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Open access

Anne Jouinot, Juliane Lippert, Martin Fassnacht, Bruno De La Villeon, Amandine Septier, Mario Neou, Karine Perlemoine, Silke Appenzeller, Mathilde Sibony, Sebastien Gaujoux, Bertrand Dousset, Rosella Libe, Lionel Groussin, Cristina L Ronchi, Guillaume Assie and Jerome Bertherat

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n=26), chromosome alteration profiles were determined using SNP arrays (n=14) and methylation profiles were determined using 4-gene bisulfite pyrosequencing (n=12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable, and might be more robust for the prognostic assessment.

Open access

Milica Popovic, Fahim Ebrahimi, Sandrine Andrea Urwyler, Marc Yves Donath and Mirjam Christ-Crain

Arginine vasopressin (AVP) was suggested to contribute to cardiovascular risk and type 2 diabetes in patients with metabolic syndrome. The proinflammatory cytokine interleukin-(IL)-1 is able to induce AVP secretion and plays a causal role in cardiovascular mortality and type 2 diabetes. We investigated in two studies whether copeptin levels – the surrogate marker for AVP – are regulated by IL-1-mediated chronic inflammation in patients with metabolic syndrome. Study A was a prospective, interventional, single-arm study (2014-2016). Study B was a randomized, placebo-controlled, double-blind study (2016-2017). n=73 (Study A) and n=66 (Study B) adult patients with metabolic syndrome were treated with 100 mg anakinra or placebo (only in study B) twice daily for 1 day (study A), and 28 days (study B). Fasting blood samples were drawn at day 1, 7, and 28 of treatment for measurement of serum copeptin. Patients with chronic low-grade inflammation (C-reactive protein levels ≥2 mg/l) and BMI >35 kg/m2 had higher baseline copeptin levels (7.7 [IQR 4.9-11.9] vs. 5.8 [IQR 3.9-9.3] pmol/l, pinflamm=0.009; 7.8 [IQR 5.4-11.7] vs. 4.9 [IQR 3.7-9.8] pmol/l, pBMI=0.008). Copeptin levels did not change neither in the anakinra nor in the placebo group and remained stable throughout the treatment (p=0.44). Subgroup analyses did not reveal effect modifications. Therefore, we conclude that although IL-1-mediated inflammation is associated with increased circulating copeptin levels, antagonizing IL-1 does not significantly alter copeptin levels in patients with metabolic syndrome.

Open access

Marie Reeberg Sass, Nicolai Jacob Wewer Albrechtsen, Jens Pedersen, Kristine Juul Hare, Nis Borbye Pedersen, Katalin Kiss, Tina Vilsbøll, Filip Krag Knop, Steen S. Poulsen, Niklas Rye Jørgensen, Jens Juul Holst, Cathrine Ørskov and Bolette Hartmann

Objective: Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

Methods: Intact PTH was measured in plasma from patients with T1D and matched healthy individuals employing 4-hour oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion on two separate experimental. In addition, expression of insulin receptors on archived, surgical specimens of parathyroid glands were assessed by immunochemistry (IHC) and quantitative polymerase chain reaction (qPCR).

Results: The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min×ng/L and -2408 ± 1435 min×ng/L, P=0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P=0.002). Expression of insulin receptors in human parathyroid gland were detected by IHC and qPCR.

Conclusion: Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.

Open access

Jana Ernst, Katharina Gert, Frank Bernhard Kraus, Ulrike Elisabeth Rolle-Kampczyk, Martin Wabitsch, Faramarz Dehghani and Kristina Schaedlich

