BackgroundMarinobufagenin (MBG) is an endogenous cardiotonic steroid (CTS) that inhibits the Na+/K+-ATPase. Human MBG is significantly increased in end-stage renal disease and immunization against MBG attenuates cardiovascular fibrosis in a rat model of uremic cardiomyopathy. Mineralocorticoid antagonists (MRA) block MBG binding sites and decrease proteinuria in chronic kidney disease (CKD) patients. We therefore aimed to investigate the association of MBG and albuminuria, as a marker of renal damage, as well as MBG and decline of glomerular filtration rate (GFR).MethodsThe Graz endocrine causes of hypertension (GECOH) study is a single center study of adults routinely referred for screening of endocrine hypertension. Plasma MBG was measured by an enzyme-linked immunoassay, and in a post-hoc analysis, follow-up creatinine levels were obtained. Patients with proteinuria >3.5g/day at baseline were excluded from further evaluation.ResultsWe measured MBG concentrations in 40 hypertensive subjects and excluded one patient due to pre-existing proteinuria. Plasma MBG was significantly correlated with albuminuria (Spearman ρ = .357; p = .028) and proteinuria (ρ = .336; p = .039). In linear regression analysis, the association remained significant after adjustment for age, sex, and BMI (β = .306; p = .036), and for mean systolic blood pressure (β = .352; p = .034). In follow-up analyses (N = 30), MBG was significantly associated with decline in GFR after adjustment for time-to-follow-up (β = -.374; p = .042).ConclusionThe findings suggest that MBG plasma concentrations were associated with albuminuria as well as decline in kidney function. Whether MBG predicts hard renal endpoints warrants further investigations.

OBJECTIVE:A conversion from Hashimoto's thyroiditis to Graves' disease and vice versa leads to diagnostic and therapeutic challenges.CLINICAL PRESENTATION AND INTERVENTION:A 30-year-old female presented with overt hyperthyroidism and negative thyroid-stimulating hormone receptor antibodies (TRAbs). Since hashitoxicosis was assumed, the patient was treated with propranolol. Within the next few weeks, the patient developed severe overt hypothyroidism, which was treated with levothyroxine. However, after several more weeks, she presented with overt hyperthyroidism once again, this time showing elevated TRAbs.CONCLUSION:We suggest educating patients and physicians to recognize changes in thyroid function and close monitoring of unclear cases of overt hyperthyroidism.

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.

(in alphabetischer Reihenfolge der Presenting Authors)

Objective: Cardiovascular disease manifestation and several associated surrogate markers, such as vitamin D, have shown substantial seasonal variation. A promising cardiovascular biomarker, soluble ST2 (sST2), has not been investigated in this regard – we therefore determined if systemic levels of sST2 are affected by seasonality and/or vitamin D in order to investigate their clinical interrelation and usability. Design: sST2 levels were measured in two cohorts involving hypertensive patients at cardiovascular risk, the Styrian Vitamin D Hypertension Trial (study A; RCT design, 8 weeks 2800 IU cholecalciferol daily) and the Ludwigshafen Risk and Cardiovascular Health Study (LURIC; study B; cross-sectional design). Methods: The effects of a vitamin D intervention on sST2 levels were determined in study A using ANCOVA, while seasonality of sST2 levels was determined in study B using ANOVA. Results: The concentrations of sST2 remained unchanged by a vitamin D intervention in study A, with a mean treatment effect (95% confidence interval) of 0.1 (−0.6 to 0.8) ng/mL; P = 0.761), despite a rise in 25(OH)D (11.3 (9.2–13.5) ng/mL; P < 0.001) compared to placebo. In study B, seasonal variations were present in 25(OH)D levels in men and women with or without heart failure (P < 0.001 for all subgroups), while sST2 levels remained unaffected by the seasons in all subgroups. Conclusions: Our study provides the first evidence that systemic sST2 levels are not interrelated with vitamin D levels or influenced by the seasons in subjects at cardiovascular risk.

