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Open access

Stan Ursem, Vito Francic, Martin Keppel, Verena Schwetz, Christian Trummer, Marlene Pandis, Felix Aberer, Martin R Grübler, Nicolas D Verheyen, Winfried März, Andreas Tomaschitz, Stefan Pilz, Barbara Obermayer-Pietsch and Annemieke C Heijboer

Objective

PTH can be oxidised in vivo, rendering it biologically inactive. Non-oxidised PTH (n-oxPTH) may therefore give a better image of the hormonal status of the patient. While vitamin D supplementation decreases total PTH (tPTH) concentration, the effect on n-oxPTH concentration is unexplored. We investigated the effect of vitamin D on n-oxPTH concentration in comparison to tPTH and compared the correlations between parameters of calcium, bone and lipid metabolism with n-oxPTH and tPTH.

Methods

N-oxPTH was measured in 108 vitamin D-insufficient (25(OH)D <75 nmol/L) hypertensive patients, treated with vitamin D (2800 IE daily) or placebo for 8 weeks in the Styrian Vitamin D Hypertension Trial (NCT02136771). We calculated the treatment effect and performed correlation analyses of n-oxPTH and tPTH with parameters of calcium, bone and lipid metabolism and oxidative stress.

Results

After treatment, compared to placebo, 25(OH)D concentrations increased, tPTH decreased by 9% (P < 0.001), n-oxPTH by 7% (P = 0.025) and the ratio of n-oxPTH/tPTH increased (P = 0.027). Changes in phosphate and HDL concentration correlated with changes in n-oxPTH, but not tPTH.

Conclusions

tPTH and n-oxPTH decrease upon vitamin D supplementation. Our study suggests that vitamin D supplementation reduces the oxidation of PTH, as we observed a small but significant increase in the non-oxidised proportion of PTH upon treatment. In addition, we found that changes in phosphate and HDL concentration showed a relationship with changes in n-oxPTH, but not tPTH. This may be explained by the biological activity of n-oxPTH. Further research should be carried out to establish the clinical relevance of n-oxPTH.

Open access

Arpna Sharma, Vijay Simha Baddela, Frank Becker, Dirk Dannenberger, Torsten Viergutz and Jens Vanselow

High-yielding dairy cows postpartum face the challenge of negative energy balance leading to elevated free fatty acids levels in the serum and follicular fluid thus affecting the ovarian function. Here, we investigated effects of physiological concentrations of palmitic acid (PA), stearic acid (SA) and oleic acid (OA) on the viability, steroid production and gene expression in a bovine granulosa cell (GC) culture model. Treatment with individual and combined fatty acids increased the CD36 gene expression, while no significant apoptotic effects were observed. Both PA and SA significantly upregulated the expression of FSHR, LHCGR, CYP19A1, HSD3B1, CCND2 and increased 17β-estradiol (E2) production, while OA downregulated the expression of these genes and reduced E2. Interestingly, STAR was equally downregulated by all fatty acids and combination treatment. E2 was significantly reduced after combination treatment. To validate the effects of OA, in vivo growing dominant follicles (10–19 mm) were injected with bovine serum albumin (BSA) with/without conjugated OA. The follicular fluid was recovered 48 h post injection. As in our in vitro model, OA significantly reduced intrafollicular E2 concentrations. In addition, expression of CD36 was significantly up- and that of CYP19A1 and STAR significantly downregulated in antral GC recovered from aspirated follicles. The ovulation rates of OA-injected follicles tended to be reduced. Our results indicate that elevated free fatty acid concentrations specifically target functional key genes in GC both in vitro and in vivo. Suggestively, this could be a possible mechanism through which elevated free fatty acids affect folliculogenesis in dairy cows postpartum.

Open access

Wenqi Yang, Ling Liu, Yuan Wei, Chunlu Fang, Fu Zhou, Jinbao Chen, Qinghua Han, Meifang Huang, Xuan Tan, Qiuyue Liu, Qiang Pan, Lu Zhang, Xiaojuan Lei and Liangming Li

Objective

The protective effects of exercise against glucose dysmetabolism have been generally reported. However, the mechanism by which exercise improves glucose homeostasis remains poorly understood. The FGF21–adiponectin axis participates in the regulation of glucose metabolism. Elevated levels of FGF21 and decreased levels of adiponectin in obesity indicate FGF21–adiponectin axis dysfunction. Hence, we investigated whether exercise could improve the FGF21–adiponectin axis impairment and ameliorate disturbed glucose metabolism in diet-induced obese mice.