The rapid increase of obesity during the last few decades and its future prospects are alarming. Besides the generally discussed causes of obesity, the 'Developmental Origins of Health and Disease' (DOHaD) hypothesis has received more attention in recent years. This hypothesis postulates an adverse influence during early development that programs the unborn child for metabolic dysfunctions later in life. Childhood obesity – an as much increasing problem – can be predisposed by maternal overweight and diabetes. Both, obesity and hyperinsulinemia are major causes of female hyperandrogenemia. As predicted by the DOHaD hypothesis and shown in animal models, developmental androgen excess can lead to metabolic abnormalities in offspring. In this study, we investigated, if androgen-exposure adversely affects the adipogenic differentiation of preadipocytes and the endocrine function of adult adipocytes. The human SGBS preadipocyte model was used to affirm the de-novo biosynthesis of steroid hormones under normal adipogenesis conditions. Normal adipogenesis was paralleled by an increase of corticosteroids and androgens, whereas estrogen remained at a steady level. Treatment with androstenedione had no effect on SGBS proliferation and differentiation, but adult adipocytes exhibited a significant higher accumulation of triglycerides. Progesterone (up to 2-fold), testosterone (up to 38-fold) and cortisone (up to 1.4-fold) – but not cortisol – were elevated by androstenedione-administration in adult adipocytes. Estrogen was not altered. Data suggest that androgen does not negatively influence adipogenic differentiation but steroidogenic function of SGBS adipocytes.

Open access

Mojca Zerjav Tansek, Ana Bertoncel, Brina Sebez, Janez Zibert, Urh Groselj, Tadej Battelino and Magdalena Avbelj Stefanija

Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, body mass index, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, body mass index and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in body mass index, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (p <0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (p=0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensures adequate nutrition without significant consequences in body mass index, body composition, and bone mineral density. A low protein diet may delay the growth in childhood, but the treated patients gain a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA has no negative physiological effect on bone mineral density.

Open access

Tomás P Griffin, Caroline M Joyce, Sumaya Alkanderi, Liam M Blake, Derek T O’Keeffe, Delia Bogdanet, Md Nahidul Islam, Michael C Dennedy, John E Gillan, John J Morrison, Timothy O’Brien, John A Sayer, Marcia Bell and Paula M O’Shea

Introduction

Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.

Methods

The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.

Results

The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up.

Conclusions

W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.

Open access

Jung Soo Lim, Seung-Eun Lee, Jung Hee Kim, Jae Hyeon Kim and The Korean Adrenal Gland and Endocrine Hypertension Study Group, Korean Endocrine Society

Purpose

To evaluate the clinical characteristics and prognostic factors in patients with adrenocortical carcinoma (ACC) in South Korea.

Methods

A nationwide, registry-based survey was conducted to identify pathologically proven ACC at 25 tertiary care centers in South Korea between 2000 and 2014. Cox proportional hazard model and log-rank test were adopted for survival analysis.

Results

Two hundred four patients with ACC were identified, with a median follow-up duration of 20 months (IQR 5–52 months). The median age at diagnosis was 51.5 years (IQR 40–65.8 years), and ACC was prevalent in women (n = 110, 53.9%). Abdominal pain was the most common clinical symptom (n = 70, 40.2%), and ENSAT stage 2 was most common (n = 62, 30.4%) at the time of diagnosis. One hundred sixty-nine patients underwent operation, while 17 were treated with other modalities. The remission rate was 48%, and median recurrence-free survival time was 46 months. Estimated 5-year recurrence-free rate was 44.7%. There were more women, large tumor, atypical mitosis, venous invasion, and higher mitotic count in cancer recurrence group. Estimated 5-year overall survival and disease-specific survival rates were 64.5 and 70.6%, respectively. Higher ENSAT stage and advanced pathologic characteristics were risk factors for all-cause mortality of ACC. Large tumor size and cortisol-secreting tumor were additional risk factors for ACC-specific death.

Conclusions

We report the first epidemiologic study regarding ACC in an Asian population. ENSAT stage 4; lymph node involvement; non-operative group; and invasion of vein, sinusoid, or capsule were associated with an increased risk for all-cause mortality.

Open access

Mark R Postma, Pia Burman and André P van Beek

Introduction: Adult-onset growth hormone deficiency (AGHD) is usually the last deficiency to be substituted in hypopituitarism. In children with documented GH deficiency, treatment without delay is crucial for achieving optimal effects on growth and development. In adults, it is not known whether a delay in treatment initiation influences biochemical response and the favourable physiological effects resulting from GH replacement therapy (GHRT).

