The stable somatostatin analog octreotide has been successfully used for imaging and treatment of a variety of human tumors. In pheochromocytoma, data on somatostatin receptor subtyping have thus far been sparse. Pheochromocytomas often express more than one somatostatin receptor, and it is uncertain by which receptor subtype the functional responses of octreotide are mediated. Here, we have examined somatostatin receptor protein expression in a panel of 52 pheochromocytomas from 35 randomly selected patients by immunostaining with specific polyclonal anti-sst(1-5) and monoclonal mouse anti-SS-14 antibodies. Staining pattern, distribution and subcellular localization of somatostatin receptor subtypes were investigated. Seventeen patients received (111)In-octreotide scintigraphy. Although the vast majority of tumors (90%) showed positive immunohistochemical staining for sst(3), immunoreactive sst(2A) receptors were only seen in 13 tumors (25%). All other somatostatin receptor subtypes were less frequently detected. Interestingly, among sst(3)-positive tumors strikingly different subcellular distributions of immunoreactive sst(3) receptors were observed. In most cases, immunoreactive sst(3) receptors were distributed throughout the cytosol. Scintigraphic localization of tumors larger than 1 cm in diameter was always successful in the presence of immunoreactive sst(2A) receptors. In the absence of sst(2A), true-positive octreotide scintigraphy was only seen in the presence of membrane-associated sst(3) immunoreactivity. Our findings suggest that selective expression of functional membrane-associated sst(3) receptors is sufficient for high tracer uptake during octreotide scintigraphy in a subgroup of human pheochromocytomas. These tumors may represent a potential target treatment with somatostatin receptor agonists with improved sst(3) activity.

Ghrelin is a peptide thought to be involved in the regulation of appetite. Furthermore, significant effects on the release of growth hormone (GH) and ACTH were demonstrated. Contributing to the physiological relevance of this hormone, we investigated the expression of ghrelin and its receptor (GHS-R) in several normal human tissues. RNA samples (BD Biosciences) underwent one-step TaqMan Real-Time RT-PCR. Immunohistochemistry was performed on paraffin-embedded tissues using specific primary antibodies against ghrelin and its receptor. Relevant ghrelin mRNA levels were detected in all human tissues with the highest levels in stomach, pituitary, and small intestine. By immunohistochemistry, ghrelin peptide expression was detectable in reproductive and endocrine organs (ovary, anterior pituitary, adrenal gland), and organs of the gastrointestinal tract (stomach, pancreas). GHS-R1a mRNA expression was demonstrated in 10 of 24 human organs analyzed with the highest levels in pituitary, adrenal gland, and spinal cord. Expression of the receptor peptide was detected by immunohistochemistry in endocrine and reproductive organs (anterior pituitary, thyroid, pancreas, testis), parts of the CNS (cerebrum, cerebellum), and in single cells of bone marrow. Expression of both ghrelin and its receptor in endocrine and reproductive organs may indicate new endocrine or paracrine mechanisms of regulation in these tissues.

Objective: Pheochromocytomas are neoplasms generally characterized by the autonomous production of catecholamines. This study compared various biochemical parameters for the diagnosis of adrenal pheochromocytoma in patients with adrenal mass. Design: One hundred and fifty subjects were studied, including 24 histologically proven pheochromocytomas, 17 aldosterone-secreting and 21 cortisol-secreting adrenal adenomas and 30 nonfunctioning adrenal masses, 16 patients with essential hypertension and 42 healthy normotensive volunteers. Spontaneous blood samples and 24-h urine samples were collected prospectively. Methods: Plasma and urinary epinephrine and norepinephrine levels were measured by high performance liquid chromatography, whereas plasma and urinary metanephrine and normetanephrine levels were determined by radioimmunoassay (RIA). Putative ratio thresholds were calculated by receiver operating characteristic (ROC) analysis to balance between sensitivity and specificity. Results: Plasma normetanephrine was found to be the best single parameter with the highest sensitivity (91.7%) and specificity (95.6%) using a threshold of 126 pg/ml. In combination, plasma normetanephrine and metanephrine had a higher sensitivity of 95.8% with lower specificity (79.4%). All other combinations of plasma and/or urinary parameters demonstrated a lower accuracy. Conclusion: Plasma metanephrines measured by RIA are reliable screening parameters for the diagnosis of pheochromocytoma.European Journal of Endocrinology 154 409-417

In normal human tissues (68)Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis.

