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Aimilia Eirini Papathanasiou, Eric Nolen-Doerr, Olivia M Farr and Christos S Mantzoros

The discovery of leptin, an adipocyte-secreted hormone, set the stage for unraveling the mechanisms dictating energy homeostasis, revealing adipose tissue as an endocrine system that regulates appetite and body weight. Fluctuating leptin levels provide molecular signals to the brain regarding available energy reserves modulating energy homeostasis and neuroendocrine response in states of leptin deficiency and to a lesser extent in hyperleptinemic states. While leptin replacement therapy fails to provide substantial benefit in common obesity, it is an effective treatment for congenital leptin deficiency and states of acquired leptin deficiency such as lipodystrophy. Current evidence suggests that regulation of eating behavior in humans is not limited to homeostatic mechanisms and that the reward, attention, memory and emotion systems are involved, participating in a complex central nervous system network. It is critical to study these systems for the treatment of typical obesity. Although progress has been made, further studies are required to unravel the physiology, pathophysiology and neurobehavioral mechanisms underlying potential treatments for weight-related problems in humans.

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Hanneke J B H Beijers, Nike M L Stikkelbroeck, Arjen R Mensenkamp, Rolph Pfundt, Rob B van der Luijt, Henri J L M Timmers, Ad R M M Hermus and Marlies J E Kempers

Context

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disease caused by mutations in the tumor suppressor gene MEN1 and can be diagnosed based on clinical, familial and/or genetic criteria. We present a family in which we found both germline and somatic mosaicism for MEN1.

Family description

In our proband, we diagnosed MEN1. The mutation was not detected in her parents (DNA extracted from leucocytes). When her brother was found to harbor the same MEN1 mutation as our proband and, around the same time, their father was diagnosed with a neuroendocrine carcinoma, this tumor was investigated for the MEN1 mutation as well. In the histologic biopsy of this tumor, the same MEN1 mutation was detected as previously found in his children. Re-analysis of his blood using multiplex ligation-dependent probe amplification (MLPA) showed a minimal, but consistently decreased signal for the MEN1-specific MLPA probes. The deletion was confirmed in his son by high-resolution array analysis. Based on the array data, we concluded that the deletion was limited to the MEN1 gene and that the father had both germline and somatic mosaicism for MEN1.

Conclusions

To our knowledge, this is the first reported family with combined germline and somatic mosaicism for MEN1. This study illustrates that germline mosaicism is important to consider in apparently sporadic de novo MEN1 mutations, because of its particular importance for genetic counseling, specifically when evaluating the risk for family members and when considering the possibility of somatic mosaicism in the parent with germline mosaicism.

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Annewieke W van den Beld, Olga D Carlson, Maire E Doyle, Dimitris Rizopoulos, Luigi Ferrucci, Aart Jan van der Lely and Josephine M Egan

Objective

Insulin-like growth factor-binding protein-2 (IGFBP-2) concentrations are low in subjects with metabolic syndrome and type 2 diabetes. Intriguingly, recent studies have demonstrated an association between high IGFBP-2 concentrations and increased mortality not only in populations with certain types of cancer, but also in relatively healthy populations. We evaluated the role of IGFBP-2 in relation to BMI and mortality.

Design and Participants

BMI, insulin sensitivity, insulin-like growth factor 1 (IGF-I) and IGFBP-2 were assessed repeatedly in 539 participants of the Baltimore Longitudinal Study of Aging around the ages of 55, 65 and 75 years.

Results

IGFBP-2 concentrations positively correlated with insulin sensitivity and inversely with BMI, both at baseline and follow-up. Independent of IGF-I, sex, BMI and insulin sensitivity, circulating IGFBP-2 levels positively correlated with age (P < 0.001). Changes over time in BMI were associated with an inverse correlation in IGFBP-2 concentrations. Furthermore, we found indications of a relationship between low baseline IGFBP-2 levels and mortality. Remarkably, after adjustment for insulin sensitivity, the opposite association was found, as a unit increase of log(IGFBP2) was associated with an increase in the log hazard by 1.43 (95% CI: 0.3–2.6). This accounted for both baseline (P = 0.02) as well as serial (P < 0.001) measurements of IGFBP2. Finally, in this longitudinal study, we found that IGF-I concentrations increased with age (0.82 ± 0.2 (µg/L)/year, P < 0.001).

Conclusion

This is the first study investigating the relationship between IGFBP-2 levels and age in a longitudinal setting. Serum IGFBP-2 levels increase with age after the age of 50 years and evolve in parallel with insulin sensitivity. IGFBP-2 may therefore be a potential marker for insulin sensitivity. We further show that IGFBP-2 levels can predict mortality in this aging population. However, its predictive value for mortality can only be interpreted in relation to insulin sensitivity. After adjustment for insulin sensitivity, high IGFBP-2 levels are predictive of increased mortality.