Methods: A total of 1085 GH-deficient adults from KIMS (Pfizer International Metabolic Database) were included, adequately replaced with all pituitary hormones except for GH at baseline. Patients were stratified by sex and age (20-50 years and ≥50 years) and subsequently divided into two groups below and above the median duration of unsubstituted AGHD for that subgroup. The median time of unsubstituted GHD for the total cohort was 2.53 years (P5=0.35, P95=24.42).

Results: Beneficial effects of 4 years of GHRT were observed on lipids and quality of life in all subgroups. A decrease in waist circumference was observed only in older (>50 years) patients. There was no difference in IGF-I SDS and in GH dose required to normalize IGF-I in patients with a duration of unsubstituted AGHD above or below the median. No relevant differences were found between the groups for anthropometric measures, cardiovascular risk factors and quality of life scores.

Conclusion: In contrast to GHD in children and adolescents, no difference could be established in treatment response between early or late initiation of GHRT in AGHD in terms of required GH dose, IGF-I, metabolic health and quality of life.

Open access

Zeeshan Javed, Maria Papageorgiou, Leigh A Madden, Alan S Rigby, Eric S Kilpatrick, Stephen L Atkin and Thozhukat Sathyapalan

Context

Endothelial microparticles (EMPs) are novel, surrogate biomarkers of endothelial function and have been shown to be elevated in women with polycystic ovary syndrome (PCOS). It remains poorly understood how pharmacological options for managing PCOS affect EMP levels.

Objective

To characterise and compare the effects of empagliflozin vs metformin on the circulating levels of EMPs in overweight/obese women with PCOS.

Methods

This was a randomised, comparative, 12-week single-centre trial conducted at the Academic Diabetes, Endocrinology and Metabolism Research Centre, Hull, UK. This analysis includes data from 39 overweight/obese women with PCOS who completed the study and were randomised to empagliflozin (15 mg/day) (n = 19) or metformin (1500 mg/day) (n = 20). Blood samples were collected at baseline and 12 weeks after treatment and analysed for specific surface proteins (ICAM-1, VCAM-1, PECAM-1, E-selectin and endoglin) expressed by circulating EMPs using flow cytometry.

Results

In the empagliflozin group, ICAM-1 (P = 0.006), E-selectin (P = 0.016) and VCAM-1 (P = 0.001) EMPs increased significantly following 12 weeks of treatment, but no changes were seen in PECAM-1 (P = 0.93) or endoglin (P = 0.13) EMPs. In the metformin group, VCAM-1 EMPs (P < 0.001) increased significantly after 12 weeks of treatment, whereas all other EMPs remained unchanged. When data were expressed as percentage change from baseline in each group, no significant differences were seen between groups for any biomarker (P-values from 0.22 to 0.80).

Conclusions

Short-term administration of empagliflozin and metformin in overweight/obese women with PCOS appear to increase EMPs expressed by endothelial cells during their activation.

Open access

Rosalie Cabry, Philippe Merviel, Aicha Madkour, Elodie Lefranc, Florence Scheffler, Rachel Desailloud, Véronique Bach and Moncef Benkhalifa

The negative impact of endocrine-disrupting pesticides on human fertility is now a key issue in reproductive health. There are much fewer literature data about the impact of pesticide exposure on women than on men and very few studies of women participating in an in vitro fertilization (IVF) programme. In the present review, we found that (1) various pesticides with an endocrine-disrupting action are associated with poor oocyte maturation and competency, embryonic defects and poor IVF outcomes, and (2) some pesticide compounds are linked to specific causes of female infertility, such as premature ovarian insufficiency, polycystic ovarian syndrome, and endometriosis. IVF participants living in agricultural regions should be informed about the fertility decline, low ongoing pregnancy rates, and elevated risk of miscarriage associated with exposure to high doses of pesticides.