Methods

Eight-week-old C57BL/6J mice were randomly assigned to three groups: low-fat diet control group, high-fat diet group and high-fat diet plus exercise group. Glucose metabolic parameters, the ability of FGF21 to induce adiponectin, FGF21 receptors and co-receptor levels and adipose tissue inflammation were evaluated after 12 weeks of intervention.

Results

Exercise training led to reduced levels of fasting blood glucose and insulin, improved glucose tolerance and better insulin sensitivity in high-fat diet-induced obese mice. Although serum FGF21 levels were not significantly changed, both total and high-molecular-weight adiponectin concentrations were markedly enhanced by exercise. Importantly, exercise protected against high-fat diet-induced impaired ability of FGF21 to stimulate adiponectin secretion. FGF21 co-receptor, β-klotho, as well as receptors, FGFR1 and FGFR2, were upregulated by exercise. We also found that exercise inhibited adipose tissue inflammation, which may contribute to the improvement in the FGF21–adiponectin axis impairment.

Conclusions

Our data indicate exercise protects against high-fat diet-induced FGF21–adiponectin axis impairment, and may thereby exert beneficial effects on glucose metabolism.

Open access

Marilena Nakaguma, Fernanda A Correa, Lucas S Santana, Anna F F Benedetti, Ricardo V Perez, Martha K P Huayllas, Mirta B Miras, Mariana F A Funari, Antonio M Lerario, Berenice B Mendonca, Luciani R S Carvalho, Alexander A L Jorge and Ivo J P Arnhold

Aim

Congenital hypopituitarism has an incidence of 1:3500–10,000 births and is defined by the impaired production of pituitary hormones. Early diagnosis has an impact on management and genetic counselling. The clinical and genetic heterogeneity of hypopituitarism poses difficulties to select the order of genes to analyse. The objective of our study is to screen hypopituitarism genes (candidate and previously related genes) simultaneously using a target gene panel in patients with congenital hypopituitarism.

Methods

Screening of 117 subjects with congenital hypopituitarism for pathogenic variants in 26 genes associated with congenital hypopituitarism by massively parallel sequencing using a customized target gene panel.

Results

We found three novel pathogenic variants in OTX2 c.295C>T:p.Gln99*, GLI2 c.1681G>T:p.Glu561* and GHRHR c.820_821insC:p.Asp274Alafs*113, and the previously reported variants in GHRHR c.57+1G>A and PROP1 [c.301_302delAG];[c.109+1G>A].

Conclusions

Our results indicate that a custom-designed panel is an efficient method to screen simultaneously variants of biological and clinical relevance for congenital GH deficiency. A genetic diagnosis was possible in 5 out of 117 (4%) patients of our cohort. We identified three novel pathogenic variants in GHRHR, OTX2 and GLI2 expanding the spectrum of variants associated with congenital hypopituitarism.

Open access

Monica F Stecchini, Zilda Braid, Candy B More, Davi C Aragon, Margaret Castro, Ayrton C Moreira and Sonir R Antonini

Objective

To investigate the impact of early exposure to androgen excess on gonadotropin-dependent puberty (GDP) and final height (FH) of patients with androgen-secreting adrenocortical tumors (ACT) in childhood.

Methods

Retrospective cohort study. Occurrence of GDP and achievement of FH were evaluated. Central precocious puberty (CPP) and early fast puberty (EFP) were considered pubertal disorders. Patients with normal puberty and pubertal disorders were compared.

Results

The study included 63 patients (44F), followed in a single institution from 1975 until 2017. At diagnosis of ACT, median age was 25.8 months; duration of signs, 6 months; stature SDS, 0.5 (−3.6 to 3.9) and bone age advancement, 14.7 months (−27.9 to 85.4). To date, 37 patients developed GDP: 26 had normal puberty; one, precocious thelarche; seven, CPP and three, EFP. GnRHa effectively treated CPP/EFP. Tall stature and older age at diagnosis of ACT were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.04–8.65)). Recurrence/metastasis during follow-up were associated with risk of CPP alone (RR 4.17 (95% CI 1.17–14.80)) and CPP/EFP (RR 3.0 (95% CI 1.12–8.02)). Among the 19 patients that reached FH, stature SDS dropped from 1.4 to −0.02 since diagnosis of ACT (P = 0.01). Seventeen achieved normal FH. There was no difference in FH SDS between patients with normal puberty and pubertal disorders (P = 0.75).

