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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.

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Giuseppa Patti, Saverio Scianguetta, Domenico Roberti, Alberto Di Mascio, Antonio Balsamo, Milena Brugnara, Marco Cappa, Maddalena Casale, Paolo Cavarzere, Sarah Cipriani, Sabrina Corbetta, Rossella Gaudino, Lorenzo Iughetti, Lucia Martini, Flavia Napoli, Alessandro Peri, Mariacarolina Salerno, Roberto Salerno, Elena Passeri, Mohamad Maghnie, Silverio Perrotta and Natascia Di Iorgi

Background: Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone.

Aim: To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus.

Patients and methods: We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating.

Results: Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser), c.215 C>A (p.Ala72Glu) missense mutations and additional 8 different mutations previously described were identified; nine were missense and 1 non sense mutation. Most mutations (8 out of 10) occurred in the region encoding for the NPII moiety; 2 mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype-phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case.

Conclusion: adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

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Alex Faje, Kerry Reynolds, Leyre Zubiri, Donald Lawrence, Justine Cohen, Ryan Sullivan, Lisa B Nachtigall and Nicholas Tritos

Objective: Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients, and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI, and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients.

Design and methods: We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n=22), ipilimumab (n=64), and combo (n=20). Encounter notes, radiologic imaging, and laboratory results for these patients were comprehensively reviewed.

Results: Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3,522) compared to ipilimumab (13.6%, 34/250), p <0.0001. Hypophysitis was diagnosed later in nivolumab/pembrolizumab (median 25.8 weeks, interquartile range[IR] 18.4-44.0) compared to ipilimumab (9.3, IR 7.2-11.1) or combo patients (12.5, IR 7.4-18.6), p <0.0001 for both. Headache and pituitary enlargement occurred less commonly in nivolumab/pemrolizumab patients (23% and 5/18, respectively) compared to ipilimumab (75%, 60/61) and combo (75%, 16/17) treatment groups (p<0.0001 versus ipilimumab and p=0.001 versus combo for headache and p<0.0001 for both for enlargement).

Conclusions: This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

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Leonie H.a. Broersen, Femke M. Van Haalen, Tina Kienitz, Olaf Dekkers, Christian J Strasburger, Alberto M Pereira and N R Biermasz

Background: Adrenal crisis, the most feared complication of adrenal insufficiency, is a potentially life-threatening state of acute glucocorticoid deficiency. After successful surgery for Cushing’s syndrome, many patients develop (transient) adrenal insufficiency. The incidence of adrenal crisis in patients treated for hypercortisolism is unknown.

Methods: Cohort study including consecutive patients with Cushing’s syndrome with adrenal insufficiency after surgery from Leiden and Berlin from 2000-2015. We summarized incidence of adrenal crisis, compared patients with and without adrenal crisis regarding potential risk factors for its occurrence, and assessed the effect of better education in time on incidence of adrenal crisis.

Results: We included 106 patients, of whom 19 patients had a total of 41 adrenal crises. There were 9.0 crises per 100 patient-years at risk (95% confidence interval [CI]: 6.7-12.0). All crises occurred while on hydrocortisone replacement. The risk ratio for a recurrent crisis was 2.3 (95% CI: 1.2-4.6). No clear change in incidence of adrenal crisis due to better education in time was observed. There was no difference in recurrence rate between patients with, and without any crisis, but patients with adrenal crisis had more often pituitary deficiencies.

Conclusions: The incidence of adrenal crises after treatment for Cushing’s syndrome is substantial, and patients who suffered from an adrenal crisis have higher risk for recurrent crisis. Adrenal crisis tends to present early after remission of Cushing’s syndrome, which is probably the period of severest HPA-axis suppression, despite in general higher hydrocortisone replacement doses for withdrawal complaints in this period. Additional pituitary hormone deficiencies may be a risk marker for increased risk of adrenal crisis. However, further risk factor analysis is needed to identify risks for a first crisis. Effective education methods to prevent adrenal crises should be identified and implemented, including stress instructions by trained nursing staff before hospital discharge.

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Dong Hyun Sinn, Danbee Kang, Soo Jin Cho, Seung Woon Paik, Eliseo Guallar, Juhee Cho and Geum-Youn Gwak

Objective: Non-alcoholic fatty liver disease (NAFLD), a condition associated with multiple metabolic abnormalities, is frequently observed in normal weight individuals (lean NAFLD). The metabolic consequences of lean NAFLD, however, are not well characterized. Thus, this study aimed to evaluate the risk of incident diabetes in lean NAFLD.

Methods: This is a cohort study of 51,463 adults without diabetes, history of liver disease or cancer at baseline who participated in a regular health screening exam. Fatty liver was diagnosed by ultrasonography. The study outcome was the development of diabetes during follow-up.

Results: During 236,446.6 person-years of follow-up (median follow-up of 4.0 years), 5,370 participants developed diabetes. In fully-adjusted models, the hazard ratios (HRs) for incident diabetes comparing lean participants with NAFLD, overweight/obese participants without NAFLD, and overweight/obese participants with NAFLD to lean participants without NAFLD, were 1.18 (95% CI 1.03–1.35), 1.06 (0.98–1.14), and 1.45 (1.34–1.57), respectively. The fully-adjusted HR for incident diabetes for lean NAFLD participants with low NAFLD fibrosis score (NFS) (〈-1.455) and with intermediate to high NFS (≥-1.455) compared to lean participants without NAFLD were 1.32 (1.14–1.53) and 2.73 (2.10–3.55), respectively.

Conclusions: In this large cohort study, the presence and severity of NAFLD in normal-weight adults was associated with an increased incidence of diabetes independently of established risk factors. Indeed, isolated lean NAFLD was a stronger risk factor for incident diabetes than the presence of overweight/obesity without NAFLD. Subjects with lean NAFLD require careful monitoring for the development of metabolic abnormalities.

Open access

Jens Bollerslev, Camilla Schalin-Jantti, Lars Rejnmark, Heide Siggelkow, Hans Morreau, Rajesh V Thakker, Antonio Sitges-Serra, Filomena Cetani and Claudio Marcocci

PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed.

PHPT has a high prevalence in Western communities, PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the

natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations, or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas Quality of Life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with an increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity, and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy.

HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function, and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy.

Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field.

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Chin-Hsiao Tseng


Whether metformin might affect the risk of benign nodular goiter in patients with type 2 diabetes mellitus has not been investigated.


Patients with new-onset type 2 diabetes mellitus during 1999–2005 were enrolled from Taiwan’s National Health Insurance database. Analyses were conducted in a propensity score matched-pairs of 20,048 ever users and 20,048 never users of metformin. The patients were followed until December 31, 2011, for the incidence of benign nodular goiter. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the propensity score.


Among the never users and ever users of metformin, 392 and 221 cases were diagnosed of benign nodular goiter during follow-up, with incidence of 457.88 and 242.45 per 100,000 person-years, respectively. The overall hazard ratio for ever versus never users was 0.527 (95% confidence interval: 0.447–0.621). When cumulative duration of metformin therapy was divided into tertiles, the hazard ratios for the first (<25.3 months), second (25.3–57.3 months) and third (>57.3 months) tertiles were 0.815 (0.643–1.034), 0.648 (0.517–0.812) and 0.255 (0.187–0.348), respectively. Sensitivity analyses estimating the overall hazard ratios for patients enrolled in each specific year from 1999 to 2005 consistently showed a lower risk of benign nodular goiter among users of metformin.


Metformin use is associated with a lower risk of benign nodular goiter in patients with type 2 diabetes mellitus.