[Show abstract][Hide abstract] ABSTRACT: Context: ovary syndrome (PCOS) is a heterogeneous disease with many different aspects, including hyperandrogenism and metabolic disturbances. Clinical phenotypes show different patterns of steroid hormones that have been investigated to some extent. Objective: This study intended to determine the role of the testosterone (TT) to dihydrotestosterone (DHT) ratio (TT/DHT ratio) in PCOS patients and to further assess the correlation of this ratio with hormonal, anthropometric, and metabolic parameters. Design and Setting: Serum samples of 275 premenopausal PCOS patients fulfilling Rotterdam criteria and 35 BMI-matched, premenopausal, healthy controls were analyzed for testosterone, dihydrotestosterone, dehydroepiandrosterone (DHEA), and androstenedione using liquid chromatography/mass spectrometry. Main Outcome Measures: We measured total levels of testosterone and dihydrotestosterone and calculated unbound hormone levels as well as the ratio of testosterone to dihydrotestosterone. Further, impaired glucose tolerance, basal and stimulated serum insulin levels, metabolic syndrome and insulin resistance according to the homeostatic model assessment (HOMA-IR) were assessed. Results: PCOS patients showed significantly higher levels of TT (p < 0.001), free testosterone (p < 0.001), and free DHT (p < 0.001) compared to healthy controls. The TT/DHT ratio was significantly higher in PCOS patients (p < 0.001). No difference was found for total DHT levels (p = 0.072). In PCOS patients alone, the TT/DHT ratio was significantly higher in obese patients (p < 0.001) and patients with metabolic syndrome (p < 0.001), impaired glucose tolerance (IGT) (p < 0.001) or insulin resistance (p < 0.001). Significant correlations of the TT/DHT ratio with various adverse anthropometric, hormonal, lipid and liver parameters and parameters of glucose metabolism were found. Conclusion: Our data provide evidence for a strong link between a high TT/DHT ratio and an adverse metabolic phenotype in PCOS patients. This correlation was only found in PCOS patients, suggesting the TT/DHT ratio to be a new biomarker for an adverse metabolic phenotype in PCOS patients.
[Show abstract][Hide abstract] ABSTRACT: There is accumulating evidence that vitamin D (VD) has important effects besides its well-known role in calcium and bone metabolism. Hypovitaminosis D is associated with cardiovascular disease, the metabolic syndrome, type 2 diabetes mellitus, cancer as well as with increased mortality. Further, VD deficiency is related to depression and impaired cognitive function. Increasing age and elevated body fat mass contribute to an increased risk of VD deficiency. Further, some studies report a relationship between VD and estrogen metabolism.
During menopause, the decline of estrogens results in increased bone turnover, a decrease in bone mineral density and elevated fracture risk. Musculoskeletal discomfort might impair quality of life, mood disturbances do frequently occur and the risk of metabolic and cardiovascular disease increases. Moreover, body composition changes including increased fat mass and decreased lean mass, which results in an increased risk of VD deficiency. Conversely, VD deficiency might aggravate discomfort as well as diseases that occur during menopause.
There are precise recommendations regarding a sufficient VD intake in order to prevent bone loss in peri- and postmenopausal women. Considering the fact that VD deficiency and menopause share risk factors beyond bone health such as cardiovascular, metabolic, cognitive and affective disorders, a sufficient VD status should be obtained in all peri- and postmenopausal women. This might be beneficial not only considering bone health but also regarding cognitive, affective, metabolic and cardiovascular health of women.