AIMS OF THE STUDY Allostatic load (AL), as a marker of cumulative stress, is associated with higher morbidity and mortality, and reduced health-related quality of life (HrQoL) in healthy adults. In patients with hypertension, AL and its association with HrQoL have not been investigated. Therefore, this study aimed to (1) explore AL in a cohort of hypertensive patients and to (2) determine its association with HrQoL, while controlling for other health-related variables. METHODS Cross-sectional data from the Styrian Hypertension Study were analysed and included 126 participants (50% female) with a history of arterial hypertension; the mean age was 60.9 years (standard deviation 9.9). AL was derived from a set of 10 biomarkers including neurophysiological, neuroendocrine, metabolic, cardiovascular and inflammatory parameters. The 36-Item Short Form Health Survey (SF-36) was administered for assessment of HrQoL. Additional health-related variables included sociodemographic data, lifestyle factors and comorbidities. RESULTS Calculation of AL resulted in sum scores based on 10 binary variables, which were used to categorise patients as either “low AL” (<3) or “high AL” (≥3). Multivariate adjusted analyses revealed that higher AL was associated with better HrQoL with regard to the mental health domain F(1,1243) = 7.017; p = 0.009). All other components of HrQoL were not related to AL. CONCLUSIONS In contrast to results in healthy populations, we found a positive association between AL and the mental health domain of HrQoL. This finding suggests a specific coping pattern among a subgroup of hypertensive patients, possibly influencing their clinical management and outcome.

Vitamin D status may be associated with insulin resistance and other key features of polycystic ovary syndrome (PCOS), but data from preliminary randomized controlled trials (RCTs) are conflicting. Therefore, we aimed to investigate the effects of vitamin D supplementation on plasma glucose area under the curve (AUCgluc, primary outcome measure) and on other metabolic and endocrine parameters (secondary outcome measures).

BACKGROUND: Vitamin D deficiency is associated with an unfavorable lipid profile, but whether and how vitamin D supplementation affects lipid metabolism is unclear. OBJECTIVE: To examine the effects of vitamin D supplementation on lipid and lipoprotein parameters. METHODS: This is a post hoc analysis of the single-center, double-blind, randomized, placebo controlled Styrian Vitamin D Hypertension Trial (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D concentrations of <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for 8 weeks. RESULTS: One hundred sixty-three participants (62.2 [53.1-68.4] years of age; 46% women) had available lipid data and were included in this analysis. Vitamin D supplementation significantly increased total cholesterol, triglycerides, very-low-density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) triglycerides, high-density lipoprotein (HDL) triglycerides, apolipoprotein B (ApoB), LDL-ApoB, ApoCII, ApoCIII, phospholipids, and ApoE (P < .05 for all). Except for ApoCII and ApoCII and HDL-triglycerides, all other treatment effects remained statistically significant after adjustment for multiple testing with the Benjamini and Hochberg false discovery rate method. There was a nonsignificant increase in LDL cholesterol. Furthermore, no significant effects were seen on free fatty acids, lipoprotein (a), ApoAI, ApoAII, VLDL cholesterol, VLDL ApoB, HDL cholesterol, LDL diameter, and VLDL diameter. CONCLUSIONS: The effects of vitamin D on lipid metabolism are potentially unfavorable. They require further investigation in view of the wide use of vitamin D testing and treatment. (C) 2018 National Lipid Association. All rights reserved.

Abstract Steroid‐induced hyperglycemia (SIHG) has shown to independently increase the risk for mortality in patients with acute graft‐versus‐host disease, and it is still unclear whether SIHG might be a modifiable risk factor. Therefore, a feasibility trial was carried out aiming to evaluate the performance of a standardized decision support system (GlucoTab [GT]) for insulin therapy in patients with SIHG. A total of 10 hyperglycemic acute graft‐versus‐host disease patients were included and treated either with GT or standard of care during hospitalization. Follow‐up duration was 6 months. Comparing the GT versus standard of care group, 364 versus 1,020 glucose readings were available during a median of 41 days (interquartile range [IQR] 22–89) and 101 days (IQR 55–147) of hospitalization. The median overall glucose levels were 151 mg/dL (123–192) versus 162 mg/dL (IQR 138–193) for GT and standard of care, respectively (P < 0.001); hypoglycemia rates were comparably low. Treatment of SIHG with an algorithm‐based system for subcutaneous insulin was feasible and safe.

Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations.

Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT). Patients were 1:1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or placebo for 8 weeks. Second, we measured the ARR in 4 PA patients from the Graz Endocrine Causes of Hypertension Study (GECOH) before and after MR blocker treatment. Ninety-seven participants completed the EPATH trial, and the mean treatment effect (95% confidence interval) for log(e)ARR was 0.08 (-0.32 to 0.48) ng/dl/μU/ml (p=0.694). The treatment effect was 0.71 (0.47 to 0.96; p<0.001) ng/dl for log(e)PAC and 0.64 (0.19 to 1.10; p=0.006) μU/ml for log(e)DRC, respectively. In the 4 PA patients, the ARR decreased from 11.24±3.58 at baseline to 2.70±1.03 (p=0.013) ng/dl/μU/ml after MR blocker treatment. In this study with limited sample size, MR blocker treatment did not significantly alter the ARR in pHPT patients but significantly reduced the ARR in PA patients. Diagnostic utility of ARR and its components for PA diagnostics under MR blocker treatment warrants further study.

Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10–≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 μg (400–800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.

Objective: T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4(+) T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. Methods: This includes a prospective study of consecutive patients with RA (n = 107), patients with primary osteopenia/-porosis (n = 75), and healthy individuals (n = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4(+)CD28- T-cells. Results: Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4(+)CD28- T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4(+)CD28- T-cells as compared to CD28(+) T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28- T-cells. CD4(+)CD28-T- cells induced osteoclastogenesis more efficiently than CD28(+) T-cells. Conclusion: Our data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28(+) T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Dexamethasone intravitreal implant 0.7 mg (DEX 0.7) is successfully used in the treatment of diabetic macular oedema (DME). Subfoveal choroidal thickness has been shown to significantly decrease after injection of DEX 0.7 in eyes with DME (Kim et al. 2016). In this study, we aimed to investigate whether DEX 0.7 injection also had an effect on choroidal volume. Unlike subfoveal choroidal thickness, a decrease in choroidal volume suggests a global rather than a localized effect. Our second objective was to see whether an effect on the choroidal volume can be seen in the unaffected contralateral eye. In this prospective study, we included 16 eyes from 12 patients with DME scheduled for intravitreal DEX 0.7 injection. Exclusion criteria were intravitreal injection with VEGF inhibitors and/or steroids in the study eye six months prior to study inclusion, systemic glucocorticoid treatment six months prior to study inclusion, presence of other retinal disorders in the study eye (excluding diabetic retinopathy) and no or poor view of the fundus. We included seven fellow eyes (7 patients) as control eyes. Inclusion criteria for the fellow eye were presence of diabetic retinopathy (five eyes proliferative, two eyes severe nonproliferative). Exclusion criteria for fellow eyes were current treatment with intravitreal VEGF inhibitors and/or steroids and/or treatment six months prior to study inclusion, presence of other retinal disorders and no or poor view of the fundus. One untreated fellow eye had to be excluded due to poor image quality. All OCT images were performed using the Spectralis® OCT device (Spectralis, Heidelberg Engineering, Heidelberg, Germany). Mean choroidal volume in the study eye was 6.44 mm3 (±1.6), and mean subfoveal choroidal thickness was 257.5 μm (±72.3) at baseline. After injection of DEX 0.7, mean choroidal volume decreased significantly by 0.2 mm3 (95%CI: −0.31 to −0.1, p = 0.001) after 1 month, by 0.35 mm3 (95%CI: −0.56 to −0.15, p = 0.003) after 2 months and by 0.23 mm3 (95%CI: −0.41 to −0.05, p = 0.016) after 3 months (see Fig. 1). Similarly, subfoveal choroidal thickness decreased significantly after one month (MD −9.33 μm, 95%CI: −14.1 to −4.6, p = 0.001), after two months (MD −11.1 μm, 95%CI: −17.3 to −4.8, p = 0.003) and after three months (MD −19.6 μm, 95%CI: −36.5 to −2.6, p = 0.027). For the fellow eye, mean choroidal volume at baseline was 4.88 mm3 (±0.75), and mean subfoveal choroidal thickness was 190.6 μm (±34.2). No significant changes in mean choroidal volume and subfoveal choroidal thickness were observed during follow-up. This is, to the best of our knowledge, the first study to show a significant decrease in choroidal volume after DEX 0.7 injection in eyes with DME. The decrease in choroidal volume observed in this study suggests a global effect on the choroid. Choroidal volume is known to increase among other reasons due to inflammation, vasodilation and intersitital oedema (Zhang et al. 2014). As glucocorticoids are known to be anti-inflammatory, enhance vascular reactivity to vasoconstrictors and are antiexudative, a decrease in choroidal volume after DEX 0.7 seems plausible (Yang & Zhang 2004). Choroidal volume did not change in the fellow eye during the follow-up, again suggesting that the decrease in the study eye is a direct consequence of the DEX 0.7 injection. In addition, this study confirmed the findings of Kim et al. (2016) that subfoveal choroidal thickness significantly decreases after DEX 0.7 injection in eyes with DME. In conclusion, choroidal volume decreased significantly in eyes with DME after DEX 0.7 injection, while choroidal volume in the fellow eyes remained unchanged.

