Effectiveness of transmural team-based palliative care in prevention of hospitalizations in patients at the end of life: A systematic review and meta-analysis.

BACKGROUND: Team-based palliative care interventions have shown positive results for patients at the end of life in both hospital and community settings. However, evidence on the effectiveness of transmural, that is, spanning hospital and home, team-based palliative care collaborations is limited. AIM: To systematically review whether transmural team-based palliative care interventions can prevent hospital admissions and increase death at home. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE (Ovid), Embase (Ovid), CINAHL (Ebsco), PsychINFO (Ovid), and Cochrane Library (Wiley) were systematically searched until January 2021. Studies incorporating teams in which hospital and community professionals co-managed patients, hospital-based teams with community follow-up, and case-management interventions led by palliative care teams were included. Data was extracted by two researchers independently. RESULTS: About 19 studies were included involving 6614 patients, of whom 2202 received an intervention. The overall pooled odds ratio of at least one hospital (re)admissions was 0.46 (95% confidence interval (CI) 0.34-0.68) in favor of the intervention group. The highest reduction in admission was in the hospital-based teams with community follow-up: OR 0.21 (95% CI 0.07-0.66). The pooled effect on home deaths was 2.19 (95% CI 1.26-3.79), favoring the intervention, with also the highest in the hospital-based teams: OR 4.77 (95% CI 1.23-18.47). However, studies had high heterogeneity regarding intervention, study population, and follow-up time. CONCLUSION: Transmural team-based palliative care interventions, especially hospital-based teams that follow-up patients at home, show an overall effect on lowering hospital admissions and increasing the number of patients dying at home. However, broad clinical and statistical heterogeneity of included studies results in uncertainty about the effect size.

Polypharmacy, comorbidity and frailty: a complex interplay in older patients at the emergency department.

PURPOSE: Older adults at the emergency department (ED) with polypharmacy, comorbidity, and frailty are at risk of adverse health outcomes. We investigated the association of polypharmacy with adverse health outcomes, in relation to comorbidity and frailty. METHODS: This is a prospective cohort study in ED patients ≥ 70 years. Non-polypharmacy was defined as 0-4 medications, polypharmacy 5-9 and excessive polypharmacy ≥ 10. Comorbidity was classified by the Charlson comorbidity index (CCI). Frailty was defined by the Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) score. The primary outcome was 3-month mortality. Secondary outcomes were readmission to an ED/hospital ward and a self-reported fall < 3 months. The association between polypharmacy, comorbidity and frailty was analyzed by logistic regression. RESULTS: 881 patients were included. 43% had polypharmacy and 18% had excessive polypharmacy. After 3 months, 9% died, 30% were readmitted, and 21% reported a fall. Compared with non-polypharmacy, the odds ratio (OR) for mortality ranged from 2.62 (95% CI 1.39-4.93) in patients with polypharmacy to 3.92 (95% CI 1.95-7.90) in excessive polypharmacy. The OR weakened after adjustment for comorbidity: 1.80 (95% CI 0.92-3.52) and 2.32 (95% CI 1.10-4.90). After adjusting for frailty, the OR weakened to 2.10 (95% CI 1.10-4.00) and OR 2.40 (95% CI 1.15-5.02). No significant association was found for readmission or self-reported fall. CONCLUSIONS: Polypharmacy is common in older patients at the ED. Polypharmacy, and especially excessive polypharmacy, is associated with an increased risk of mortality. The observed association is complex given the confounding effect of comorbidity and frailty.

An Interprofessional Student-Run Medication Review Program: The Clinical STOPP/START-Based Outcomes of a Controlled Clinical Trial in a Geriatric Outpatient Clinic.

As the population ages, more people will have comorbid disorders and polypharmacy. Medication should be reviewed regularly in order to avoid adverse drug reactions and medication-related hospital visits, but this is often not done. As part of our student-run clinic project, we investigated whether an interprofessional student-run medication review program (ISP) added to standard care at a geriatric outpatient clinic leads to better prescribing. In this controlled clinical trial, patients visiting a memory outpatient clinic were allocated to standard care (control group) or standard care plus the ISP team (intervention group). The medications of all patients were reviewed by a review panel ("gold standard"), resident, and in the intervention arm also by an ISP team consisting of a group of students from the medicine and pharmacy faculties and students from the higher education school of nursing for advanced nursing practice. For both groups, the number of STOPP/START-based medication changes mentioned in general practitioner (GP) correspondence and the implementation of these changes about 6 weeks after the outpatient visit were investigated. The data of 216 patients were analyzed (control group = 100, intervention group = 116). More recommendations for STOPP/START-based medication changes were made in the GP correspondence in the intervention group than in the control group (43% vs. 24%, P = < 0.001). After 6 weeks, a significantly higher proportion of these changes were implemented in the intervention group (19% vs. 9%, P = 0.001). The ISP team, in addition to standard care, is an effective intervention for optimizing pharmacotherapy and medication safety in a geriatric outpatient clinic.

Managing older patients with heart failure calls for a holistic approach.