[Show abstract][Hide abstract] ABSTRACT: There is inconsistent evidence on a possible association of vitamin D and androgen levels in men. We therefore aim to investigate the association of 25-hydroxyvitamin D (25(OH)D) with androgen levels in a cohort of middle-aged men. This cross-sectional study included 225 men with a median (interquartile range) age of 35 (30–41) years. We measured 25(OH)D, total testosterone (TT) and SHBG concentrations. Hypogonadism was defined as TT <10.4 nmol/L. We found no significant correlation of 25(OH)D and androgen levels. Furthermore, androgen levels were not significantly different across 25(OH)D quintiles. The overall prevalence of hypogonadism was 21.5% and lowest in men within 25(OH)D quintile 4 (82–102 nmol/L). We found a significantly increased risk of hypogonadism in men within the highest 25(OH)D quintile (>102 nmol/L) compared to men in quintile 4 (reference) in crude (OR 5.10, 1.51–17.24, p = 0.009) as well as in multivariate adjusted analysis (OR 9.21, 2.27–37.35, p = 0.002). We found a trend towards increased risk of hypogonadism in men within the lowest 25(OH)D quintile (≤43.9 nmol/L). In conclusion, our data suggest that men with very high 25(OH)D levels (>102 nmol/L) might be at an increased risk of hypogonadism. Furthermore, we observed a trend towards increased risk of hypogonadism in men with very low vitamin D levels indicating a U-shaped association of vitamin D levels and hypogonadism. With respect to risk of male hypogonadism, our results suggest optimal serum 25(OH)D concentrations of 82–102 nmol/L.
[Show abstract][Hide abstract] ABSTRACT: Apart from the well known effects of vitamin D on maintaining calcium homeostasis and promoting bone mineralization, there is some evidence suggesting that vitamin D also modulates human reproductive processes. We will review the most interesting and relevant studies on vitamin D and female fertility published over the past year.
In the past year, several observational studies reported a better in-vitro fertilization outcome in women with sufficient vitamin D levels (≥30 ng/ml), which was mainly attributed to vitamin D effects on the endometrium. One randomized controlled trial found an increased endometrial thickness in women with polycystic ovary syndrome (PCOS) receiving vitamin D during intrauterine insemination cycles. Further, vitamin D supplementation had a beneficial effect on serum lipids in PCOS women. Vitamin D treatment improved endometriosis in a rat model and increased vitamin D intake was related to a decreased risk of incident endometriosis. Vitamin D was also favorably associated with primary dysmenorrhea, uterine leiomyoma, and ovarian reserve in late reproductive aged women.
In women undergoing in-vitro fertilization, a sufficient vitamin D level (≥30 ng/ml) should be obtained. Vitamin D supplementation might improve metabolic parameters in women with PCOS. A high vitamin D intake might be protective against endometriosis.
Current opinion in obstetrics & gynecology 04/2014; · 2.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Background- Copper and its main transport protein ceruloplasmin have been suggested to promote the development of atherosclerosis. Most of the data come from experimental and animal model studies. Copper and mortality have not been simultaneously evaluated in patients undergoing coronary angiography. Methods and Results - We examined whether serum copper and ceruloplasmin concentrations are associated with angiographic CAD and mortality from all causes and cardiovascular causes in 3253 participants of the Ludwigshafen Risk and Cardiovascular Health Study. Age and sex-adjusted hazard ratios (HR) for death from any cause were 2.23 (95 % CI 1.85-2.68) for copper and 2.63 (95 % CI 2.17-3.20) for ceruloplasmin when we compared the highest with the lowest quartiles. Corresponding hazard ratios (HR) for death from cardiovascular causes were 2.58 (95 % CI 2.05-3.25) and 3.02 (95 % CI 2.36-3.86), respectively. Further adjustments for various risk factors and clinical variables considerably attenuated these associations, which, however were still statistically significant and results remained consistent across subgroups. Conclusions- Both, elevated concentrations of copper and ceruloplasmin are independently associated with increased risk of mortality from all causes and from cardiovascular causes.
Free Radical Research 03/2014; · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There is evidence suggesting a strong genetic background of polycystic ovary syndrome (PCOS). We aim to study the metabolic and endocrine characteristics of PCOS women with and without a family history (FHx) of type 2 diabetes (T2DM) and PCOS.
Cross-sectional study METHODS: We analysed the association of T2DM FHx and PCOS FHx with metabolic and endocrine parameters in 714 PCOS women.
