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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

Qing Zhu, Jianbin Su, Xueqin Wang, Mengjie Tang, Yingying Gao and Dongmei Zhang

Graves' disease (GD), an organ-specific autoimmune disease, is the most common cause of hyperthyroidism. Tumour necrosis factor-alpha (TNF-α) exhibits immunological and metabolic activities involved in the induction and maintenance of immune responses. We attempted to evaluate the relationship between GD and serum TNF-α and its soluble receptors (sTNFRs), soluble tumour necrosis factor receptor 1 and 2 (sTNF-R1 and sTNF-R2). A total of 72 GD patients and 72 matched healthy individuals were recruited for this study. Serum TNF-α and sTNFRs were measured by sandwich ELISA. In our study, no significant difference was observed in TNF-α, but sTNFRs were found to be significantly elevated in GD patients compared to healthy individuals. Serum sTNFR levels were positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), and TNF-α was negatively correlated with thyroid-stimulating hormone (TSH) in the GD group. It was also shown that thyrotropin receptor antibody (TRAb) was positively correlated with TNF-α and sTNFRs. Spearman’s correlation analysis showed that only sTNF-R1 was positively correlated with complement C3. Multiple linear regression analysis suggests that serum levels of sTNF-R1 and FT4 may play an important role in the serum level of FT3. According to the median value of FT3 level, GD patients were further divided into a high FT3 group and a low FT3 group. The serum levels of sTNF-R1 in the high FT3 GD group were significantly higher than those in the low FT3 GD group. In conclusion, sTNFRs may play an important role in anti-inflammatory and immune response in GD.

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.

Open access

Ferdinand Roelfsema, Peter Y Liu, Rebecca Yang, Paul Y Takahashi and Johannes D Veldhuis

Background: Interleukin-2 (IL-2), one of the proinflammatory cytokines, is used in the treatment of certain malignancies. In some studies, transient increases in cortisol and ACTH secretion occurred. Thus, this agent may be used as an experimental probe of adrenal cortisol secretion.

Objective: This study quantifies effects of low and moderate doses of IL-2 on cortisol secretion, and assesses the modulation by age, dose and body composition.

Site: Mayo Clinical Translational Research Unit.

Subjects: Study comprised 35 healthy men, 17 young and 18 older.

Methods: Randomized prospective double-blind saline-controlled study of IL-2 administration in 2 doses with concurrent 10-min blood sampling for 24 h.

Outcome measures: Deconvolution analysis and Approximate Entropy of cortisol secretion.

Results: Low dose IL-2 administration increased nocturnal pulsatile cortisol secretion from 1460±160 to 2120±220 nmol/L/8h in young subjects and from 1680±105 to 1960±125 nmol/L/8h (treatment P<0.0001, but more in young than older, P=0.02). Comparable results were obtained for total cortisol secretion (P treatment <0.0001, age effect P=0.005). The higher IL2 dose caused a large increase in young (P<0.0001), but not in older (P=0.90) subjects. This dose also increased approximate entropy from 0.877±0.041 to 1.024±0.049 (P=0.008), pointing to reduced secretory orderliness. Incremental cortisol (nocturnal) secretion correlated negatively with visceral fat mass (R=-0.41, P=0.019).

Conclusion: In healthy men, IL-2 injection drives pulsatile cortisol secretion in a dose-dependent way in young, but not older, individuals, and erodes cortisol secretory orderliness at a higher dose in young subjects. Cortisol responses are diminished with increasing abdominal visceral fat mass.

Open access

Hichem Bouguerra, Gorrab Amal, Stephan Clavel, Hamouda Boussen, Jean-François Louet and Asma Gati

Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, the peroxisome proliferator activated receptor coactivator-1 α (PGC1A). Using adenoviral approaches, we show that acute elevation of PGC1A enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified the involvement of PGC1A and leptin in the regulation of hypoxia inducible factor-1 alpha (HIF1A) expression by tumor cells. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC1A mRNA level and an enhanced oxidative phosphorylation activity; in comparison with luminal BC cells MCF7 and MDA-361, which are associated with more resistance NK92 lysis. Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC1A activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.