Associations between Fatty Acid Intakes and Plasma Phospholipid Fatty Acid Concentrations in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: The aim of this study is to determine the correlations between dietary fatty acid (FA) intakes and plasma phospholipid (PL) FA levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: The dietary intake of 60 individual FAs was estimated using centre-specific validated dietary questionnaires. Plasma PL FA concentrations of these FAs were measured in non-fasting venous plasma samples in nested case-control studies within the EPIC cohort (n = 4923, using only non-cases). Spearman rank correlations were calculated to determine associations between FA intakes and plasma PL FA levels. RESULTS: Correlations between FA intakes and circulating levels were low to moderately high (-0.233 and 0.554). Moderate positive correlations were found for total long-chain n-3 poly-unsaturated FA (PUFA) (r = 0.354) with the highest (r = 0.406) for n-3 PUFA docosahexaenoic acid (DHA). Moderate positive correlations were also found for the non-endogenously synthesized trans-FA (r = 0.461 for total trans-FA C16-18; r = 0.479 for industrial trans-FA (elaidic acid)). CONCLUSIONS: Our findings indicate that dietary FA intakes might influence the plasma PL FA status to a certain extent for several specific FAs. The stronger positive correlations for health-enhancing long-chain PUFAs and the health-deteriorating trans-FA that are not endogenously produced are valuable for future cancer prevention public health interventions.

Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.

OBJECTIVE: Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS: We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10-8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS: These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

Six months vitamin K treatment does not affect systemic arterial calcification or bone mineral density in diabetes mellitus 2.

PURPOSE: Vitamin K-dependent proteins are involved in (patho)physiological calcification of the vasculature and the bones. Type 2 diabetes mellitus (DM2) is associated with increased arterial calcification and increased fractures. This study investigates the effect of 6 months vitamin K2 supplementation on systemic arterial calcification and bone mineral density (BMD) in DM2 patients with a history of cardiovascular disease (CVD). METHODS: In this pre-specified, post hoc analysis of a double-blind, randomized, controlled clinical trial, patients with DM2 and CVD were randomized to a daily, oral dose of 360 µg vitamin K2 or placebo for 6 months. CT scans were made at baseline and follow-up. Arterial calcification mass was quantified in several large arterial beds and a total arterial calcification mass score was calculated. BMD was assessed in all non-fractured thoracic and lumbar vertebrae. RESULTS: 68 participants were randomized, 35 to vitamin K2 (33 completed follow-up) and 33 to placebo (27 completed follow-up). The vitamin K group had higher arterial calcification mass at baseline [median (IQR): 1694 (812-3584) vs 1182 (235-2445)] for the total arterial calcification mass). Six months vitamin K supplementation did not reduce arterial calcification progression (ß [95% CI]: - 0.02 [- 0.10; 0.06] for the total arterial calcification mass) or slow BMD decline (ß [95% CI]: - 2.06 [- 11.26; 7.30] Hounsfield units for all vertebrae) when compared to placebo. CONCLUSION: Six months vitamin K supplementation did not halt progression of arterial calcification or decline of BMD in patients with DM2 and CVD. Future clinical trials may want to pre-select patients with very low vitamin K status and longer follow-up time might be warranted. This trial was registered at clinicaltrials.gov as NCT02839044.

The association between circulating 25-hydroxyvitamin D metabolites and type 2 diabetes in European populations: A meta-analysis and Mendelian randomisation analysis.

BACKGROUND: Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. METHODS AND FINDINGS: We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]-InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1-standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. CONCLUSIONS: Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D.

Fatty acids from dairy and meat and their association with risk of coronary heart disease.

