Morbidities and mortality among hospitalized patients with hypopituitarism: Prevalence, causes and management.

Hypopituitarism is a highly heterogeneous multisystem disorder that can have a major impact on long-term morbidity and mortality, but even more so during acute medical conditions requiring hospitalization. Recent studies suggest a significant in-hospital burden with prolonged length of stay, increased rate of intensive care unit (ICU) admission, and initiation of mechanical ventilation - all of which may lead to an increased risk of in-hospital mortality. On the one hand, patients with hypopituitarism are often burdened by metabolic complications, including obesity, hypertension, dyslipidemia, and hyperglycemia, which alone, or in combination, are known to significantly alter relevant physiological mechanisms, including metabolism, innate and adaptive immune responses, coagulation, and wound healing, thereby contributing to adverse in-hospital outcomes. On the other hand, depending on the extent and the number of pituitary hormone deficiencies, early recognition of hormone deficiencies and appropriate management and replacement strategy within a well-organized multidisciplinary team are even stronger determinants of short-term outcomes during acute hospitalization in this vulnerable patient population. This review aims to provide an up-to-date summary of recent advances in pathophysiologic understanding, clinical implications, and recommendations for optimized multidisciplinary management of hospitalized patients with hypopituitarism.

In-vivo inhibition of neutral endopeptidase 1 results in higher absorbed tumor doses of [177Lu]Lu-PP-F11N in humans: the lumed phase 0b study.

BACKGROUND: A new generation of radiolabeled minigastrin analogs delivers low radiation doses to kidneys and are considered relatively stable due to less enzymatic degradation. Nevertheless, relatively low tumor radiation doses in patients indicate limited stability in humans. We aimed at evaluating the effect of sacubitril, an inhibitor of the neutral endopeptidase 1, on the stability and absorbed doses to tumors and organs by the cholecystokinin-2 receptor agonist [177Lu]Lu-PP-F11N in patients. In this prospective phase 0 study eight consecutive patients with advanced medullary thyroid carcinoma and a current somatostatin receptor subtype 2 PET/CT scan were included. Patients received two short infusions of ~ 1 GBq [177Lu]Lu-PP-F11N in an interval of ~ 4 weeks with and without Entresto® pretreatment in an open-label, randomized cross-over order. Entresto® was given at a single oral dose, containing 48.6 mg sacubitril. Adverse events were graded and quantitative SPECT/CT and blood sampling were performed. Absorbed doses to tumors and relevant organs were calculated. RESULTS: Pretreatment with Entresto® showed no additional toxicity and increased the stability of [177Lu]Lu-PP-FF11N in blood significantly (p < 0.001). Median tumor-absorbed doses were 2.6-fold higher after Entresto® pretreatment (0.74 vs. 0.28 Gy/GBq, P = 0.03). At the same time, an increase of absorbed doses to stomach, kidneys and bone marrow was observed, resulting in a tumor-to-organ absorbed dose ratio not significantly different with and without Entresto®. CONCLUSIONS: Premedication with Entresto® results in a relevant stabilization of [177Lu]Lu-PP-FF11N and consecutively increases radiation doses in tumors and organs. Trial registration clinicaltrails.gov, NCT03647657. Registered 20 August 2018.

Canagliflozin and Metabolic Associated Fatty Liver Disease in Patients With Diabetes Mellitus: New Insights From CANVAS.

