vaptans in SIADH outside of carefully monitored clinical trials remains still rather limited. Thus, careful postmarketing surveillance will be crucial to fully appreciate the risks and benefits of this new class of drugs in SIADH.

Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines.

To characterize intraadrenal adaptations for inhibition of cortisol synthesis, we analyzed the effects of etomidate (ETO) on steroid hormone secretion and expression of key regulators of steroidogenesis and proliferation in human NCI-h295 adrenocortical cancer cells. Etomidate potently blocked 11beta-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and side chain cleavage enzyme (CYP11A1). This inhibition of steroidogenesis was associated with increased expression of steroidogenic acute regulatory protein (StAR), and CYP11A1 and 17alpha-hydroxylase/17, 20-lyase (CYP17A1) protein levels, but not of the respective mRNA levels. Promoter activity of CYP11A1 and melanocortin 2 receptor (MC2R) was not increased by etomidate in treated cells compared to controls. The increase in protein levels was partially reversed by cycloheximide suggesting post-transcriptional mechanisms but also protein stabilization as underlying cause. Furthermore, ETO exhibited antiproliferative activity paralleled by a decrease in phosphorylation of MEK and ERK1, 2. In summary, ETO exhibits pleiotropic effects on adrenal function in vitro. Inhibition of steroidogenesis is followed by increased levels of steroidogenic key proteins and reduced proliferation. These changes reflect adaptations to maintain steroidogenesis at the cost of adrenal proliferation.

Low circulating androgens and mortality risk in heart failure.

OBJECTIVE: Deficiency of anabolic sex steroids is common in heart failure (HF). The pathophysiological implications of this phenomenon, however, have not been fully elucidated. This clinical study investigated the significance of low serum androgen levels in HF. DESIGN: Prospective cohort study. Patients and Methods In 191 consecutively recruited men with HF (mean age 64 years; New York Heart Association (NYHA) class I-IV 24%/35%/35%/6%) and reduced (ejection fraction (EF) 40%, n=95) left ventricular function total and free serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and sex hormone binding globulin (SHBG) were measured. The median observation period was 859 days. RESULTS: During follow-up 53 patients (28%) died. Whereas total serum testosterone was normal in most patients (91%), free testosterone and DHEAS were reduced in 79% and 23%, respectively. DHEAS and free testosterone, but not total testosterone, were inversely associated with NYHA class (both p<0.01). Lower free testosterone and DHEAS and higher SHBG predicted all-cause mortality risk (hazard ratio (HR) 0.89, 95% CI 0.82 to 0.96 per 1 ng/dl free testosterone, p=0.004; HR 0.95, 95% CI 0.89 to 1.00 per 10 microg/dl DHEAS, p=0.058; and HR 1.18, 95% CI 1.05 to 1.33 per 10 nmol/l SHBG, p=0.006, respectively; adjusted for age and NYHA class). However, further adjustment for carefully selected confounding factors abolished these associations. CONCLUSION: In male HF patients, low serum levels of androgens are associated with adverse prognosis, but this relation is confounded by indicators of a poor health state. The results suggest that low serum androgens develop as a sequel of this progressive multifaceted systemic disorder.

Merits and pitfalls of mifepristone in Cushing's syndrome.

OBJECTIVE: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). DESIGN: Retrospective study of patients treated in seven European centers. METHODS: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. RESULTS: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. CONCLUSION: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

Sex-specific regulation of ENaC and androgen receptor in female rat kidney.

With the beginning of puberty blood pressure increases and is persistently higher in men than in premenopausal women. Sex steroids are known to have complex effects on the renal and cardiovascular system and are involved in blood pressure regulation. The epithelial sodium channel (ENaC) modulates sodium reabsorption in the kidney, but little is known about sex-specific regulation of ENaC subunit expression. Regulation of the androgen receptor (AR) is known to be tissue-specific and age-dependent, but not well studied in the kidney. We investigated the effects of sex steroids on ENaC subunits and renal AR expression in an in vivo rat model. Ovariectomized female Wistar rats were treated with placebo, testosterone, 5 alpha-dihydrotestosterone (DHT) or 17 beta-estradiol (E2) for 14 days, and quantitative PCR and Western immunoblots were performed. DHT significantly decreased expression of all ENaC subunits in female rats, whereas testosterone showed only a trend to lower ENaC expression. These results are in contrast to previous studies where stimulating effects of androgens on the alpha-subunit of ENaC were seen. AR mRNA expression showed a trend to lower levels in females after testosterone treatment in this study. However, estrogen treatment significantly downregulated AR mRNA expression. In male control animals we were able to show a significantly increased expression of AR mRNA upon testosterone treatment. Our data demonstrate that AR and ENaC are regulated by sex steroids. That way sex steroids might modulate renal sodium reabsorption and therefore provide a possible explanation for sex differences in blood pressure.

[Obesity and heart failure]. / Adipositas und Herzinsuffizienz.