A positive FHx of T2DM and PCOS were prevalent in 36.8% and 21.4% of PCOS women, respectively. We found an independent association of T2DM FHx with central fat accumulation, obesity, prediabetes, metabolic syndrome (MS), insulin resistance, low HDL and elevated blood pressure (p<0.05 for all). PCOS FHx was independently associated with prediabetes (p<0.05). We observed an independent association of PCOS FHx with clinical and biochemical hyperandrogenism (p<0.05 for all), whereas there was no independent association of T2DM FHx with hyperandrogenism. PCOS women with a positive FHx of both T2DM and PCOS had an adverse metabolic and endocrine profile including a linear increase in risk of obesity, central fat accumulation, MS, prediabetes and low HDL (p<0.05 for all).
Our findings suggest that the assessment of FHx might allow risk stratification of PCOS women which is important considering the high prevalence of PCOS.
European Journal of Endocrinology 03/2014; · 3.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Insulin-sensitizer treatment with metformin is common in polycystic ovary syndrome (PCOS). OCT alleles were investigated in PCOS patients to identify genetic 'bad responders' and 'nonresponders' to metformin including their possible effects on glucose metabolism without treatment. We genotyped eight SNPs in OCT1, OCT2 and ATM genes in 676 women with PCOS and 90 control women, we also measured oral glucose tolerance tests prior to treatment. Nonfunctional alleles were present in 29.8% and low-functional alleles in 57.9% of our PCOS cohort. OCT variants were significantly associated with elevated baseline and glucose-induced C-peptide levels in PCOS. Metformin bad responders or nonresponders based on OCT genotypes might be relevant in clinical practice - their modulation of metformin pharmacokinetics and pharmacodynamics and metformin-independent glucose effects remain to be elucidated. Original submitted 7 June 2013; Revision submitted 28 October 2013.
[Show abstract][Hide abstract] ABSTRACT: Polycystic ovary syndrome (PCOS) shows not only hyperandrogenemia, hirsutism and fertility problems, but also metabolic disturbances including obesity, cardiovascular events and type-2 diabetes. Accumulating evidence suggests some degree of inflammation associated with prominent aspects of PCOS. We aimed to investigate the association of genetic variants 3'UTR rs17468190 (G/T) of the inflammation-associated gene MEP1A (GeneBank ID: NM_005588.2) with metabolic disturbances in PCOS and healthy control women. Genetic variants rs17468190 (G/T) of MEP1A gene were analyzed in 576 PCOS women and 206 controls by using the Taqman fluorogenic 5'-exonuclease assay. This polymorphism was tested for association with anthropometric, metabolic, hormonal, and functional parameters of PCOS. There was a borderline significant difference in genotype distribution between PCOS and control women (p=0.046). In overweight/obese PCOS patients, the variants rs17468190 (G/T) in the MEP1A gene are associated with glucose and insulin metabolism. In a dominant model, the GG genotype of the MEP1A gene was more strongly associated with insulin metabolism in overweight/obese PCOS women (body mass index, BMI>25kg/m(2)), than in GT+TT genotypes. The MEP1A GG-carriers showed a significantly increased homeostatic model assessment-insulin resistance (HOMA-IR) (p=0.003), elevation of fasting insulin (p=0.004) and stimulated insulin (30min, p<0.001; 60min, p=0.009; 120min, p=0.009) as well as triglyceride (p=0.032) levels. MEP1A is a possible target gene for disease modification in PCOS. It might contribute to the abnormalities of glucose metabolism and insulin sensitivity and serve as a diagnostic or therapeutic target gene for PCOS.