CONTEXT: Metabolic dysfunction-associated fatty liver disease (MAFLD) is highly prevalent among patients with type 2 diabetes mellitus (T2DM); however, there is still no approved pharmacological treatment. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been suggested to beneficially modify liver-related outcomes in patients with diabetes. OBJECTIVE: We aimed to investigate the effects of the SGLT-2 inhibitor canagliflozin on liver-related outcomes in patients with advanced T2DM and high cardiovascular risk. METHODS: We performed a secondary post hoc analysis of 2 large double-blind randomized controlled trials, CANVAS (NCT01032629) and CANVAS-R (NCT01989754), which included patients with T2DM and high cardiovascular risk who were randomized to receive either canagliflozin or placebo once daily. The primary endpoint was a composite of improvement of alanine aminotransferase (ALT) levels >30% or normalization of ALT levels. Secondary endpoints included change in noninvasive tests of fibrosis and weight reduction of >10%. RESULTS: In total, 10 131 patients were included, with a median follow-up of 2.4 years (mean age 62 years; mean duration of diabetes 13.5 years; 64.2% male). Of those patients, 8967 (88.5%) had MAFLD according to hepatic steatosis index and 2599 (25.7%) exhibited elevated liver biochemistry at baseline. The primary composite endpoint occurred in 35.2% of patients receiving canagliflozin and in 26.4% with placebo (adjusted odds ratio [aOR] 1.51; 95% CI, 1.38-1.64; P < .001). Canagliflozin led to improvements in some noninvasive tests of fibrosis (NFS, APRI, FNI). Significant weight reduction of >10% (within 6 years) was achieved in 12.7% with canagliflozin compared to 4.1% with placebo (aOR 3.45; 95% CI, 2.91-4.10; P < .001). CONCLUSION: In patients with T2DM, treatment with canagliflozin vs placebo resulted in improvements in liver biochemistry and metabolism and might beneficially affect liver fibrosis.

Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis.

BACKGROUND: Several available therapies for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. OBJECTIVES: To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis. SEARCH METHODS: We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. SELECTION CRITERIA: We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data to a pre-designed data extraction form. Multi-arm studies were included in the network meta-analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression-free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta-analyses. A frequentist approach was used to compare the efficacy of therapies. MAIN RESULTS: We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression-free survival in the network meta-analysis. Precision-of-treatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta-analysis of progression-free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]), interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin analogues. The results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta-analysis (and underlying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). AUTHORS' CONCLUSIONS: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Glucagon-like Peptide-1 Receptor as Emerging Target: Will It Make It to the Clinic?

The glucagon-like peptide-1 receptor (GLP-1R) is an emerging target due to its high expression in benign insulinomas as well as in islet cell hypertrophia/hyperplasia (nesidioblastosis) and pancreatic ß-cells. In 2008, occult insulinomas were localized for the first time in men using the metabolically stable radiolabeled glucagon-like peptide-1 (GLP-1) agonist [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 (111In-DTPA-exendin-4). Afterward, several radiopharmaceuticals for GLP-1R PET/CT imaging were synthesized and evaluated, for example, [Nle14,Lys40(Ahx-DOTA-68Ga)NH2]-exendin-4 (68Ga-DOTA-exendin-4), [Cys40(MAL-NOTA-68Ga)NH2]-exendin-4 (68Ga-NOTA-exendin-4), and [Lys40(NODAGA-68Ga)NH2]-exendin-4 (68Ga-NODAGA-exendin-4). Several prospective comparison studies provided evidence that GLP-1R PET/CT is significantly more sensitive than contrast-enhanced MRI (ceMRI), contrast-enhanced CT (ceCT), GLP-1R SPECT/CT, somatostatin receptor PET/CT, and SPECT/CT in the detection of benign insulinomas, and insulinomas in the context of multiple endocrine neoplasia type 1. As a result, the European Neuroendocrine Tumor Society guidelines recommend GLP-1R imaging or selective intraarterial calcium stimulation and venous sampling (ASVS) in patients for whom there is a clinical suspicion of having an insulinoma but who have a negative ceMRI/ceCT or negative endoscopic ultrasound. Furthermore, there is growing evidence that GLP-1R PET/CT can visualize and localize adult nesidioblastosis. This is clinically relevant as the distinction between focal and diffuse nesidioblastosis is critical in directing a therapeutic strategy in these patients. Prospective studies have proven the clinical relevance of GLP-1R imaging as it is often the only imaging modality able to localize the insulinoma or nesidioblastosis. It is therefore likely that this noninvasive imaging modality will replace the invasive localization of insulinomas using ASVS. More experimental indications for GLP-1R imaging include the diagnosis of an insulinoma/nesidioblastosis in patients with postprandial hypoglycemia after bariatric bypass surgery and monitoring ß-cells in patients with brittle type 1 diabetes after islet-cell transplantation. We believe that these indications and possibly future indications will bring GLP-1R imaging to the clinic.

Excess Mortality Among Hospitalized Patients With Hypopituitarism-A Population-Based, Matched-Cohort Study.