Obesity doubles the risk of heart failure independent of comorbidities like hypertension or coronary artery disease potentially mediated by altered hemodynamics to compensate increased mass and metabolic activity. Symptoms of obesity cardiomyopathy do not differ from other forms of cardiomyopathy, but may be easily mixed up with obesity associated symptoms. The diagnosis can be made with imaging techniques like echocardiography or magnetic resonance imaging. Therapeutic approaches include weight control by dietary intervention and exercise, as well as bariatric surgery for the morbidly obese. Heart failure treatment should otherwise follow the general heart failure guidelines.

[Adrenocortical carcinoma. Diagnostic work-up and treatment]. / Das Nebennierenkarzinom. Diagnostik und Therapie.

Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. Preoperatively, a thorough hormonal work-up is mandatory, as the hormonal status may influence the perioperative management and may also provide marker hormones for monitoring of tumour recurrence. CT and MRI are equally sensitive and specific imaging tools for adrenal tumours. For discerning malignancy, assessment of the fat content of the tumour and contrast media wash-out after 10 min are of great value. Complete surgical resection of the tumour offers the only chance for cure. Open adrenalectomy via a flank or thoracoabdominal approach is the standard surgical technique. Intraoperative tumour spillage should be carefully avoided. Even after R0 resection, recurrence of the disease is frequent and regular follow-up for a minimum of 5 years is required. In advanced ACC, the treatment of choice is mitotane with or without cytotoxic chemotherapy (preferably after inclusion into the FIRM-ACT trial).

Detrimental effects of testosterone on post-myocardial infarction remodelling in female rats.

Clinical data suggest an association of increased serum androgens with cardiovascular mortality in females, but not in males. Therefore, we examined effects of chronic anabolic testosterone administration on left ventricular remodeling after myocardial infarction in female rats. Ovariectomized adult female rats were treated with placebo, supraphysiologic testosterone undecanoate (T), estradiol (E(2)), or T+E(2). Two weeks after ovarcectomy, animals underwent sham-operation or coronary artery ligation. Left ventricular remodeling and function were assessed by echocardiography and hemodynamic investigation. In sham operated animals T administration increased serum T levels and led to cardiac hypertrophy, with an increase in the beta/alpha-MHC-ratio and in IGF-1 expression. After coronary artery ligation, infarct size and mortality were similar among the groups. T treatment aggravated left ventricular hypertrophy and chamber dilatation (end-diastolic diameter, E(2) vs. T vs. E(2)+T, 8.6 +/- 0.6 vs. 9.9 +/- 0.3 vs. 9.8 +/- 0.3 mm, p<0.05) and reduced fractional shortening 8 weeks after myocardial infarction. Extracellular matrix remodeling was not altered by hormonal treatment. In conclusion, chronic anabolic T treatment causes myocardial hypertrophy under basal conditions and adversely affects left ventricular remodeling following myocardial infarction in female rats.

Adrenocortical carcinoma -- improving patient care by establishing new structures.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumour with a poor prognosis. Patients present with signs of steroid hormone excess (e.g., Cushing's syndrome) or symptoms due to an abdominal mass. DIAGNOSIS: In case of an adrenal mass, hormonal workup before surgery is required for differential diagnosis, perioperative management, and for follow-up. The imaging of choice is CT or MRI with MRI being of additional use when invasion of big vessels is suspected. Apart from that, the use of 18-FDG-PET is becoming increasingly established. TREATMENT: Surgical resection is the therapeutic option of choice in stages 1 - 3. In stage 4, the adrenolytic compound mitotane is part of the first-line treatment, but often needs to be combined with cytotoxic chemotherapy. Most patients will eventually have a recurrence, so adjuvant treatment (mitotane/tumour bed radiation) has to be considered in high risk patients, even if randomized controlled trials on adjuvant treatment are still lacking. STRUCTURAL PROGRESS: Several national and European structures have recently been established in order to increase our knowledge of ACC, improve therapeutic options and diagnostic procedures, and promote research. GANIMED, as a Germany-wide network of experts on adrenal diseases, has been founded allowing for improved gathering of data and joint studies. ENSAT (European Network for the Study of Adrenal Tumours) has been brought to life, aiming at European standards for therapy, diagnosis and tumour banking. Since 2003, patients can be enrolled in the German ACC Registry. France and Italy have also developed a central registry to collect nationwide data from patients with ACC. For the first time, patients with metastatic/unresectable ACC can participate in a prospective controlled randomized trial comparing two different cytotoxic chemotherapy regimes (FIRM-ACT).

Failure of recombinant human growth hormone treatment to improve congestive heart failure in hypopituitarism.

Growth hormone (GH) deficiency decreases left ventricular (LV) contractility, induces LV chamber dilatation and promotes progression to congestive heart failure. It is, however, controversial, whether GH replacement therapy in addition to standard medical heart failure therapy should be considered as routine treatment in GH deficient patients with heart failure. In the present report of a 64-year-old GH deficient patient with heart failure, we demonstrate by using Doppler echocardiography, magnetic resonance imaging and 31P NMR spectroscopy that even a 12 month period of GH replacement therapy had no sustained effect on morphometric or functional parameters of LV performance nor on clinical signs or symptoms of heart failure. It is concluded that GH replacement therapy should currently not be regarded as standard heart failure therapy in patients with GH deficiency and should only be employed under careful monitoring including close follow-up in a standardized way.