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Laura Dauben, Marie-Christine Simon, Klaus Strassburger, Volker Burkart, Katharina S Weber, Sven Schinner, Michael Roden and Karsten Müssig


Insulinomas are rare pancreatic endocrine tumors characterized by hypoglycemia. Guidelines by the Endocrine Society (ES), the European (ENETS) and the North American (NANETS) Neuroendocrine Tumor Societies provide divergent diagnostic criteria. This study compared the diagnostic accuracy of these different criteria during the 72-h fasting test.


Retrospective cohort study.


From 2000 to 2014, 64 patients with a suspected insulinoma underwent a 72-h fasting test and were included in the analysis. This study assessed the diagnostic sensitivity, specificity and accuracy based on venous blood glucose and corresponding insulin levels measured by electrochemiluminescence immunoassay (ECLIA).


Based on 64 individuals (18 with, 46 without insulinoma), the ES criteria provided a diagnostic sensitivity of 0.94 (0.73–1.00), specificity of 0.89 (0.76–0.96) and accuracy of 0.91 (0.81–0.96). ENETS/NANETS criteria reached a diagnostic sensitivity of 0.78 (0.52–0.94), specificity of 1.00 (0.92–1.00) and accuracy of 0.94 (0.85–0.98).


These results point to a higher diagnostic sensitivity with less specificity for diagnosing insulinoma using ES criteria and a higher specificity at lower sensitivity by using ENETS/NANETS criteria. Before considering these results when applying the different criteria in clinical practice, the results should be confirmed in further studies comprising larger cohorts.

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Iulia Potorac, Ashutosh Trehan, Kamila Szymanska, Julie Fudvoye, Albert Thiry, Ilpo T Huhtaniemi, Adrian F Daly, Albert Beckers, Anne-Simone Parent and Adolfo Rivero-Müller

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males.

A phenotypically-female patient with pubertal delay, had a 46,XY karyotype and was diagnosed with 46X,Y disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin.

cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower molecular weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry.

This novel case of 46X,Y DSD illustrates how three different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations.

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Selveta Sanne van Santen, Daniel S Olsson, Casper Hammarstrand, Mark Wijnen, Marry M. van den Heuvel - Eibrink, A J Van der Lely, Gudmundur Johannsson, Joseph A.m.j.l. Janssen and Sebastian J. C. M. M. Neggers

Objective: Craniopharyngioma patients often have poor metabolic profiles due to hypothalamic-pituitary damage. Previously, using body mass index (BMI) as obesity marker, the occurrence of the metabolic syndrome in these patients was estimated at 46%. Our aim was to determine if Dual X-ray Absorptiometry (DXA-) scan in evaluation of obesity and metabolic syndrome would be superior.

Design: Retrospective study of craniopharyngioma patients for whom DXA-scan results were available.

Methods: BMI, fat percentage and fat mass index were used to evaluate obesity and as components for obesity in metabolic syndrome.

Results: Ninety-five craniopharyngioma patients were included (51% female, 49% childhood-onset disease). Metabolic syndrome occurred in 34-53 (45-51%) subjects (depending on the definition of obesity, although all definitions occurred in higher frequency than in the general population). Metabolic syndrome frequency was higher if obesity was defined by fat percentage (52% vs. 42%) or fat mass index (51% vs. 43%) compared to BMI. Misclassification appeared in 9% (fat percentage vs. BMI) and 7% (fat mass index vs. BMI) for metabolic syndrome and 29% and 13% for obesity itself, respectively. For metabolic syndrome, almost perfect agreement was found for BMI compared with fat percentage or fat mass index. For obesity, agreement was fair to moderate (BMI vs. fat percentage).

Conclusion: Using BMI to evaluate obesity underestimates the true prevalence of metabolic syndrome in patients with craniopharyngioma. Furthermore, fat percentage contributes to a better evaluation of obesity than BMI. The contribution of DXA-scan might be limited for identification of the metabolic syndrome.