CONTEXT: Patients with hypopituitarism face excess mortality in the long-term outpatient setting. However, associations of pituitary dysfunction with outcomes in acutely hospitalized patients are lacking. OBJECTIVE: The objective of this work is to assess clinical outcomes of hospitalized patients with hypopituitarism with or without diabetes insipidus (DI). DESIGN, SETTING, AND PATIENTS: In this population-based, matched-cohort study from 2012 to 2017, hospitalized adult patients with a history of hypopituitarism were 1:1 propensity score-matched with a general medical inpatient cohort. MAIN OUTCOME MEASURES: The primary outcome was in-hospital mortality. Secondary outcomes included all-cause readmission rates within 30 days and 1 year, intensive care unit (ICU) admission rates, and length of hospital stay. RESULTS: After matching, 6764 cases were included in the study. In total, 3382 patients had hypopituitarism and of those 807 (24%) suffered from DI. All-cause in-hospital mortality occurred in 198 (5.9%) of patients with hypopituitarism and in 164 (4.9%) of matched controls (odds ratio [OR] 1.32, [95% CI, 1.06-1.65], P = .013). Increased mortality was primarily observed in patients with DI (OR 3.69 [95% CI, 2.44-5.58], P < .001). Patients with hypopituitarism had higher ICU admissions (OR 1.50 [95% CI, 1.30-1.74], P < .001), and faced a 2.4-day prolonged length of hospitalization (95% CI, 1.94-2.95, P < .001) compared to matched controls. Risk of 30-day (OR 1.31 [95% CI, 1.13-1.51], P < .001) and 1-year readmission (OR 1.29 [95% CI, 1.17-1.42], P < .001) was higher among patients with hypopituitarism as compared with medical controls. CONCLUSIONS: Patients with hypopituitarism are highly vulnerable once hospitalized for acute medical conditions with increased risk of mortality and adverse clinical outcomes. This was most pronounced among those with DI.

Pitfalls in the Detection of Insulinomas With Glucagon-Like Peptide-1 Receptor Imaging.

PURPOSE: Physiological pancreaticoduodenal uptake of radiolabeled exendin-4 in Brunner glands of the proximal duodenum is the most common pitfall for false interpretation of glucagon-like peptide-1 receptor (GLP-1R) imaging. The aim of this study was to analyze the pancreaticoduodenal uptake in GLP-1R PET/CT and SPECT/CT images and to identify additional potential reading pitfalls in patients with suspected insulinoma. METHODS: A post hoc analysis of a prospective study, including 52 consecutive patients, was performed. All patients underwent 1 Ga-exendin-4 PET/CT and 2 In-exendin-4 SPECT/CT scans (4 and 72 hours postinjection) in a randomized crossover order. Three board-certified nuclear medicine physicians read all scans independently. They were unaware of other results. Reference standard was surgery with histopathological confirmation of an insulinoma/nesidioblastosis and normalization of blood glucose levels after surgery. RESULTS: There were no false-positive readings. However, there were a number of false-negative PET/CT and SPECT/CT readings, respectively: (1) due to false interpretation of uptake in the pancreaticoduodenal region (falsely interpreted as physiological uptake in Brunner glands instead of an insulinoma in 0.6% vs 9.0%), (2) due to ectopic insulinoma (0% vs 2.6%), (3) due to small insulinoma (1.9% vs 5.1%), (4) due to insulinoma overlap with kidneys (1.9% vs 4.5%), and (5) due to nesidioblastosis (0.6% and 1.9%). Pitfalls were identified in all GLP-1R PET/CT and SPECT/CT scans. CONCLUSIONS: Peripancreatic uptake, small size of an insulinoma, insulinoma overlap with kidneys, and presence of nesidioblastosis are potential pitfalls in GLP-1R imaging, which can lead to false reading results.

Brunner's Gland Hyperplasia in a Patient after Roux-Y Gastric Bypass: An Important Pitfall in GLP-1 Receptor Imaging.