Conclusions

Gonadotropin-dependent pubertal disorders are common in patients with androgen-secreting ACT in childhood. FH is usually not impaired. The study reinforces the importance of close follow-up after surgery to identify and treat consequences of early exposure to androgen excess.

Open access

T Szarvas, B Jardin-Watelet, N Bourgoin, M J Hoffmann, P Nyirády, C Oláh, T Széll, A Csizmarik, B Hadaschik and H Reis

Recently, a neuroendocrine-like molecular subtype has been discovered in muscle-invasive urothelial bladder cancer (BC). Chromogranin A (CGA) is a widely used tissue and serum marker in neuroendocrine tumors. Our aim was to evaluate serum CGA (sCGA) concentrations and their associations with clinical and follow-up data in BC and renal cell carcinoma (RCC). sCGA concentrations were analyzed in the following cohorts: (1) BC training set (n = 188), (2) BC validation set (n = 125), (3) RCC patients (n = 77), (4) healthy controls (n = 97). CGA immunohistochemistry and RT-qPCR analyses were performed in 20 selected FFPE and 29 frozen BC tissue samples. Acquired data were correlated with clinicopathological parameters including comorbidities with known effect on sCGA as well as with patients’ follow-up data. sCGA levels were significantly higher in BC but not in RCC patients compared to healthy controls. High sCGA levels were independently associated with poor overall and disease-specific survival both in the BC training (P < 0.001, P = 0.002) and validation set (P = 0.009, P = 0.017). sCGA levels were inversely correlated with glomerulus filtrating rate (GFR) and linearly correlated with creatinine clearance and urea concentrations. These correlations were not related to the prognostic value of sCGA. Tissue CGA levels were low to absent independently of sCGA concentrations. Our results demonstrate elevated levels and an independent prognostic value for sCGA in BC but not in RCC. Despite the significant correlation between sCGA and GFR, the prognostic relevance of sCGA seems not related to impaired renal function or other comorbidities.

Open access

Madalena von Hafe, João Sergio Neves, Catarina Vale, Marta Borges-Canha and Adelino Leite-Moreira

Thyroid hormones have a central role in cardiovascular homeostasis. In myocardium, these hormones stimulate both diastolic myocardial relaxation and systolic myocardial contraction, have a pro-angiogenic effect and an important role in extracellular matrix maintenance. Thyroid hormones modulate cardiac mitochondrial function. Dysfunction of thyroid axis impairs myocardial bioenergetic status. Both overt and subclinical hypothyroidism are associated with a higher incidence of coronary events and an increased risk of heart failure progression. Endothelial function is also impaired in hypothyroid state, with decreased nitric oxide-mediated vascular relaxation. In heart disease, particularly in ischemic heart disease, abnormalities in thyroid hormone levels are common and are an important factor to be considered. In fact, low thyroid hormone levels should be interpreted as a cardiovascular risk factor. Regarding ischemic heart disease, during the late post-myocardial infarction period, thyroid hormones modulate left ventricular structure, function and geometry. Dysfunction of thyroid axis might even be more prevalent in the referred condition since there is an upregulation of type 3 deiodinase in myocardium, producing a state of local cardiac hypothyroidism. In this focused review, we summarize the central pathophysiological and clinical links between altered thyroid function and ischemic heart disease. Finally, we highlight the potential benefits of thyroid hormone supplementation as a therapeutic target in ischemic heart disease.

Open access

Eugenie S Lim, Shanty G Shah, Mona Waterhouse, Scott Akker, William Drake, Nick Plowman, Daniel M Berney, Polly Richards, Ashok Adams, Ewa Nowosinska, Carmel Brennan and Maralyn Druce

Context

Differentiated thyroid cancer (DTC) is usually treated by thyroidectomy followed by radioiodine ablation and generally has a good prognosis. It may now be possible to limit the amount of treatment without impacting on efficacy. It is not known whether coexistent thyroiditis impacts on radioiodine uptake or on its potential efficacy, but this could provide a rationale for modification to current therapeutic protocols.