BACKGROUND:Accumulating evidence from animal and human studies suggests that vitamin D is involved in many functions of the reproductive system in both genders.AIM:The aim of this review was to provide an overview on the effects of vitamin D on polycystic ovary syndrome (PCOS) in women and androgen metabolism in men.METHODS:We performed a systematic literature search in PubMed for relevant English language publications published from January 2012 until September 2017.RESULTS AND DISCUSSION:The vitamin D receptor and vitamin D-metabolizing enzymes are found in reproductive tissues of women and men. In women, vitamin D status has been associated with several features of PCOS. In detail, cross-sectional data suggest a regulatory role of vitamin D in PCOS-related aspects such as ovulatory dysfunction, insulin resistance as well as hyperandrogenism. Moreover, results from randomized controlled trials (RCTs) suggest that vitamin D supplementation may be beneficial for metabolic, endocrine and fertility aspects in PCOS. In men, vitamin D status has been associated with androgen levels and hypogonadism. Further, there is some evidence for a favorable effect of vitamin D supplementation on testosterone concentrations, although others failed to show a significant effect on testosterone levels.CONCLUSION:In summary, vitamin D deficiency is associated with adverse fertility outcomes including PCOS and hypogonadism, but the evidence is insufficient to establish causality. High-quality RCTs are needed to further evaluate the effects of vitamin D supplementation in PCOS women as well as on androgen levels in men.

Context Intake of hormonal contraceptives (HC) is associated with higher total 25-hydroxyvitamin D [25(OH)D] concentrations, but the effect of HC on free 25(OH)D is unclear. Objective We investigated whether free 25(OH)D concentrations differ according to use of HC. Design This is a post hoc analysis of a randomized open trial. Setting This study was conducted from 13 January to 9 May, 2016, at a clinical research organization in Esslingen, Germany. Participants We included 201 apparently healthy women of childbearing age. Intervention Participants were randomly assigned to receive a daily multimicronutrient supplement for 8 weeks; the supplement contained 200 IU (n =100) or 800 IU (n = 101) of vitamin D3. Main Outcome Measures Primary outcome was the difference in free 25(OH)D between users and nonusers of HC. Results Overall, 176 participants [median (25th to 75th percentiles) age: 25 (22 to 29) years] with available free 25(OH)D were included in the present analysis. At baseline, total 25(OH)D was significantly higher in users (n = 110) than in nonusers (n = 66) of HC [49.2 (33.4 to 63.4) vs 39.1 (23.8 to 52.5) nmol/L; P < 0.001], whereas there was no difference in free 25(OH)D [7.87 (6.50 to 10.11) vs 7.88 (6.35 to 10.12) pmol/L; P = 0.923]. These results were confirmed after multimicronutrient supplementation and in subgroups according to treatment allocation. Conclusions Use of HC was associated with, on average, 26% higher total 25(OH)D, whereas free 25(OH)D values did not differ according to use of HC. These findings are relevant for epidemiological studies, but the physiological implications remain to be clarified.

AbstractBackground:Primary hyperparathyroidism (pHPT) is associated with low-grade inflammation, left ventricular hypertrophy and increased cardiovascular mortality, but the association between inflammatory markers and parameters of adverse cardiac remodeling is unknown. We investigated the relationship between C-reactive protein (CRP), the essential amino acid tryptophan and its pro-inflammatory derivatives kynurenine and quinolinic acid (QUIN) with echocardiographic parameters.Methods:Cross-sectional baseline data from the “Eplerenone in Primary Hyperparathyroidism” trial were analyzed. Patients with any acute illness were excluded. We assessed associations between CRP, serum levels of tryptophan, kynurenine and QUIN and left ventricular mass index (LVMI), left atrial volume index (LAVI) and E/e′.Results:Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%. Multivariate linear regression analyses with LVMI, LAVI and E/e′ as respective dependent variables, and C-reactive protein and tryptophan, kynurenine and QUIN as respective independent variables were performed. Analyses were adjusted for age, sex, blood pressure, parathyroid hormone, calcium and other cardiovascular risk factors. LVMI was independently associated with CRP (adjusted β-coefficient=0.193, p=0.030) and QUIN (β=0.270, p=0.007), but not kynurenine. LAVI was related with CRP (β=0.315, p<0.001), kynurenine (β=0.256, p=0.005) and QUIN (β=0.213, p=0.044). E/e′ was related with kynurenine (β=0.221, p=0.022) and QUIN (β=0.292, p=0.006). Tryptophan was not associated with any of the remodeling parameters.[Correction added after online publication (22 April 2017: The sentence “Among 136 subjects with pHPT (79% females), 100 (73%) had left ventricular hypertrophy.” was corrected to “Among 136 subjects with pHPT (79% females), 100 (73%) had arterial hypertension and the prevalence of left ventricular hypertrophy was 52%.”]Conclusions:Cardiac remodeling is common in pHPT and is associated with low-grade inflammation and activation of the tryptophan-kynurenine pathway. The potential role of kynurenine and QUIN as cardiovascular risk factors may be further investigated in future studies.