Severe cases of postprandial hypoglycaemia after bariatric surgery can be a diagnostic and therapeutic challenge. The diagnostic role of 68Ga-DOTA-Exendin-4 PET/CT in postbariatric hypoglycaemia for further treatment decisions is unclear. We present a case of a 50-year-old woman with frequent and severe postprandial hypoglycaemic (≤2.5 mmol/L) episodes starting three years after Roux-Y gastric bypass. Despite strict dietary adherence and several medical therapies, the patient remained severely affected, and 68Ga-DOTA-Exendin-4 PET/CT was performed to exclude atypical presentation of an insulinoma or nesidioblastosis. No pancreatic abnormalities were found, but intensive tracer accumulation in the first and second part of the duodenum was detected, which proved to be hyperplastic Brunner's glands on histology and were strongly positive for the glucagon-like peptide-1 receptor. This case provides histopathological verification that duodenal 68Ga-DOTA-Exendin-4 uptake is caused by uptake in Brunner's glands and points to a potential relationship between bariatric surgery and Brunner's glands.

Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 µg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion:177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.

HbA1c-testing: Evaluation of two point-of-care analysers.

BACKGROUND: HbA1c is a critical parameter for the medical management of patients with diabetes mellitus. Interventions that reduce HbA1c levels lead to a diminution of microvascular complications. For two decades, point of care testing (POCT) methods have been regularly used to measure HbA1c. The results significantly impact on the management of patients with diabetes mellitus and the accuracy of the results is critical. It is important to know the performance of common methods of HbA1c measurements in daily life. We, therefore, aimed at evaluating the accuracy of two different analysers especially developed for POCT and compared them to a reference method. METHODS: We prospectively tested two widely used POCT methods to measure HbA1c, namely Afinion™ AS100 Analyzer (Axis-Shield, Oslo Norway) and DCA Vantage™ Analyzer (Siemens Healthcare Diagnostics, Tarrytown NY, US) in venous samples of 100 patients. As a reference method, we used the high-performance liquid chromatography method G8 HPLC used in the Biochemistry Laboratory of the Inselspital Bern. The National Glycohaemoglobin Standardization Program (NGSP) has certificated all methods used in this study. The comparability and degree of agreement was assessed using Bland-Altman plot. RESULTS: The HbA1c levels ranged from 33 to 116 mmol/mol (5.2-12.8%), 31-122 mmol/mol (5.0-13.3%) and 30-119 mmol/mol (4.9-13%) for Afinion™, DCA Vantage™ and G8 HPLC Analyzer, respectively. The 95% limits of agreement were between -0.84 and +0.30 for the Afinion™ and -0.71 and +0.29 for DCA Vantage™. The results of both POCT were significantly lower with a bias of -0.27% and -0.21% (p < 0.0001) for Afinion™ and DCA Vantage™ Analyzer, respectively. CONCLUSIONS: The POCT methods tested in this study showed a good correlation with the laboratory reference method, however, with an overall negative bias.

Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis.

IMPORTANCE: Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs). OBJECTIVE: To assess the relative safety and efficacy of therapies for NETs. DATA SOURCES: PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial. STUDY SELECTION: Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used. MAIN OUTCOMES AND MEASURES: Disease control, progression-free survival, overall survival, adverse events, and quality of life. RESULTS: The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177-dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies. CONCLUSIONS AND RELEVANCE: The findings from this study suggest that a range of efficient therapies with different safety profiles is available for patients with NETs.

Changes of Thyroid Hormones and Their Binding Proteins during Plasma Exchange for Polyneuropathy in a Patient with Substituted Hypothyroidism due to Hashimoto's Thyroiditis.

BACKGROUND: Pharmacodynamic studies and data concerning adaptation of thyroid substitution in patients with substituted hypothyroidism during plasma exchange (PE) is not available. CASE REPORT: We measured TSH, fT3 and fT4, total T4, thyroxin binding globulin (TBG), and albumin before and after 5 PE procedures in a 37-year-old women who underwent PE for a therapy-resistant polyneuropathy. Thyroxin was increased empirically by 8% resulting in a dose of 1.95 µg/kg per day. RESULTS: Despite larger reductions of total T4 and TBG over a series of 5 PEs (40-50% from baseline), only small reductions of 8% in fT3 and fT4 concentrations were documented with a concomittant increase in TSH level. Changes of fT4, fT3, and TSH remained within normal range. CONCLUSIONS: i) Despite a significant decrease in total thyroid hormone pool following PE, fT4, fT3, and TSH concentrations changed only slightly. ii) Based on this observation, a general increase in thyroid replacement therapy before PE cannot be recommended, but considered in case of a high normal TSH level.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy.

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

Peak oxygen uptake test in the assessment of growth hormone deficiency.