[Show abstract][Hide abstract] ABSTRACT: Objective: Osteocalcin (OC) might play a hormone-like role in energy metabolism and the regulatory circuit between pancreas and osteoblasts. Effects of a 75g oral glucose tolerance test (OGTT) on total OC, undercarboxylated (ucOC), and carboxylated osteocalcin (cOC) in insulin-resistant (IR) and non-insulin-resistant (nIR) premenopausal women is evaluated and the relationship of changes in OC, ucOC, and cOC with AUCinsulin and Matsuda index examined.Methods: In this cross-sectional study, 105 premenopausal women underwent OGTT. 18 were IR (HOMA-IR > 2.6) (2 with type 2 diabetes, 2 with impaired glucose tolerance) and 87 nIR (3 with impaired glucose tolerance). After glucose load, changes in total OC, ucOC, and cOC were evaluated after 60 and 120 minutes.Results: At baseline, IR women had significantly lower levels of total OC, cOC, and ucOC. In nIR women, total OC decreased by 19% from 18.0ng/ml (14.5-24.7) at baseline to 14.6ng/ml (10.9-17.8) after 120 minutes; ucOC decreased by 22% from 3.2ng/ml (2.1-4.5) to 2.5ng/ml (1.7-3.5); cOC decreased by 26% from 14.9ng/ml (12.1-20.4) to 11.1ng/ml (9.0-14.5) (p<0.001, respectively). In IR women, neither decreased significantly. The declines in OC and cOC predicted AUCinsulin (ΔOC: beta=0.301, p=0.001; ΔcOC: beta=0.315, p<0.001) and Matsuda (ΔOC: beta=-0.235, p=0.003; ΔcOC: beta=-0.245, p=0.002).Conclusions: Glucose intake lowers levels of OC, ucOC, and cOC in nIR women, the extent of which predicts insulin resistance and sensitivity in premenopausal women. In IR women OC parameters seem suppressed. There might be a differing osteoblast response to oral glucose in IR and nIR women - OC reflects this finding.
[Show abstract][Hide abstract] ABSTRACT: We examined the association of fatal events with beta-crosslaps (β-CTX) and osteocalcin (OC) concentrations in women. We observed an independent association of β-CTX and OC concentrations with fatal events in women at high to intermediate cardiovascular risk. INTRODUCTION: There is some evidence suggesting an association of β-CTX and OC with fatal events in men and frail elderly subjects. We aimed to examine the association of fatal events with β-CTX and OC in women. METHODS: We measured β-CTX and OC in 986 women aged 65 (58-72) years referred to coronary angiography. RESULTS: Compared to the first β-CTX quartile, the crude hazard ratios (HRs) for all-cause and cardiovascular mortality in the highest β-CTX quartile were 2.50 (1.65-3.81) and 3.28 (1.82-5.91), respectively. In multivariate adjusted models, HRs for all-cause and cardiovascular mortality in the highest β-CTX quartile were 1.72 (1.09-2.70) and 2.31 (1.24-4.32), respectively. The lowest 25-hydroxyvitamin D [25(OH)D] quartile was significantly associated with increased risk of all-cause and cardiovascular mortality in multivariate adjusted models. In those models, the highest β-CTX quartile was associated with an increased risk of all-cause and cardiovascular mortality. For OC concentrations, we found a reverse J-shaped association with noncardiovascular mortality. Using the first quartile as reference, crude and multivariate adjusted HRs for noncardiovascular mortality in the second and third OC quartile were 0.41 (0.19-0.90) [multivariate: 0.40 (0.18-0.88)] and 0.51 (0.25-1.06) [multivariate: 0.43 (0.20-0.94)], respectively. The lowest 25(OH)D quartile was associated with a trend towards increased risk of noncardiovascular mortality in multivariate analysis. In that analysis, OC quartile 2 and 3 were significantly associated with lower risk of noncardiovascular mortality. CONCLUSIONS: We observed an independent association of high β-CTX with all-cause and cardiovascular mortality and a reverse J-shaped association of OC with noncardiovascular mortality.
Osteoporosis International 06/2013; · 4.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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/m(2). 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. STUDY FUNDING/COMPETING INTEREST(S): The authors declare no study funding and no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.
