Verena Schwetz

Effects of vitamin D on blood pressure and cardiovascular risk factors: a randomized controlled trial.

Vitamin D deficiency is a risk factor for arterial hypertension, but randomized controlled trials showed mixed effects of vitamin D supplementation on blood pressure (BP). We aimed to evaluate whether vitamin D supplementation affects 24-hour systolic ambulatory BP monitoring values and cardiovascular risk factors. The Styrian Vitamin D Hypertension Trial is a single-center, double-blind, placebo-controlled study conducted from June 2011 to August 2014 at the endocrine outpatient clinic of the Medical University of Graz, Austria. We enrolled 200 study participants with arterial hypertension and 25-hydroxyvitamin D levels below 30 ng/mL. Study participants were randomized to receive either 2800 IU of vitamin D3 per day as oily drops (n=100) or placebo (n=100) for 8 weeks. Primary outcome measure was 24-hour systolic BP. Secondary outcome measures were 24-hour diastolic BP, N-terminal-pro-B-type natriuretic peptide, QTc interval, renin, aldosterone, 24-hour urinary albumin excretion, homeostasis model assessment-insulin resistance, triglycerides, high-density lipoprotein cholesterol, and pulse wave velocity. A total of 188 participants (mean [SD] age, 60.1 [11.3] years; 47% women; 25-hydroxyvitamin D, 21.2 [5.6] ng/mL) completed the trial. The mean treatment effect (95% confidence interval) for 24-hour systolic BP was −0.4 (−2.8 to 1.9) mm Hg (P=0.712). Triglycerides increased significantly (mean change [95% confidence interval], 17 [1–33] mg/dL; P=0.013), but no further significant effects were observed for secondary outcomes. Vitamin D supplementation in hypertensive patients with low 25-hydroxyvitamin D has no significant effect on BP and several cardiovascular risk factors, but it was associated with a significant increase in triglycerides. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02136771.

MECHANISMS IN ENDOCRINOLOGY: The endocrine role of the skeleton: background and clinical evidence

Based on the observation that diabetes, obesity, and hypogonadism influence bone metabolism, the existence of a feedback loop and a common regulation was postulated and an endocrine role ascribed to the skeleton. In the first part of this review, two pathways are described whereby adipose tissue acts on bone mass. In the first, leptin activates the sympathetic nervous system via serotonin and diminishes bone mass accrual. The second pathway functions via the activation of CART (CARTPT) and inhibits bone resorption. The first pathway leads to a decrease in bioactivity of the osteoblast-produced hormone osteocalcin (OC) (part 2). In its undercarboxylated form, OC acts on the three targets pancreas, adipose tissue, and gonads (part 3) and thereby causes an increase in insulin secretion and sensitivity, β-cell proliferation, and male fertility. Insulin (part 4) is part of a recently discovered regulatory feedback loop between pancreas and osteoblasts. It is a strong counterplayer of leptin as it causes a decrease in OPG expression and enhances bone resorption and OC decarboxylation. Numerous clinical studies (part 5) have shown associations of total and undercarboxylated OC and markers of energy metabolism. Interventional studies, to date only performed in murine models, have shown positive effects of OC administration on energy metabolism. Whether bone tissue has an even further-reaching endocrine role remains to be elucidated.

Assessment of glucose metabolism in polycystic ovary syndrome: HbA1c or fasting glucose compared with the oral glucose tolerance test as a screening method