PURPOSE: The relationship of total, saturated, mono-unsaturated and poly-unsaturated fatty acids (SFA, MUFA, PUFA) with coronary heart disease (CHD) is debated. We hypothesized that the association of dairy-derived FA with CHD may be different than the association of meat-derived FA with CHD. We therefore aimed to directly compare association of FA intakes from dairy and meat with risk of CHD using substitution models. METHODS: Baseline (1993-1997) FA intake was measured using a validated food frequency questionnaire among 35,767 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort (EPIC-NL). Incident CHD events (n = 2374) were obtained through linkage with national registries during a mean follow-up of 15 years. Association of FA from dairy substituted with FA from meat with CHD risk was estimated through multivariable Cox regression. RESULTS: Participants consumed 81.9 (SD 28.7) grams of FA per day, of which 17.9 (SD 5.2) was from dairy and 15.3 (SD 9.5) from meat. Substituting 1 en% of dairy-derived SFA with meat-derived SFA was associated with higher CHD risk (HR 1.06, 95% CI 1.02-1.10), but substituting dairy-derived MUFA or PUFA did not (HRMUFA 1.03, 95% CI 0.97-1.09; HRPUFA 1.17, 95% CI 0.90-1.53). CONCLUSIONS: Our modelling suggests that substituting dairy SFA with meat SFA is associated with a higher risk of CHD, but substituting dairy MUFA or PUFA with meat FA is not. These results need to be replicated in other cohorts with different fat intakes, preferably with larger variation in the intake of MUFA and PUFA from dairy and meat.

Osteoporosis management in patients with breast cancer: EMAS position statement.

Aromatase inhibitors (AIs) are the first-line recommended standard of care for postmenopausal estrogen receptor-positive breast cancer. Because they cause a profound suppression of estrogen levels, concerns regarding their potential to increase the risk of fracture were rapidly raised. There is currently a general consensus that a careful baseline evaluation is needed of the risk of fracture in postmenopausal women about to start treatment with AIs but also in all premenopausal women with early disease. Bisphosphonates have been shown in several phase III trials to prevent the bone loss induced by cancer treatment, although no fracture data are available. Even though they do not have regulatory approval for this indication, their use must be discussed with women at high risk of fracture. Accordingly, several guidelines recommend considering treatment in women with a T-score ≤-2 or those with two or more clinical risk factors. Moreover, recent data suggest that bisphosphonates, especially intravenous zoledronic acid, may have an anticancer effect, in that they reduce bone recurrence as well as extra-skeletal metastasis and breast cancer mortality in postmenopausal women. The anti-RANK ligand antibody denosumab is also emerging as a new adjuvant therapeutic option to prevent AI-induced bone loss. It has been shown to extend the time to first fracture in postmenopausal women treated with AIs. Several issues still need to be addressed regarding the use of these different agents in an adjuvant setting. The purpose of this position statement is to review the literature on antifracture therapy and to discuss the current guidelines for the management of osteoporosis in women with early breast cancer.

A model of care for healthy menopause and ageing: EMAS position statement.

Worldwide, the number of menopausal women is increasing. They present with complex medical issues that lie beyond the traditional scope of gynaecologists and general practitioners (GPs). The European Menopause and Andropause Society (EMAS) therefore provides a holistic model of care for healthy menopause (HM). The HM healthcare model's core consists of a lead clinician, specialist nurse(s) and the woman herself, supported by an interdisciplinary network of medical experts and providers of alternative/complementary medicine. As HM specialist teams are scarce in Europe, they are also responsible for structuring and optimizing processes in primary care (general gynaecologists and GPs) and secondary care (HM specialists). Activities for accreditation of the subspecialty Women's Health are encouraged.

Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study.

BACKGROUND: Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations. METHODS AND FINDINGS: Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88-0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77-0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85-0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs. CONCLUSIONS: These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.

The association between dietary saturated fatty acids and ischemic heart disease depends on the type and source of fatty acid in the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort.