This study aimed at evaluating a peak oxygen uptake test as a simple diagnostic tool to assess growth-hormone deficiency (GHD) in adults. Based on the findings of multiple growth hormone (GH) samplings after the exercise, a single GH sample taken 15 min postexercise revealed high accuracy in the diagnosis of GHD in the present study. A standardized peak oxygen uptake test may, therefore, provide an accurate alternative to more invasive tests of GHD.

Klinik und Diagnose von Hypogonadismus und Andropause.

Diagnosis and therapy of male hypogonadism is still a challenge because of the unspecific clinical signs and symptoms. The clinical presentation of a androgen deficiency is age-related. In the adult men, one can often observe fatigue, decrease in physical capacity, loss of libido and erectile dysfunction. At the physical examination, genitalia have always to be assessed in search of a testes/penis atrophy. Two fasting measurements of total testosterone concentrations by a reliable assay are needed to confirm the diagnosis. By assessing gonadotropines the origin of hypogonadism can be determined (central/secondary or peripheral/primary). Exogenous administration of androgens should be considered in young, sportive, healthy and muscular males. Patients with metabolic syndrome should only be screened for hypogonadism in the presence of suggestive symptoms. Prostate disease, hematocrit higher than 50 %, uncontrolled heart failure and severe obstructive sleep apnea are contraindications of a testosterone replacement therapy. Patients with metabolic-syndrome-associated low testosterone levels should firstly benefit from a lifestyle intervention that can normalize clinical and biochemical hypogonadism. So far, there is no clear evidence for a possible benefit of testosterone therapy in patients with the metabolic syndrome. Similarly, in patients with PADAM (partial androgen deficiency of the aging male) testosterone therapy is not established or recommended.

Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma.

Non-functioning pituitary adenoma (NFPA) with higher proliferation index (WHO II) are often a therapeutical challenge. Low somatostatin receptor expression in these tumors usually prevents a treatment with somatostatin analogs. In 1996, a 55-year-old patient was referred due to right-sided headache. A pituitary macroadenoma with infiltration into the right cavernous sinus was diagnosed. There was no visual field deficit and the clinical and biochemical work up was consistent with a NFPA. The patient underwent transsphenoidal surgery. Residual adenoma remained in the right cavernous sinus. Histologically, a null-cell adenoma with a high proliferation index was documented (MIB-1: 11.6%, WHO II). Somatostatin receptor autoradiography was performed in the surgical specimen showing a homogenous expression of sst2 receptors. Radiosurgery was completed with stable disease for 8 years. In 2004, the patient was diagnosed with an incomplete palsy of the right oculomotorius nerve and a significant increase in the volume of the adenoma in the right cavernous sinus. After a positive Octreoscan(®) the patient consented to an experimental therapy approach using Lutetium DOTATOC (3 × 200 mCi). The palsy of the oculomotorius nerve improved and remained stable until today (March 2013), the follow-up MRI scans demonstrated stable disease. This is the first case of a patient with a NFPA (WHO II) in whom PRRT successfully improved the local complications of the tumor for more than 8 years after ineffective surgery and gamma knife therapy. The determination of sst2 in vitro using autoradiography and in vivo by Octreoscan was instrumental to administer this therapy in a challenging situation.

The effect of aerobic exercise on intrahepatocellular and intramyocellular lipids in healthy subjects.

BACKGROUND: Intrahepatocellular (IHCL) and intramyocellular (IMCL) lipids are ectopic lipid stores. Aerobic exercise results in IMCL utilization in subjects over a broad range of exercise capacity. IMCL and IHCL have been related to impaired insulin action at the skeletal muscle and hepatic level, respectively. The acute effect of aerobic exercise on IHCL is unknown. Possible regulatory factors include exercise capacity, insulin sensitivity and fat availability subcutaneous and visceral fat mass). AIM: To concomitantly investigate the effect of aerobic exercise on IHCL and IMCL in healthy subjects, using Magnetic Resonance spectroscopy. METHODS: Normal weight, healthy subjects were included. Visit 1 consisted of a determination of VO2max on a treadmill. Visit 2 comprised the assessment of hepatic and peripheral insulin sensitivity by a two-step hyperinsulinaemic euglycaemic clamp. At Visit 3, subcutaneous and visceral fat mass were assessed by whole body MRI, IHCL and IMCL before and after a 2-hours aerobic exercise (50% of VO(2max)) using ¹H-MR-spectroscopy. RESULTS: Eighteen volunteers (12M, 6F) were enrolled in the study (age, 37.6±3.2 years, mean±SEM; VO(2max), 53.4±2.9 mL/kg/min). Two hours aerobic exercise resulted in a significant decrease in IMCL (-22.6±3.3, % from baseline) and increase in IHCL (+34.9±7.6, % from baseline). There was no significant correlation between the exercise-induced changes in IMCL and IHCL and exercise capacity, subcutaneous and visceral fat mass and hepatic or peripheral insulin sensitivity. CONCLUSIONS: IMCL and IHCL are flexible ectopic lipid stores that are acutely influenced by physical exercise, albeit in different directions. TRIAL REGISTRATION: ClinicalTrial.gov NCT00491582.