STUDY QUESTION Are HbA1c and fasting glucose (FG) useful in predicting the presence of prediabetes and type 2 diabetes (T2DM) in a large cohort of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER HbA1c and FG are not suitable as screening tools for prediabetes in a large cohort of PCOS women but do show a good level of agreement with T2DM. WHAT IS KNOWN ALREADY Women with PCOS have an increased risk of prediabetes and T2DM. As performing an oral glucose tolerance test (OGTT) is time consuming, HbA1c and FG have been suggested as screening tools for prediabetes and T2DM. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study of 671 women with PCOS conducted from 2006 to 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was carried out at the endocrinological outpatient department of the Medical University of Graz, Austria. We performed 75 g 2-h OGTTs and measured HbA1c in 671 women with PCOS aged 16-45 years with a median BMI of 24.2 (21.3-30.1) kg/m². PCOS was defined according to the Rotterdam criteria. Prediabetes (FG 100-125 mg/dl and/or 2-h glucose 140-199 mg/dl and/or HbA1c 5.7-6.4%) and T2DM (FG ≥ 126 mg/dl and/or 2-h glucose ≥200 mg/dl and/or HbA1c ≥ 6.5%) were diagnosed according to the American Diabetes Association (ADA) criteria. Levels of agreement between different definitions were analyzed using κ-index. MAIN RESULTS AND THE ROLE OF CHANCE According to the ADA criteria, we found prediabetes and T2DM in 12.8% (n = 76) and 1.5% (n = 9) of PCOS women, respectively. When using elevated HbA1c (5.7-6.4%) for defining prediabetes, 19 (3.2%) of all PCOS women had prediabetes with a κ-index of 0.36. When using elevated FG (100-125 mg/dl) for defining prediabetes, 31 (5.2%) of all the PCOS women were diagnosed with prediabetes with a κ-index of 0.05. Further, elevated HbA1c (≥6.5% defining T2DM) was found in six (0.9%) PCOS women (κ-index 0.80), and elevated FG (≥126 mg/dl diagnosing T2DM) was found in seven PCOS women (1%; κ-index 0.82). LIMITATIONS, REASONS FOR CAUTION Our results are limited to an Austrian cohort of PCOS women diagnosed by Rotterdam criteria with a median BMI in the normal weight range. WIDER IMPLICATIONS OF THE FINDINGS Our results are in line with results from previous smaller PCOS cohorts. Our findings do not support the recommendation that FG or HbA1c can be used for the screening of prediabetes in women with PCOS. For such women, OGTT should be performed for screening of prediabetes. Whether this finding is generalizable to other cohorts remains to be determined in further studies.

Fatty liver index in polycystic ovary syndrome.

INTRODUCTION Women with polycystic ovary syndrome (PCOS) frequently suffer from metabolic disturbances and might be affected by hepatic steatosis. The fatty liver index (FLI) was developed as a simple and accurate predictor of hepatic steatosis. We aimed to analyze the association of FLI with endocrine and metabolic parameters in a cohort of PCOS and control women. METHODS FLI was calculated using body mass index (BMI), waist circumference, triglycerides, and gamma-glutamyl transferase in 611 PCOS and 139 BMI-matched control women within the same age range. Elevated FLI was defined as >60. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed. RESULTS PCOS women had significantly higher FLI levels than control women in age-adjusted analyses (11.4 (4.3-48.8) and 8.8 (3.9-35.0), respectively, P=0.001), whereas fibrosis indices were similar (aspartate amino transferase-to-platelet ratio index) or lower (FIB-4) respectively. In binary logistic regression analysis adjusted for age, odds ratio (OR) for elevated FLI was 2.52 (1.31-4.85), P=0.006, for PCOS women when compared with controls. PCOS women with high FLI levels had an adverse anthropometric, metabolic, and endocrine risk profile. The prevalence of elevated FLI was 88.7% in PCOS women with metabolic syndrome (MS) and 11.3% in PCOS women without MS (P<0.001). In control women, elevated FLI was present in 66.7% of women with MS and 30.8% of women without MS. CONCLUSION High FLI levels are a common finding in obese PCOS women and are closely linked to MS. FLI calculation might be a useful tool for identifying PCOS patients at high risk for metabolic and hepatic disturbances.

Testicular synthesis and vitamin D action.

CONTEXT The vitamin D system has pleiotropic effects not only in bone metabolism. Its role in testicular steroidogenesis is new and deserves intensive research. OBJECTIVE We hypothesize that vitamin D, especially 1,25 dihydroxyvitamin D3 [1,25(OH)2D3 (calcitriol)] induces male steroidogenesis and intend to identify its impact on genes and pathways in testicular androgen regulation. METHODS Human adult primary testicular cells were isolated, treated with 1,25(OH)2D3, and their gene expression levels profiled by microarray analysis. Highly regulated genes were confirmed by real-time quantitative PCR. In addition, the effects of 1,25(OH)2D3 in combination with LH and IGF-I on the gene expression level of androgens were assessed. T levels in the culture media were determined by a high-resolution ELISA. The expression of vitamin D receptor was confirmed at baseline and after 1,25(OH)2D3 stimulation using immunocytochemistry. RESULTS Microarrays depicted 63 genes significantly regulated by 1,25(OH)2D3, including genes related to male androgen and vitamin D metabolism, mainly triggered by the vitamin D receptor/retinoid X receptor activation. 1,25(OH)2D3 led to significant changes in the expression profiles of reproductive genes and significantly increased T synthesis in human testicular cell cultures. CONCLUSIONS Data from our human primary testicular cell culture model suggest that vitamin D plays a major role in male steroidogenesis in vitro.