BACKGROUND: The association between saturated fatty acid (SFA) intake and ischemic heart disease (IHD) risk is debated. OBJECTIVE: We sought to investigate whether dietary SFAs were associated with IHD risk and whether associations depended on 1) the substituting macronutrient, 2) the carbon chain length of SFAs, and 3) the SFA food source. DESIGN: Baseline (1993-1997) SFA intake was measured with a food-frequency questionnaire among 35,597 participants from the European Prospective Investigation into Cancer and Nutrition-Netherlands cohort. IHD risks were estimated with multivariable Cox regression for the substitution of SFAs with other macronutrients and for higher intakes of total SFAs, individual SFAs, and SFAs from different food sources. RESULTS: During 12 y of follow-up, 1807 IHD events occurred. Total SFA intake was associated with a lower IHD risk (HR per 5% of energy: 0.83; 95% CI: 0.74, 0.93). Substituting SFAs with animal protein, cis monounsaturated fatty acids, polyunsaturated fatty acids (PUFAs), or carbohydrates was significantly associated with higher IHD risks (HR per 5% of energy: 1.27-1.37). Slightly lower IHD risks were observed for higher intakes of the sum of butyric (4:0) through capric (10:0) acid (HRSD: 0.93; 95% CI: 0.89, 0.99), myristic acid (14:0) (HRSD: 0.90; 95% CI: 0.83, 0.97), the sum of pentadecylic (15:0) and margaric (17:0) acid (HRSD: 0.91: 95% CI: 0.83, 0.99), and for SFAs from dairy sources, including butter (HRSD: 0.94; 95% CI: 0.90, 0.99), cheese (HRSD: 0.91; 95% CI: 0.86, 0.97), and milk and milk products (HRSD: 0.92; 95% CI: 0.86, 0.97). CONCLUSIONS: In this Dutch population, higher SFA intake was not associated with higher IHD risks. The lower IHD risk observed did not depend on the substituting macronutrient but appeared to be driven mainly by the sums of butyric through capric acid, the sum of pentadecylic and margaric acid, myristic acid, and SFAs from dairy sources. Residual confounding by cholesterol-lowering therapy and trans fat or limited variation in SFA and PUFA intake may explain our findings. Analyses need to be repeated in populations with larger differences in SFA intake and different SFA food sources.

EMAS position statement: Diet and health in midlife and beyond.

INTRODUCTION: There is increasing evidence that life-style factors, such as nutrition, physical activity, smoking and alcohol consumption have a profound modifying effect on the epidemiology of most major chronic conditions affecting midlife health. AIMS: To provide guidance concerning the effect of diet on morbidity and mortality of the most frequent diseases prevalent in midlife and beyond. MATERIALS AND METHODS: Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS: A healthy diet is essential for the prevention of all major chronic non-communicable diseases in midlife and beyond, both directly, through the effect of individual macro- and micronutrients and indirectly, through the control of body weight. Type 2 diabetes mellitus is best prevented or managed by restricting the total amount of carbohydrate in the diet and by deriving carbohydrate energy from whole-grain cereals, fruits and vegetables. The substitution of saturated and trans-fatty acids by mono-unsaturated and omega-3 fatty acids is the most important dietary intervention for the prevention of cardiovascular disease. Obesity is also a risk factor for a variety of cancers. Obese elderly persons should be encouraged to lose weight. Diet plans can follow the current recommendations for weight management but intake of protein should be increased to conserve muscle mass. The consumption of red or processed meat is associated with an increase of colorectal cancer. Adequate protein, calcium and vitamin D intake should be ensured for the prevention of osteoporotic fractures. Surveillance is needed for possible vitamin D deficiency in high risk populations. A diet rich in vitamin E, folate, B12 and omega-3 fatty acids may be protective against cognitive decline. With increasing longevity ensuring a healthy diet is a growing public health issue.

The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study.

BACKGROUND: Epidemiologic evidence of an association between fish intake and type 2 diabetes (T2D) is inconsistent and unresolved. OBJECTIVE: The objective was to examine the association between total and type of fish intake and T2D in 8 European countries. DESIGN: This was a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, with 3.99 million person-years of follow-up, 12,403 incident diabetes cases, and a random subcohort of 16,835 individuals from 8 European countries. Habitual fish intake (lean fish, fatty fish, total fish, shellfish, and combined fish and shellfish) was assessed by country-specific dietary questionnaires. HRs were estimated in each country by using Prentice-weighted Cox regression models and pooled by using a random-effects meta-analysis. RESULTS: No overall association was found between combined fish and shellfish intake and incident T2D per quartile (adjusted HR: 1.00; 95% CI: 0.94, 1.06; P-trend = 0.99). Total fish, lean fish, and shellfish intakes separately were also not associated with T2D, but fatty fish intake was weakly inversely associated with T2D: adjusted HR per quartile 0.97 (0.94, 1.00), with an HR of 0.84 (0.70, 1.01), 0.85 (0.76, 0.95), and 0.87 (0.78, 0.97) for a comparison of the second, third, and fourth quartiles with the lowest quartile of intake, respectively (P-trend = 0.06). CONCLUSIONS: These findings suggest that lean fish, total fish, and shellfish intakes are not associated with incident diabetes but that fatty fish intake may be weakly inversely associated. Replication of these findings in other populations and investigation of the mechanisms underlying these associations are warranted. Meanwhile, current public health recommendations on fish intake should remain unchanged.