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Cristina Eller-Vainicher, Alberto Falchetti, Luigi Gennari, Elisa Cairoli, Francesco Bertoldo, Fabio Vescini, Alfredo Scillitani and Iacopo Chiodini

An underlying disease affecting bone health is present in up to 40 and 60% of osteoporotic postmenopausal women and men respectively. Among the disorders leading to a secondary form of osteoporosis, the endocrine diseases are highly represented. A frequent finding in patients affected with an endocrine-related forms of bone disease is that the skeletal fragility is partially independent of the bone density, since the fracture risk in these patients is related more to a reduction of bone quality than to a decrease of bone mass. As a consequence, bone mineral density evaluation by dual-X-ray absorptiometry may be inadequate for establishing the risk of fracture in the setting of the endocrine-related forms of osteoporosis. In the recent years, several attempts to non-invasively estimating bone quality have been done. Nowadays, some new tools are available in the clinical practice for optimising the fracture risk estimation in patients with endocrine disorders. The aim of this review is to summarise the evidence regarding the role of the different imaging tools for evaluating bone density and bone quality in the most frequent forms of endocrine-related osteoporosis, such as obesity, diabetes, acromegaly, thyrotoxicosis, primary hyperparathyroidism, hypercortisolism and hypogonadism. For each of these disorders, data regarding both the current available tools and the future possible new techniques for assessing bone fragility in patients with endocrine diseases are reported.

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Katrine Hygum, Jakob Kau Starup-Linde, Torben Harsløf, Niklas Rye Joergensen, Bolette Hartmann, Jens Juul Holst and Bente Langdahl

Objective: Bone turnover has a diurnal variation influenced by food intake, incretin hormones, the sympathetic nervous system, and osteocyte function. The aim of the study was to compare diurnal variation in bone turnover in patients with diabetes and controls.

Design: A clinical 24-hour study with patients with type 1 diabetes (n=5), patients with type 2 diabetes (n=5), and controls (n=5).

Methods: Inclusion criterion: age >50 years. Exclusion criteria: diseases/medication that affect bone metabolism or recent use of incretin-based drugs. We drew blood samples hourly during the day and every three hours during the night. We served an identical diet on all study days. We used repeated measures one-way analysis of variance to compare the levels of the investigated markers, and we quantified the effect of time by comparing group mean standard deviations.

Results: The bone formation marker procollagen type 1 N-terminal propeptide showed significant interaction between time and group (p=0.01), and the mean standard deviation was lower in patients with type 2 diabetes compared with controls (p=0.04) and patients with type 1 diabetes (p=0.02). Other markers of bone formation and resorption showed significant effect of time. Levels of glucagon-like peptide-2, glucose-dependent insulinotropic peptide, and sclerostin only showed significant effect of time (all p-values 0.01), but levels of sclerostin tended to being highest in type 2 diabetes and lowest in controls.

Conclusions: The diurnal variation in bone formation is attenuated in patients with type 2 diabetes. This is not explained by changes in incretin hormone levels, but possibly mediated by sclerostin.

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Mads Lillevang-Johansen, Bo Abrahamsen, Henrik Løvendahl Jørgensen, Thomas Heiberg Brix and Laszlo Hegedüs


To investigate the association between hypothyroidism and cardiovascular disease (CVD) in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to cardiovascular risk.


A registry-based case–control study nested within a population-based cohort of 275 467 individuals with at least one serum thyroid stimulating hormone (TSH) measurement in the period of 1995–2011.


Incident cases of CVD were matched with controls according to gender, age and year of birth. Conditional logistic regression analyses were performed to calculate CVD risks associated with exposure to hypothyroidism, with adjustment for 19 pre-existing comorbidities, including cardiovascular disease and diabetes, using the Charlson Comorbidity Index.


Overall, 20 487 individuals experienced CVD (9.4%, incidence rate 13.1 per 1000 person-years, 95% confidence interval (CI), 13.0–13.3). Risk of CVD was increased in untreated hypothyroidism compared to euthyroidism (odds ratio (OR): 1.83 (95% CI: 1.43–2.35; P < 0.001)). Cardiovascular risk was increased in both treated and untreated hypothyroid individuals per half year of elevated TSH (OR: 1.11 (95% CI: 1.06–1.16; P < 0.001) and OR: 1.15 (95% CI: 1.09–1.23; P = 0.001), respectively). In patients treated with levothyroxine, OR for CVD was 1.12 (95% CI: 1.06–1.18; P < 0.001) for each 6 months of decreased TSH.