Association of bone turnover markers with mortality in men referred to coronary angiography

SummaryWe aimed to examine the association of fatal events with osteocalcin (OC) and beta-crosslaps (β-CTX) levels in men. We observed a U-shaped association of OC and β-CTX levels with fatal events in a large cohort of men at high cardiovascular risk.IntroductionAccumulating evidence suggests an association of low OC levels with metabolic disturbances. Whether OC levels are related to fatal events is, however, less clear. Further, high β-CTX levels are linked to increased mortality. We aimed to examine the association of fatal events with both OC and β-CTX in men.MethodsWe measured OC and β-CTX in 2,271 men referred to coronary angiography (1997–2000).ResultsWe observed a U-shaped association of OC and β-CTX with fatal events. Crude hazard ratios (HRs) for all-cause and non-cardiovascular mortality in the highest OC quintile were 1.38 (1.04–1.83) and 1.47 (0.89–2.40), respectively, and 2.11 (1.61–2.75) and 2.06 (1.29–3.29) for men in the lowest compared to the third OC quintile. In multivariate-adjusted models, HRs for all-cause, and non-cardiovascular mortality in the lowest OC quintile were 1.63 (1.23–2.16) and 1.79 (1.10–2.92), respectively, compared to the third OC quintile, whereas the association of high OC with mortality lost its significance. Crude and multivariate-adjusted HRs for cardiovascular mortality in the lowest OC quintile compared to the third OC quintile were 2.08 (1.49–2.90) and 1.74 (1.24–2.46), respectively. Moreover, high as well as low β-CTX levels were independently associated with all-cause (quintile 1 vs. quintile 3: HR 1.42 (1.05–1.92); quintile 5 vs. quintile 3: HR 1.79 (1.31–2.45)) and cardiovascular mortality (quintile 1 vs. quintile 3: HR 1.55 (1.05–2.28); quintile 5 vs. quintile 3: HR 1.85 (1.23–2.77)).ConclusionsWe observed a U-shaped association of OC and β-CTX with fatal events in a large cohort of men at high cardiovascular risk.

Hyperandrogenemia in polycystic ovary syndrome: exploration of the role of free testosterone and androstenedione in metabolic phenotype.

Objective To evaluate the association between androstenedione, testosterone, and free testosterone and metabolic disturbances in polycystic ovary syndrome. Methods We analyzed the association between androstenedione, testosterone, and free testosterone and metabolic parameters in a cross-sectional study including 706 polycystic ovary syndrome and 140 BMI-matched healthy women. Polycystic ovary syndrome women were categorized into 4 groups: normal androstenedione and normal free testosterone (NA/NFT), elevated androstenedione and normal free testosterone (HA/NFT), normal androstenedione and elevated free testosterone (NA/HFT), elevated androstenedione and free testosterone (HA/HFT). Results Polycystic ovary syndrome women with elevated free testosterone levels (HA/HFT and NA/HFT) have an adverse metabolic profile including 2 h glucose, HbA1c, fasting and 2 h insulin, area under the insulin response curve, insulin resistance, insulin sensitivity index (Matsuda), triglycerides, total and high density lipoprotein cholesterol levels compared to NA/NFT (p<0.05 for all age- and BMI-adjusted analyses). In binary logistic regression analysis adjusted for age and BMI, odds ratio for insulin resistance was 2.78 (1.34–5.75, p = 0.006) for polycystic ovary syndrome women with HA/HFT compared to NA/NFT. We found no significantly increased risk of metabolic disorders in polycystic ovary syndrome women with HA/NFT. In multiple linear regression analyses (age- and BMI-adjusted), we found a significant negative association between androstenedione/free testosterone-ratio and area under the insulin response curve, insulin resistance, and total cholesterol/high density lipoprotein cholesterol-ratio and a positive association with Matsuda-index, and high density lipoprotein cholesterol (p<0.05 for all). Conclusions Polycystic ovary syndrome women with elevated free testosterone levels but not with isolated androstenedione elevation have an adverse metabolic phenotype. Further, a higher androstenedione/free testosterone-ratio was independently associated with a beneficial metabolic profile.