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Aliya A Khan, Bart Clarke, Lars Rejnmark and Maria Luisa Brandi

Purpose

Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy.

Methods

We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review.

Conclusions

During pregnancy, calcitriol levels increase by two- to—three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.

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Julia Morera and Yves Reznik

The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA.

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Konstantinos Kalafatakis, Georgina M Russell and Stafford L Lightman

Glucocorticoids are a class of systematically secreted hormones, vital for mammalian life, which are intensively investigated for more than 80 years. They regulate multiple body processes like metabolism, fluid homeostasis, immune and stress system responsivity, as well as brain function. Glucocorticoids have a complex rhythm by which they are released to circulation from the adrenal cortex. The hormone exhibits a circadian variation, with high hormonal levels being secreted just prior and during the active part of the day, and progressively lower and lower amounts being released during the inactive part of it. Underlying this diurnal variation there is a more dynamic, ultradian rhythm composed of frequent episodes of glucocorticoid secretion (hormonal pulses). Accumulating evidence from observational, in silico, in vitro and in vivo, preclinical and clinical studies suggest that both aspects of glucocorticoid rhythmicity are preserved among mammalian species and are important for brain function. The central nervous system is exposed to both aspects of the hormonal rhythm and has developed mechanisms able to perceive them and translate them to differential cellular events, genomic and non-genomic. Thus, glucocorticoid rhythmicity regulates various physiological neural and glial processes, under baseline and stressful conditions, and hormonal dysrhythmicity has been associated with cognitive and behavioural defects. This raises a number of clinical implications concerning (i) glucocorticoid involvement in neuropsychiatric disease and (ii) improving the therapeutic efficacy or expanding the role of glucocorticoid-based treatments in such conditions.

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Sophie Schweitzer, Meik Kunz, Max Kurlbaum, Johannes Vey, Sabine Kendl, Timo Deutschbein, Stefanie Hahner, Martin Fassnacht, Thomas Dandekar and Matthias Kroiss

Objective

Current workup for the pre-operative distinction between frequent adrenocortical adenomas (ACAs) and rare but aggressive adrenocortical carcinomas (ACCs) combines imaging and biochemical testing. We here investigated the potential of plasma steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the diagnosis of malignancy in adrenocortical tumors.

Design

Retrospective cohort study of prospectively collected EDTA-plasma samples in a single tertiary reference center.

Methods

Steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) in random plasma samples and logistic regression modeling.

Results

Fifteen steroid hormones were quantified in 66 ACAs (29 males; M) and 42 ACC (15 M) plasma samples. Significantly higher abundances in ACC vs ACA were observed for 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, DHEAS and estradiol (all P < 0.05). Maximal areas under the curve (AUC) for discrimination between ACA and ACC for single analytes were only 0.76 (estradiol) and 0.77 (progesterone), respectively. Logistic regression modeling enabled the discovery of diagnostic signatures composed of six specific steroids for male and female patients with AUC of 0.95 and 0.94, respectively. Positive predictive values in males and females were 92 and 96%, negative predictive values 90 and 86%, respectively.

Conclusion

This study in a large adrenal tumor patient cohort demonstrates the value of plasma steroid hormone profiling for diagnosis of ACC. Application of LC-MS/MS analysis and of our model may facilitate diagnosis of malignancy in non-expert centers. We propose to continuously evaluate and improve diagnostic accuracy of LC-MS/MS profiling by applying machine-learning algorithms to prospectively obtained steroid hormone profiles.

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Paloma Almeda-Valdes, Donaji V Gómez Velasco, Olimpia Arellano Campos, Omar Yaxmehen Bello-Chavolla, Magdalena del Rocío Sevilla-González, Tannia Viveros Ruiz, Alexandro J Martagón Rosado, Claudia J Bautista, Liliana Muñoz Hernandez, Ivette Cruz-Bautista, Hortensia Moreno-Macias, Alicia Huerta-Chagoya, Karen Guadalupe Rodríguez-Álvarez, Geoffrey A Walford, Suzanne B R Jacobs, Luz E Guillen Pineda, Ma Luisa Ordoñez-Sánchez, Ernesto Roldan-Valadez, Joaquín Azpiroz, Jannette Furuzawa-Carballeda, Patricia Clark, Miguel F Herrera-Hernández, Elena Zambrano, Jose C Florez, María Teresa Tusié Luna and Carlos A Aguilar-Salinas

Objective

A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk.

Design

Cross-sectional study.

Methods

We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic–hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies.

Results

Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (β = −0.164, P= 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P= 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P= 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P< 0.001).

Conclusions

Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

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S Asioli, A Righi, M Iommi, C Baldovini, F Ambrosi, F Guaraldi, M Zoli, D Mazzatenta, M Faustini-Fustini, P Rucci, C Giannini and M P Foschini

Objective and design

A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome.

Methods

The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up.

Results

In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival.

Conclusions

Our data confirmed the validity of Trouillas’ score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.