[Show abstract][Hide abstract] ABSTRACT: Osteocalcin (OC) - released by osteoblasts and known as a marker of bone turnover - has been suggested to influence male fertility in murine models by enhancing testosterone production and sperm count. Results from clinical studies are scarce, however. The aim of this cross-sectional study was to investigate the proposed association of OC, undercarboxylated osteocalcin (ucOC) or carboxylated osteocalcin (cOC) with testosterone and sperm count in a cohort of 159 young male adults from infertile couples. Semen analysis was performed. Testosterone, free testosterone, LH, OC and ucOC were measured in serum samples after an overnight fast. cOC and OC correlated weakly but significantly with testosterone (OC: r = 0.165, p = 0.040, cOC: r = 0.193, p = 0.017), but not after adjusting for age and body mass index (BMI) or waist-hip ratio (WHR). %ucOC (ucOC levels expressed as percentage of total OC) correlated inversely with LH (r = -0.184, p = 0.023) and remained significant after the same adjustment. No significant correlations were observed between OC, cOC, ucOC, %ucOC and sperm count, semen volume and number of vital spermatozoa. In binary logistic regression analyses, none of the parameters of OC were predictors of oligozoospermia after adjusting for age and BMI or WHR. The weak association between %ucOC and LH has marginal clinical importance because of the lack of associations of parameters of OC with testosterone and sperm count. The current data thus cannot support the notion that OC is associated with male fertility in young men from infertile couples.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIMS: Fatty liver index (FLI), a surrogate parameter for nonalcoholic fatty liver disease, is an emerging risk factor for cardiovascular diseases and mortality. We aimed to evaluate whether FLI is associated with all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer in a cohort of subjects routinely referred to coronary angiography. METHODS AND RESULTS: FLI was calculated using BMI (body mass index), waist circumference (WC), triglycerides (TG) and gamma-glutamyl transferase (GGT) in 3270 subjects who were referred to coronary angiography (1997-2000). The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, cardiovascular causes, non-cardiovascular causes, and fatal cancer. After a median follow-up time of 7.7 years, 740 subjects (22.6%) had died. There were 437 deaths due to cardiovascular disease and 303 deaths due to non-cardiovascular disease. Age-, sex-, and BMI-adjusted HRs (with 95% confidence intervals) for all-cause, cardiovascular, and non-cardiovascular mortality in the highest compared to the lowest FLI quartile were 2.56 (1.90-3.43; p < 0.001), 2.17 (1.47-3.22; p < 0.001), and 3.49 (2.16-5.66; p < 0.001), respectively. In age-, sex-, and BMI-adjusted analyzes, we found no significant association of FLI with fatal cancer. Multivariate adjusted HRs for all-cause, cardiovascular, non-cardiovascular mortality, and fatal cancer in the highest compared to the lowest FLI quartile were 2.17 (1.58-2.99; p < 0.001), 1.64 (1.07-2.51; p = 0.023), 3.72 (2.22-6.24; p < 0.001), and 2.33 (1.01-5.41; p = 0.048) respectively. CONCLUSION: In subjects referred to coronary angiography, high FLI levels are independently associated with increased all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem is likely to be a risk for wide spectrum of acute and chronic illnesses. METHODS: A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. RESULTS: Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. CONCLUSIONS: Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for spectrum of disorders. Supplementation guidance and population strategies for eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.
[Show abstract][Hide abstract] ABSTRACT: AimsThe genetic polymorphism of apolipoprotein E (APOE) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known.Methods and resultsWe analysed the association between the APOE-genotype, smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotypes were associated with CAD [ε22 or ε23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43-0.71; ε24 or ε34 or ε44: OR 1.10, 95% CI 0.89-1.37 compared with ε33] and moderately with cardiovascular mortality [ε22 or ε23: hazard ratio (HR) 0.71, 95% CI 0.51-0.99; ε33: HR 0.92, 95% CI 0.75-1.14 compared with ε24 or ε34 or ε44]. HRs for total mortality were 1.39 (95% CI 0.39-0.1.67), 2.29 (95% CI 1.85-2.83), 2.07 (95% CI 1.64-2.62), and 2.95 (95% CI 2.10-4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one ε4 allele, respectively, compared with never-smokers. Carrying ε4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04-2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and ε4 was seen regarding non-cardiovascular mortality. Smokers with ε4 had elevated average low-density lipoprotein (LDL) diameters, oxidized LDL, and lipoprotein-associated phospholipase A2.Conclusion
In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the ε4 allele in current smokers increases cardiovascular and all-cause mortality.
European Heart Journal 02/2013; · 14.72 Impact Factor