Cardiovascular risk is increased in untreated, but not in treated hypothyroid patients. Among those with treated hypothyroidism, duration of decreased TSH (overtreatment) had a similar impact on cardiovascular risk as duration of elevated TSH (under-treatment), highlighting the importance of initiating treatment and maintaining biochemical euthyroidism in hypothyroid patients in order to reduce the risk of CVD and death.

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Kristina Elisabet Almby, Niclas Abrahamsson, Martin H Lundqvist, Ulf Hammar, Ketan Thombare, Amalia Panagiotou, F Anders Karlsson, Magnus Sundbom, Urban Wiklund and Jan Eriksson

Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

Design: Experimental hyperinsulinemic hypoglycemic clamp study.

Methods: 12 post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/l) performed on separate days with concomitant infusions of the GLP-1 analogue exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

Conclusions/interpretation: Short term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the reduction of postprandial symptoms post-GBP seen with exogenous GLP-1 may be mediated by mechanism not directly involved in counter-regulation.

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Eberhard Nieschlag and Susan Nieschlag

As the most important male hormone, testosterone has an impact on almost all organs and body functions. The biological effects of testosterone and the testes have been known since antiquity, long before testosterone was identified as the active agent. Practical applications of this knowledge were castration of males to produce obedient servants, for punishment, for preservation of the prepubertal soprano voice and even for treatment of diseases. Testes were used in organotherapy and transplanted as treatment for symptoms of hypogonadism on a large scale, although these practices had only placebo effects. In reaction to such malpractice in the first half of the 20th century science and the young pharmaceutical industry initiated the search for the male hormone. After several detours together with their teams in 1935, Ernst Laqueur (Amsterdam) isolated and Adolf Butenandt (Gdansk) as well as Leopold Ruzicka (Zürich) synthesized testosterone. Since then testosterone has been available for clinical use. However, when given orally, testosterone is inactivated in the liver, so that parenteral forms of administration or modifications of the molecule had to be found. Over 85 years the testosterone preparations have been slowly improved so that now physiological serum levels can be achieved.

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Eva C. Coopmans, Sebastiaan W. F. van Meyel, Kay J. Pieterman, Jolique A. van Ipenburg, Leo Hofland, Esther Donga, Adrian F. Daly, Albert Beckers, A J Van der Lely and Sebastian J. C. M. M. Neggers

Prolactinomas are the most commonly encountered pituitary adenomas in the clinical setting. While most can be controlled by dopamine agonists, a subset of prolactinomas are dopamine-resistant and very aggressive. In such tumors, the treatment of choice is neurosurgery and radiotherapy, with or without temozolomide.

Here, we report a patient with an highly aggressive, dopamine-resistant prolactinoma, who only achieved biochemical and tumor control during pasireotide long-acting release (PAS-LAR) therapy , a second-generation somatostatin receptor ligand (SRL). Interestingly, cystic degeneration, tumor cell necrosis, or both was observed after PAS-LAR administration suggesting an antitumor effect.

This case shows that PAS-LAR therapy holds clinical potential in selective aggressive, dopamine-resistant prolactinomas that express somatostatin (SST) receptor subtype 5 and appears to be a potential new treatment option before starting temozolomide. In addition, PAS-LAR therapy may induce cystic degeneration, tumor cell necrosis, or both in prolactinomas.

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Gerald Raverot, Alexandre Vasiljevic, Emmanuel Jouanneau and Hélène Lasolle

Recent publications suggested that pasireotide could be a good therapeutic option in some dopamine resistant or aggressive prolactinomas. We discussed the 2 published cases and describe another case of poorly-differentiated plurihormonal PIT-1 positive adenoma with moderate SSTR2 expression and intense STTR5 expression succeffuly treated with PAS-LAR 40mg/month.