Opposing effects of dehydroepiandrosterone sulfate and free testosterone on metabolic phenotype in women with polycystic ovary syndrome

OBJECTIVE To study the association of adrenal and ovarian androgen levels with metabolic parameters in a large cohort of women with polycystic ovary syndrome (PCOS). DESIGN Cross-sectional study. SETTING Outpatient clinic of an academic hospital. PATIENT(S) Six hundred twenty-two women with PCOS. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Analysis of the association of endocrine dehydroepiandrosterone sulfate (DHEAS) and free testosterone (FT) parameters with metabolic measurements. RESULT(S) In multivariate adjusted logistic regression analyses, the odds ratio (OR) for insulin resistance was statistically significantly higher (4.42, range: 2.26-8.67) for women with PCOS who had elevated FT levels compared with the women with normal DHEAS and FT levels (reference group). We found no statistically significant differences when women with PCOS with elevated DHEAS or a combined elevation of DHEAS and FT levels were compared with the reference group. Women with PCOS and a high DHEAS/FT ratio had a more beneficial metabolic profile compared with the women with a low DHEAS/FT ratio. In multivariate adjusted binary logistic regression analyses, we found a statistically significantly lower risk for insulin resistance in the women with PCOS in the highest DHEAS/FT-ratio quartile compared with women with PCOS in the lowest quartile (OR 0.35, range: 0.14-0.89). CONCLUSION(S) Our results suggest that the distinction between adrenal and ovarian hyperandrogenism is important when evaluating metabolic risk in PCOS.

Vitamin-D concentrations, cardiovascular risk and events - a review of epidemiological evidence

Vitamin D has long been established as an elemental factor of bone physiology. Beyond mineral metabolism, the expression of the vitamin D receptor has been identified throughout the cardiovascular (CV) system. Experimental studies showed beneficial effects of vitamin D on heart and vessels, but vitamin D intoxication in animals also led to hypercalcemia and vascular calcification. Our knowledge has been extended by epidemiological studies that showed that 25-hydroxyvitamin D (25(OH)D) levels are inversely associated with an increased CV risk itself, but also with established CV risk factors, such as arterial hypertension, endothelial dysfunction and atherosclerosis. Conversely, randomized controlled trials could not document significant and consistent effects of vitamin D supplementation on CV risk or events. Potential explanations may lie in differences in reference ranges or the possibility that low vitamin D in CV disease is only an epiphenomenon. In the latter case, the key question is why low 25(OH)D levels are such a strong predictor of health. While we wait for new data, the current conclusion is that vitamin D is a strong risk marker for CV risk factors and for CV diseases itself.

Mechanisms in endocrinology: thyroid and polycystic ovary syndrome.

Thyroid disorders, especially Hashimotos thyroiditis (HT), and polycystic ovary syndrome (PCOS) are closely associated, based on a number of studies showing a significantly higher prevalence of HT in women with PCOS than in controls. However, the mechanisms of this association are not as clear. Certainly, genetic susceptibility contributes an important part to the development of HT and PCOS. However, a common genetic background has not yet been established. Polymorphisms of the PCOS-related gene for fibrillin 3 (FBN3) could be involved in the pathogenesis of HT and PCOS. Fibrillins influence the activity of transforming growth factor beta (TGFβ). Multifunctional TGFβ is also a key regulator of immune tolerance by stimulating regulatory T cells (Tregs), which are known to inhibit excessive immune response. With lower TGFβ and Treg levels, the autoimmune processes, well known in HT and assumed in PCOS, might develop. In fact, lower levels of TGFβ1 were found in HT as well as in PCOS women carrying allele 8 of D19S884 in the FBN3 gene. Additionally, vitamin D deficiency was shown to decrease Tregs. Finally, high estrogen-to-progesterone ratio owing to anovulatory cycles in PCOS women could enhance the immune response. Harmful metabolic and reproductive effects were shown to be more pronounced in women with HT and PCOS when compared with women with HT alone or with controls. In conclusion, HT and PCOS are associated not only with respect to their prevalence, but also with regard to etiology and clinical consequences. However, a possible crosstalk of this association is yet to be elucidated.