Tea and coffee consumption and cardiovascular morbidity and mortality.

OBJECTIVE: To examine the associations of coffee and tea consumption with risk of morbidity and mortality of stroke and coronary heart disease (CHD) and with all-cause mortality. METHODS AND RESULTS: Coffee and tea consumption were assessed with a validated food-frequency questionnaire, and 37 514 participants were observed for 13 years for the occurrence of cardiovascular morbidity and mortality. A U-shaped association between coffee and CHD was found, with the lowest hazard ratio (HR [95% CI]) for 2.1 to 3.0 cups per day (0.79 [0.65 to 0.96]; P(trend)=0.01). Tea was inversely associated with CHD, with the lowest HR (95% CI) for more than 6.0 cups per day (0.64 [0.46 to 0.90]; P(trend)=0.02). No associations between tea or coffee and stroke were found (P(trend)=0.63 and P(trend)=0.32, respectively). Although not significant, coffee slightly reduced the risk for CHD mortality (HR, 0.64; 95% CI, 0.37 to 1.11; P(trend)=0.12) for 3.1 to 6.0 cups per day. A U-shaped association between tea and CHD mortality was observed, with an HR of 0.55 (95% CI, 0.31 to 0.97; P(trend)=0.03) for 3.1 to 6.0 cups per day. Neither coffee nor tea was associated with stroke (P(trend)=0.22 and P(trend)=0.74, respectively) and all-cause mortality (P(trend)=0.33 and P(trend)=0.43, respectively). CONCLUSIONS: High tea consumption is associated with a reduced risk of CHD mortality. Our results suggest a slight risk reduction for CHD mortality with moderate coffee consumption and strengthen the evidence on the lower risk of CHD with coffee and tea consumption.

Region-specific nutrient intake patterns exhibit a geographical gradient within and between European countries.

Until recently, the study of nutrient patterns was hampered at an international level by a lack of standardization of both dietary methods and nutrient databases. We aimed to describe the diversity of nutrient patterns in the European Prospective Investigation into Cancer and Nutrition (EPIC) study at population level as a starting point for future nutrient pattern analyses and their associations with chronic diseases in multi-center studies. In this cross-sectional study, 36,034 persons aged 35-74 y were administered a single, standardized 24-h dietary recall. Intake of 25 nutrients (excluding intake from dietary supplements) was estimated using a standardized nutrient database. We used a graphic presentation of mean nutrient intakes by region and sex relative to the overall EPIC means to contrast patterns within and between 10 European countries. In Mediterranean regions, including Greece, Italy, and the southern centers of Spain, the nutrient pattern was dominated by relatively high intakes of vitamin E and monounsaturated fatty acids (MUFA), whereas intakes of retinol and vitamin D were relatively low. In contrast, in Nordic countries, including Norway, Sweden, and Denmark, reported intake of these same nutrients resulted in almost the opposite pattern. Population groups in Germany, The Netherlands, and the UK shared a fatty acid pattern of relatively high intakes of PUFA and SFA and relatively low intakes of MUFA, in combination with a relatively high intake of sugar. We confirmed large variability in nutrient intakes across the EPIC study populations and identified 3 main region-specific patterns with a geographical gradient within and between European countries.

Food frequency questionnaires and overnight urines are valid indicators of daidzein and genistein intake in U.S. women relative to multiple 24-h urine samples.

Data regarding convenient, valid methods for measuring U.S. isoflavone intake are limited. We evaluated a soy food questionnaire (SFQ), the Willett food frequency questionnaire (FFQ), and overnight urine samples relative to excretion in 24-h urine samples. We also described intake among women in a high-risk program for breast or ovarian cancer. Between April 2002 and June 2003, 451 women aged 30 to 50 yr with a family history of breast or ovarian cancer completed the SFQ and FFQ. Of them, 27 provided four 24-h and overnight urine specimens. In these women, 24-h sample measures were correlated with SFQ estimates of daidzein (Spearman r = .48) and genistein (r = .54) intake, moderately correlated with the Willett FFQ (daidzein r = .38, genistein r = .33), and strongly correlated with overnight urine excretion (daidzein r = .84, genistein r = 0.93). Among all 451 SFQ respondents, mean (median) daidzein and genistein intakes were 2.8 (0.24) and 3.9 (0.30) mg/day. Primary sources of both were soymilk, soy nuts, and tofu. We conclude that targeted soy food questionnaires, comprehensive FFQs, and multiple overnight urines are all reasonable options for assessing isoflavone intake in epidemiologic studies.

Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial.

CONTEXT: Serum testosterone levels decline significantly with aging. Testosterone supplementation to older men might beneficially affect the aging processes. OBJECTIVE: To investigate the effect of testosterone supplementation on functional mobility, cognitive function, bone mineral density, body composition, plasma lipids, quality of life, and safety parameters in older men with low normal testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial of 237 healthy men between the ages of 60 and 80 years with a testosterone level lower than 13.7 nmol/L conducted from January 2004 to April 2005 at a university medical center in the Netherlands. INTERVENTION: Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for 6 months. MAIN OUTCOME MEASURES: Functional mobility (Stanford Health Assessment Questionnaire, timed get up and go test, isometric handgrip strength, isometric leg extensor strength), cognitive function (8 different cognitive instruments), bone mineral density of the hip and lumbar spine (dual-energy x-ray absorptiometry scanning), body composition (total body dual-energy x-ray absorptiometry and abdominal ultrasound of fat mass), metabolic risk factors (fasting plasma lipids, glucose, and insulin), quality of life (Short-Form Health 36 Survey and the Questions on Life Satisfaction Modules), and safety parameters (serum prostate-specific antigen level, ultrasonographic prostate volume, International Prostate Symptom score, serum levels of creatinine, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, hemoglobin, and hematocrit). RESULTS: A total of 207 men completed the study. During the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol decreased; by the end of the study, 47.8% in the testosterone group vs 35.5% in the placebo group had the metabolic syndrome (P = .07). Quality-of-life measures were no different except for one hormone-related quality-of-life measure that improved. No negative effects on prostate safety were detected. CONCLUSION: Testosterone supplementation during 6 months to older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN23688581.

Dietary phytoestrogen intake and cognitive function in older women.

BACKGROUND: Aging is associated with a decline in cognitive function; we explored the possible influence of dietary phytoestrogens on this decline. METHODS: We conducted a cross-sectional study in 301 Dutch women aged 60-75 years. Dietary isoflavone and lignan intake was assessed with a food-frequency questionnaire covering habitual diet in the year preceding enrolment. The endpoints were cognitive function measured in three domains: memory, processing capacity and speed, and executive function. Data were analyzed using linear regression models, after adjusting for confounders. RESULTS: No association between dietary isoflavone intake and cognitive function was found. High lignan intake was associated with a better performance in processing capacity and speed, and in executive function (p for trend over quartiles =.01 and.02, respectively). CONCLUSIONS: This finding calls for further research to elucidate the relatively underexplored role of lignans within the range of phytoestrogens.

Variations in plasma phytoestrogen concentrations in European adults.

Dietary phytoestrogens may play a role in chronic disease occurrence. The aim of our study was to assess the variability of plasma concentrations in European populations. We included 15 geographical regions in 9 European countries (Denmark, France, Germany, Greece, Italy, Spain, Sweden, The Netherlands, and UK) and a 16th region, Oxford, UK, where participants were recruited from among vegans and vegetarians. All subjects were participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma concentrations of 3 isoflavones (daidzein, genistein, and glycitein), 2 metabolites of daidzein [O-desmethylangolensin (O-DMA) and equol] and 2 mammalian lignans (enterodiol and enterolactone) were measured in 1414 participants. We computed geometric means for each region and used multivariate regression analysis to assess the influence of region, adjusted for gender, age, BMI, alcohol intake, smoking status, and laboratory batch. Many subjects had concentrations below the detection limit [0.1 microg/L (0.4 nmol/L)] for glycitein (80%), O-DMA (73%) and equol (62%). Excluding subjects from Oxford, UK, the highest concentrations of isoflavones were in subjects from the Netherlands and Cambridge, UK [2-6 microg/L (7-24 nmol/L); P < 0.05], whereas concentrations for lignans were highest in Denmark [8 microg/L (27 nmol/L); P < 0.05]. Isoflavones varied 8- to 13-fold, whereas lignans varied 4-fold. In the vegetarian/vegan cohort of Oxford, concentrations of isoflavones were 5-50 times higher than in nonvegetarian regions. Region was the most important determinant of plasma concentrations for all 7 phytoestrogens. Despite the fact that plasma concentrations of phytoestrogens in Europe were low compared with Asian populations, they varied substantially among subjects from the 16 different regions.