Design

This was a retrospective cohort study of radioiodine uptake on imaging after radioiodine ablation for DTC in patients with and without concurrent thyroiditis. All patients with histologically confirmed DTC treated with radioiodine ablation after thyroidectomy in a single centre from 2012 to 2015 were included. The primary outcome assessed was the presence of low or no iodine uptake on post-ablation scan, as reported by a nuclear medicine physician blinded to the presence or absence of thyroiditis.

Results

One hundred thirty patients with available histopathology results were included. Thyroiditis was identified in 42 post-operative specimens and 15 of these patients had low or no iodine uptake on post-ablation scan, compared to only 2 of 88 patients without thyroiditis (P < 0.0001) with further data analysis dividing the groups by ablation activity received (1100 MBq or 3000 MBq).

Conclusions

Concurrent thyroiditis may impair the uptake of radioactive iodine in management of DTC. Given that patients with DTC and thyroiditis already have a good prognosis, adopting a more selective approach to this step in therapy may be indicated. Large, longitudinal studies would be required to determine if omitting radioactive iodine therapy from those patients with concurrent thyroiditis has a measurable impact on mortality from thyroid cancer.

Open access

Yusaku Mori, Hiroyuki Shimizu, Hideki Kushima, Tomomi Saito, Munenori Hiromura, Michishige Terasaki, Masakazu Koshibu, Hirokazu Ohtaki and Tsutomu Hirano

Nesfatin-1 is a novel anorexic peptide hormone that also exerts cardiovascular protective effects in rodent models. However, nesfatin-1 treatment at high doses also exerts vasopressor effects, which potentially limits its therapeutic application. Here, we evaluated the vasoprotective and vasopressor effects of nesfatin-1 at different doses in mouse models. Wild-type mice and those with the transgene nucleobindin-2, a precursor of nesfatin-1, were employed. Wild-type mice were randomly assigned to treatment with vehicle or nesfatin-1 at 0.2, 2.0 or 10 μg/kg/day (Nes-0.2, Nes-2, Nes-10, respectively). Subsequently, mice underwent femoral artery wire injury to induce arterial remodeling. After 4 weeks, injured arteries were collected for morphometric analysis. Compared with vehicle, nesfatin-1 treatments at 2.0 and 10 μg/kg/day decreased body weights and elevated plasma nesfatin-1 levels with no changes in systolic blood pressure. Furthermore, these treatments reduced neointimal hyperplasia without inducing undesirable remodeling in injured arteries. However, nesfatin-1 treatment at 0.2 μg/kg/day was insufficient to elevate plasma nesfatin-1 levels and showed no vascular effects. In nucleobindin-2-transgenic mice, blood pressure was slightly higher but neointimal area was lower than those observed in littermate controls. In cultured human vascular endothelial cells, nesfatin-1 concentration-dependently increased nitric oxide production. Additionally, nesfatin-1 increased AMP-activated protein kinase phosphorylation, which was abolished by inhibiting liver kinase B1. We thus demonstrated that nesfatin-1 treatment at appropriate doses suppressed arterial remodeling without affecting blood pressure. Our findings indicate that nesfatin-1 can be a therapeutic target for improved treatment of peripheral artery disease.

Open access

M I Stamou, P Varnavas, L Plummer, V Koika and N A Georgopoulos

Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a rare disease with a wide spectrum of reproductive and non-reproductive clinical characteristics. Apart from the phenotypic heterogeneity, IGD is also highly genetically heterogeneous with >35 genes implicated in the disease. Despite this genetic heterogeneity, genetic enrichment in specific subpopulations has been described. We have previously described low prevalence of genetic variation in the Greek IGD cohort discovered with utilization of Sanger sequencing in 14 known IGD genes. Here, we describe the expansion of genetic screening in the largest IGD Greek cohort that has ever been studied with the usage of whole-exome sequencing, searching for rare sequencing variants (RSVs) in 37 known IGD genes. Even though Sanger sequencing detected genetic variation in 21/81 IGD patients in 7/14 IGD genes without any evidence of oligogenicity, whole exome sequencing (WES) revealed that 27/87 IGD patients carried a rare genetic change in a total of 15 genes with 4 IGD cases being oligogenic. Our findings suggest that next-generation sequencing (NGS) techniques can discover previously undetected variation, making them the standardized method for screening patients with rare and/or more common disorders.