Assessment of three frequently used blood glucose monitoring devices in clinical routine.

BACKGROUND: Self-monitoring of blood glucose plays an important role in the management of diabetes and has been shown to improve metabolic control. The use of blood glucose meters in clinical practice requires sufficient reliability to allow adequate treatment. Direct comparison of different blood glucose meters in clinical practice, independent of the manufactures is scarce. We, therefore, aimed to evaluate three frequently used blood glucose meters in daily clinical practice. METHODS: Capillary blood glucose was measured simultaneous using the following glucose meters: Contour® (Bayer Diabetes Care, Zürich, Switzerland), Accu-Chek® aviva (Roche Diagnostics, Rotkreuz, Switzerland), Free-Style® lite (Abbott Diabetes Care, Baar, Switzerland). The reference method consisted of the HemoCue® Glucose 201+ System (HemoCue® AB, Ängelholm, Sweden) with plasma conversion. The devices were assessed by comparison of the Mean Absolute Relative Differences (MARD), the Clarke Error Grid Analysis (EGA) and the compliance with the International Organization of Standardization criteria (ISO 15197:2003). RESULTS: Capillary blood samples were obtained from 150 patients. MARD was 10.1 ± 0.65%, 7.0 ± 0.62% and 7.8 ± 0.48% for Contour®, Accu-Chek® and Free-Style®, respectively. EGA showed 99.3% (Contour®), 98.7% (Accu-Chek®) and 100% (Free-Style®) of all measurements in zone A and B (clinically acceptable). The ISO criteria were fulfilled by Accu-Chek® (95.3%) and Free-Style® (96%), but not by Contour® (92%). CONCLUSIONS: In the present study the three glucose meters provided good agreement with the reference and reliable results in daily clinical routine. Overall, the Free-Style® and Accu-Chek® device slightly outperformed the Contour® device.

Exercise-induced GH secretion in the assessment of GH deficiency in adult individuals.

OBJECTIVE: The role of exercise testing in the assessment of GH deficiency (GHD) in adult patients is currently unclear. This study aimed at evaluating the diagnostic value of exercise-induced GH levels in the detection of severe GHD in adult patients. METHODS: Fourteen patients confirmed to have severe GHD according to current guidelines and 20 healthy control individuals (CI) exercised for 120  min at 50-60% of their individual VO2(max). GH was measured before and every 30  min throughout exercise. The diagnostic value of predicting GHD was assessed by performing receiver operating characteristics (ROC) analysis for each time point of GH assessment. To optimise comparability within the study population a sub-analysis with ten individuals specifically matched for gender, age, body mass index and waist was performed. RESULTS: Exercise-induced GH secretion was significantly lower in patients with GHD than in CI (P<0.001). Area under the ROC curve (AUC(ROC)) was 0.954±0.033, 0.993±0.009, 0.989±0.012 and 0.992±0.009 for the overall population and 0.870±0.086, 0.980±0.024, 0.970±0.034 and 0.978±0.027 for the matched individuals at 30, 60, 90 and 120  min of exercise respectively. At 60  min of exercise a cut off GH value of 2.4  ng/ml translates into a sensitivity of 100% and a specificity of 95 and 90% in the diagnosis of GHD for the overall population and matched individuals respectively. CONCLUSION: GH assessment during a standardised aerobic exercise of moderate intensity is a reliable test with high diagnostic accuracy in predicting severe GHD in adult individuals. Based on the current findings exercise duration of 60  min appears to be sufficient for diagnostic purposes.