Association of endogenous sex hormone with C-reactive protein levels in middle-aged and elderly men.

BACKGROUND: In women, postmenopausal oestrogen supplementation increases levels of systemic markers of inflammation, which are important predictors of coronary heart disease (CHD) risk. Whether endogenous sex hormone levels in men are also related to systemic subclinical inflammation is still unknown. OBJECTIVE: We tested the hypothesis that higher endogenous sex hormones levels within the physiological range may be associated with systemic subclinical inflammation. METHODS: Circulating sex hormone and high-sensitivity C-reactive protein (hs-CRP) levels were determined in 400 apparently healthy men aged between 40 and 80 years. We used multivariate linear regression analysis with the various sex hormones as determinant, and natural log hs-CRP as outcome. RESULTS: Higher levels of total as well as bioavailable oestradiol (E2) were associated with increased natural log hs-CRP levels, which remained statistically significant after adjustment for age and cardiovascular risk factors. Natural log hs-CRP was 0.26 mg/l higher [95% confidence interval (CI) -0.02 to 0.54] in the fourth than in the first quartile of total E2; the P-value for linear trend was 0.05. For bioavailable E2, the difference in natural log hs-CRP between the fourth and the first quartile was 0.30 mg/l (95% CI 0.03-0.56; P-value for linear trend 0.04). After adjustment for age and cardiovascular risk factors, physiological levels of total (TT) or bioavailable testosterone or dehydroepiandrosterone sulfate (DHEAS) were not associated with hs-CRP. CONCLUSION: Endogenous total and bioavailable E2 levels are significantly associated with CRP among middle-aged and elder men.

Double blind randomized placebo-controlled trial on the effects of testosterone supplementation in elderly men with moderate to low testosterone levels: design and baseline characteristics [ISRCTN23688581].

In ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. We set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. We recruited 237 men with serum testosterone levels below 13.7 nmol/L and ages 60-80 years. They were randomized to either four capsules of 40 mg testosterone undecanoate (TU) or placebo daily for 26 weeks. Primary endpoints are functional mobility and quality of life. Secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. Effects on prostate, liver and hematological parameters will be studied with respect to safety. Measure of effect will be the difference in change from baseline visit to final visit between TU and placebo. We will study whether the effect of TU differs across subgroups of baseline waist girth (< 100 cm vs. > or = 100 cm; testosterone level (< 12 versus > or = 12 nmol/L), age (< median versus > or = median), and level of outcome under study (< median versus > or = median). At baseline, mean age, BMI and testosterone levels were 67 years, 27 kg/m2 and 10.72 nmol/L, respectively.

Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men.

BACKGROUND: It has been suggested that the age-related decline of androgens in men plays a distinct role in the development of several aspects of frailty. Therefore, hormone replacement might improve the course of frailty by increasing lean body mass and muscle strength, decreasing fat mass, and improving the subjective quality of life. OBJECTIVE: The objective of the study was to assess whether hormone replacement with dehydroepiandrosterone (DHEA) and/or atamestane might improve the course of frailty. DESIGN: This was a double-blind, randomized, controlled trial. SETTING: The study was conducted in the general community. PARTICIPANTS: Participants included 100 nonhospitalized, nondiseased, independently living men, aged 70 yr and over with low scores on strength tests. Seventeen participants did not complete the trial. INTERVENTION: Subjects were randomly assigned to one of four intervention arms: atamestane (100 mg/d) and placebo, DHEA (50 mg/d) and placebo, a combination of atamestane (100 mg/d) and DHEA (50 mg/d), or two placebo tablets for 36 wk. MAIN OUTCOME MEASURES: Physical frailty was measured by means of a specific test battery, including isometric grip strength, leg extensor power, and physical performance. RESULTS: The randomization was successful, and 83 (83%) men completed the intervention. There were no differences between the treatment arms and placebo group in any of the outcome measurements after intervention. CONCLUSIONS: The results of this double-blind, randomized trial do not support the hypothesis that hormone replacement with DHEA and/or atamestane might improve the course of frailty.