Elisabeth Lerchbaum

Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality—A review of recent evidence

BACKGROUND Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but also for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem are 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 the spectrum of disorders. Supplementation guidance and population strategies for the eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.

Vitamin D and fertility-a systematic review

BACKGROUND Vitamin D has been well-known for its function in maintaining calcium and phosphorus homeostasis and promoting bone mineralization. There is some evidence that in addition to sex steroid hormones, the classic regulators of human reproduction, vitamin D also modulates reproductive processes in women and men. AIM The aim of this review was to assess the studies that evaluated the relationship between vitamin D and fertility in women and men as well as in animals. METHODS We performed a systematic literature search in Pubmed for relevant English language publications published until October 2011. RESULTS AND DISCUSSION The vitamin D receptor (VDR) and vitamin D metabolizing enzymes are found in reproductive tissues of women and men. Vdr knockout mice have significant gonadal insufficiency, decreased sperm count and motility, and histological abnormalities of testis, ovary and uterus. Moreover, we present evidence that vitamin D is involved in female reproduction including IVF outcome (clinical pregnancy rates) and polycystic ovary syndrome (PCOS). In PCOS women, low 25-hydroxyvitamin D (25(OH)D) levels are associated with obesity, metabolic, and endocrine disturbances and vitamin D supplementation might improve menstrual frequency and metabolic disturbances in those women. Moreover, vitamin D might influence steroidogenesis of sex hormones (estradiol and progesterone) in healthy women and high 25(OH)D levels might be associated with endometriosis. In men, vitamin D is positively associated with semen quality and androgen status. Moreover, vitamin D treatment might increase testosterone levels. Testiculopathic men show low CYP21R expression, low 25(OH)D levels, and osteoporosis despite normal testosterone levels.

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.

Susceptibility Loci for Polycystic Ovary Syndrome on Chromosome 2p16.3, 2p21, and 9q33.3 in a Cohort of Caucasian Women

In a recent genome-wide association study investigating Han Chinese PCOS women 3 loci that are strongly associated with PCOS were identified on chromosome 2p16.3 (rs13405728), 2p21 (rs13429458), and 9q33.3 (rs2479106). The aim of the study was to investigate the impact of rs13405728, rs13429458, and rs2479106 variants on PCOS susceptibility in a Caucasian cohort of PCOS and control women. Metabolic, endocrine, and anthropometric measurements and oral glucose tolerance tests were performed in 545 PCOS and 317 control women. The rs13405728, rs13429458, and rs2479106 polymorphisms were genotyped. There was no significant difference in genotype frequencies of rs13405728 and rs13429458 variants between PCOS and controls. There was a trend towards an association of the rs2479106 variant with PCOS susceptibility (p=0.053). PCOS women with the rs2479106 GG genotype had significantly higher WHR than PCOS women carrying the AG and AA genotype (p=0.034 and p=0.020, respectively). Moreover, QChol/HDL and LDL levels were significantly higher in PCOS women carrying the rs2479106 GG genotype when compared to those carrying the AA genotype (p=0.024 and p=0.035, respectively). PCOS women carrying the G allele of rs13405728 had significantly higher AUCgluc, glucose-30 min, and AUCins levels than those carrying the AA genotype (p=0.039, p=0.047, and p=0.044, respectively). In PCOS women, rs13405728 genotypes are associated with glucose and insulin metabolism. Moreover, rs2479106 genotypes were associated with increased WHR levels and an adverse serum lipid profile. Further, we observed a trend towards decreased PCOS susceptibility within carriers of the rs2479106 G-allele. Further studies in large Caucasian PCOS cohorts are warranted to confirm our findings.

Vitamin D and Cancer Mortality: Systematic Review of Prospective Epidemiological Studies

Accumulating evidence from experimental and epidemiological studies suggests that vitamin D deficiency might be a causal risk factor for cancer and therewith associated mortality. We performed a systematic review in Medline up to February 2012 to identify prospective studies on 25-hydroxyvitamin D (25[OH]D) and cancer mortality as well as on 25(OH)D and survival in cancer patients. Our search retrieved 13 studies on cancer-specific mortality and 20 studies on overall mortality in cancer patients. Data on 25(OH)D and cancer mortality were mainly derived from general populations. The results were inconsistent and yielded either no, inverse or positive associations. By contrast, the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality. This relationship was particularly evident in cohorts of colorectal cancer patients. In contrast, there was no indication for increased mortality risk with higher vitamin D levels in any cancer cohort. In conclusion, the relationship of vitamin D status and cancerspecific mortality is still unclear and warrants further studies. Our results provide a strong rationale to perform prospective randomized controlled studies to document a potential effect of vitamin D supplementation on survival in cancer patients.

Testosterone to dihydrotestosterone ratio as a new biomarker for an adverse metabolic phenotype in the polycystic ovary syndrome.

CONTEXT Polycystic 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, DHT, dehydroepiandrosterone (DHEA), and androstenedione using liquid chromatography/mass spectrometry. MAIN OUTCOME MEASURES We measured total levels of testosterone and DHT and calculated unbound hormone levels as well as the ratio of testosterone to DHT. 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 < .001), free testosterone (P < .001), and free DHT (P < .001) compared to healthy controls. The TT/DHT ratio was significantly higher in PCOS patients (P < .001). No difference was found for total DHT levels (P = .072). In PCOS patients alone, the TT/DHT ratio was significantly higher in obese patients (P < .001) and patients with metabolic syndrome (P < .001), impaired glucose tolerance (IGT) (P < .001) or insulin resistance (P < .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.

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.

Vitamin D and cardiovascular disease: Update and outlook

Abstract Accumulating evidence suggests that vitamin D may play a role for cardiovascular health. Expression of the vitamin D receptor (VDR) and enzymes for vitamin D metabolism have been identified in the vasculature as well as in the heart. VDR knock-out mice suffer from cardiovascular disease (CVD) and even selective VDR deletion in cardiomyocytes causes myocardial hypertrophy. Many, but not all observational studies showed that vitamin D deficiency is associated with CVD and its risk factors. Low concentrations of 25-hydroxyvitamin D (25(OH)D) are an independent risk factor for cardiovascular events, in particular for strokes and sudden cardiac deaths. Only few randomized controlled trials (RCTs) are available on this topic. These RCTs are frequently limited by the additional supplementation of calcium which may increase the risk of CVD events. RCTs with pure vitamin D supplementation have partially but not consistently shown beneficial effects on cardiovascular risk factors such as arterial hypertension. A number of large RCTs on the impact of vitamin D supplementation on cardiovascular events and mortality have already started but limitations of the study designs such as inclusion of individuals with relatively high 25(OH)D concentrations have to be considered. At present, the evidence is not sufficient for general recommendations to supplement vitamin D in order to prevent and treat CVD. It should, however, be noted that justification for the prevention and treatment of vitamin D deficiency comes from evidence based benefits of vitamin D supplementation on musculoskeletal health.

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.

Vitamin D and female fertility.

Purpose of review 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. Recent findings 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. Summary 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.