PurposeOne of the key problems in the drug therapy of patients with chronic conditions is drug adherence. In 2010 the initiative iNephro was launched (www.inephro.de). A software to support regular and correct drug intake was developed for a smartphone platform (iOS). The study investigated whether and how smartphone users deployed such an application.MethodsTogether with cooperating partners the mobile application “Medikamentenplan” (“Medication Plan”) was developed. Users are able to keep and alter a list of their regular medication. A memory function supports regular intake. The application can be downloaded free of charge from the App Store™ by Apple™. After individual consent of users from December 2010 to April 2012 2042338 actions were recorded and analysed from the downloaded applications. Demographic data were collected from 2279 users with a questionnaire.ResultsOverall the application was used by 11688 smartphone users. 29% (3406/11688) used it at least once a week for at least four weeks. 27% (3209/11688) used the application for at least 84 days. 68% (1554/2279) of users surveyed were male, the stated age of all users was between 6–87 years (mean 44). 74% of individuals (1697) declared to be suffering from cardiovascular disease, 13% (292) had a previous history of transplantation, 9% (205) were suffering from cancer, 7% (168) reported an impaired renal function and 7% (161) suffered from diabetes mellitus. 69% (1568) of users were on <6 different medications, 9% (201) on 6 – 10 and 1% (26) on more than 10.ConclusionA new smartphone application, which supports drug adherence, was used regularly by chronically ill users with a wide range of diseases over a longer period of time. The majority of users so far were middle-aged and male.

Telomerase, a ribonucleoprotein complex that includes the telomerase RNA component, the telomerase-associated protein (TP1), the telomerase catalytic subunit (hTERT), and the heat shock protein 90 (HSP90), is closely related to the malignant potential of human tumors. In pheochromocytomas (PC) it is very difficult to predict malignant potential by conventional histology or immunohistochemical and molecular markers. To test whether the expression of telomerase subunits is reflected in the malignant transition of PCs, we determined their mRNA and/or protein expression in 28 benign and nine malignant PCs and compared the results with telomerase activity. RT-PCR analysis revealed that TP1 was ubiquitously expressed. The telomerase RNA component was found in all malignant (100%) and in 13 of 28 (46%) benign PCs. In contrast, hTERT was clearly associated with aggressive biological behavior. All of the malignant (100%), but only two of 28 benign (7%) PCs expressed hTERT. HSP90 was increased in malignant PCs, but was also expressed at a lower level in benign tumors. High telomerase activity was measurable in hTERT-positive tissues only. Our data indicate that hTERT, HSP90, and telomerase activity are up-regulated in malignant cells of the adrenal medulla. The common expression of hTERT and telomerase activity thus represents an additional prognostic marker that may identify more aggressive tumors.

Objective: Plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio is an established screening test for primary hyperaldosteronism. Due to the increased recognition of adrenal incidentalomas, reliable parameters are required. Determination of active renin concentration (ARC) in contrast to PRA offers advantages with regard to processing and standardization. The present study compared PRA and ARC under random conditions to establish thresholds for the diagnosis of primary hyperaldosteronism. Design and methods: Fifty patients with various adrenal tumors, including ten patients with aldosterone-secreting adrenal adenomas, as well as ten hypertensive patients and 23 normotensive volunteers were studied. PAC and PRA were measured by radioimmunoassay. ARC was determined by an immunoluminometric assay. Results: Receiver operating curve (ROC) analysis suggested a PAC to ARC ratio threshold of 90 ((ng/l)/(ng/l)) (sensitivity 100%, specificity 98.6%) and a ratio threshold of 62 by additional consideration of PAC $200 ng/l (sensitivity 100%, specificity 100%) for the diagnosis of aldosterone-secreting adrenal adenomas. Conclusions: A PAC to ARC ratio of $62 in patients with PAC levels $200 ng/l is a reliable screening method for primary hyperaldosteronism in patients with an aldosterone-producing adenoma under random conditions. Because of its advantages with regard to probe processing and its independence from endogenous angiotensinogen levels, ARC may be preferred to PRA.European Journal of Endocrinology 150 517-523

Objective: Accurate assessment of adrenal function is essential in patients with hypothalamicpituitary-adrenal (HPA) disease. The measurement of salivary cortisol (SaC) instead of serum cortisol (SeC) offers several advantages, such as the determination of the free hormone. We evaluated the diagnostic value of SeC and SaC both unstimulated and during a high-dose short synacthen test (HDT) in comparison to the insulin tolerance test (ITT). Design: Comparative study between 2005 and 2007. Methods: Fifty-five patients with HPA impairment and 21 healthy controls were enrolled. Samples were collected in the early morning and over 120 min during the HDT. Receiver operating characteristic analysis revealed individual thresholds for four HDT periods (0-30, 0-60, 0-90, and 0-120 min). Results: The ITT identified 30 subjects as adrenal insufficient. With respect to the four HDT periods, sensitivity and specificity were 67-79% and 71-88% for SeC, compared with 63-72% and 72-86% for SaC. If upper and lower thresholds (with specificities O95%) were applied, patients were diagnosed in 40-45% by SeC and in 25-31% by SaC. The combination of basal cortisol and HDT allowed a diagnosis in 47-49% (SeC) and in 42-45% (SaC) respectively. Conclusion: We suggest the determination of basal SeC or SaC as first-line test. In comparison to the ITT, the HDT has only limited value in screening for alterations of the HPA axis. If the HDT is performed, sampling may be limited to 30 min post-synacthen, using either SeC or SaC. Due to the ease of collection and the independence of binding proteins, SaC may be preferable.