AIMS: This study aims to assess the presence of geriatric domain impairments in an older heart failure (HF) outpatient population and to relate these domain impairments with 1 year mortality risk in comparison with a geriatric outpatient population without HF. METHODS AND RESULTS: Data were used from two different prospective cohort studies: 241 outpatients with HF (mean age 78 ± 9 years, 48% female) and 686 geriatric outpatients (mean age 80 ± 7 years, 55% female). We similarly assessed the following geriatric domains in both cohorts: physical function, nutritional status, polypharmacy, cognitive function, and activities in daily living. Cox proportional hazards analyses were used to relate individual domains to 1 year mortality risk in both populations and to compare 1 year mortality risk between both populations. Of the patients with HF, 34% had impairments in ≥3 domains, compared with 38% in geriatric patients. One-year mortality rates were 13% and 8%, respectively, in the HF and geriatric populations; age-adjusted and sex-adjusted hazard ratio (95% confidence interval) for patients with HF compared with geriatric patients was 1.7 (1.3-2.6). The individual geriatric domains were similarly associated with 1 year mortality risk in both populations. Compared with zero to two impaired domains, age-adjusted and sex-adjusted mortality risk (hazard ratio, 95% confidence interval) for three, four, or five impaired domains ranged from 1.6 (0.6-4.2) to 6.5 (2.1-20.1) in the HF population and from 1.4 (0.7-2.9) to 7.9 (2.9-21.3) in the geriatric population. CONCLUSIONS: In parallel with geriatric patients, patients with HF often have multiple geriatric domain impairments that adversely affect their prognosis. This similarity together with the findings that patients with HF have a higher 1 year mortality risk than a general geriatric population supports the integration of a multi-domain geriatric assessment in outpatient HF care.

Do Cardiovascular Risk Factors and Cardiovascular Disease Explain Sex Differences in Cognitive Functioning in Old Age?

BACKGROUND: Sex differences in cognitive functioning in old age are known to exist yet are still poorly understood. OBJECTIVE: This study examines to what extent differences in cardiovascular risk factors and cardiovascular disease between men and women explain sex differences in cognitive functioning. METHODS: Data from 2,724 older adults from the Longitudinal Aging Study Amsterdam were used. Information processing speed and episodic memory, measured three times during six years of follow-up, served as outcomes. The mediating role of cardiovascular risk factors and cardiovascular disease was examined in single and multiple mediator models. Determinant-mediator effects were estimated using linear or logistic regression, and determinant-outcome and mediator-outcome effects were estimated using linear mixed models. Indirect effects were estimated using the product-of-coefficients estimator. RESULTS: Women scored 1.58 points higher on information processing speed and 1.53 points higher on episodic memory. Several cardiovascular risk factors had small mediating effects. The sex difference in information processing speed was mediated by smoking, depressive symptoms, obesity, and systolic blood pressure. The sex difference in episodic memory was mediated by smoking, physical activity, and depressive symptoms. Effects of smoking, LDL cholesterol, and diabetes mellitus on information processing speed differed between men and women. CONCLUSION: Differences in cardiovascular risk factors between women and men partially explained why women had better cognitive functioning. A healthy cardiovascular lifestyle seems beneficial for cognition and sex-specific strategies may be important to preserve cognitive functioning at older age.

The relevance of a multidomain geriatric assessment in older patients with heart failure.

AIMS: Physical frailty screening is more commonly performed at outpatient heart failure (HF) clinics. However, this does not incorporate other common geriatric domains. This study assesses whether a multidomain geriatric assessment, in comparison with HF severity or physical frailty, is associated with short-term adverse outcomes. METHODS AND RESULTS: This is a prospective cohort study of 197 patients with HF (mean age 78, 44% female) attending outpatient HF clinics. HF severity was assessed with New York Heart Association class (I-II versus III-IV) and N-terminal pro b-type natriuretic peptide levels. Physical frailty was assessed with the Fried frailty criteria (not frail, pre-frail, and frail). The following geriatric domains were assessed: physical function, nutrition, polypharmacy, cognition, and dependency in activities of daily living. Logistic regression analyses adjusted for age, sex, diabetes and kidney function assessed 3 month risk of adverse health outcomes (emergency department visits, hospital admissions, and/or death) according to HF severity, physical frailty, and number of affected domains. Number (%) of patients with HF with no, 1, 2, and ≥3 domains affected were 36 (18%), 61 (31%), 58 (29%), and 42 (21%). Seventy-four adverse outcomes were experienced in 50 patients at follow-up. Severity of HF and physical frailty were not significantly associated with an increased risk of adverse health outcomes. However, increasing number of affected domains were significantly associated with an increased risk of adverse outcomes. Compared with no domains affected, odds ratios (95% confidence interval) for 1, 2, and ≥3 domains were 1.8 (0.5-6.5), 4.5 (1.3-15.4), and 7.2 (2.0-26.3) (P-trend <0.01). Further adjustment for HF severity and frailty status slightly attenuated the effect estimates (P-trend 0.02). CONCLUSIONS: Having limitations in multiple domains appears more strongly associated with short-term adverse outcomes than HF severity and physical frailty. This may illustrate the potential added value of a multidomain geriatric assessment in the evaluation and treatment of patients with HF with respect to relevant short-term health outcomes.

Comparative analysis of the association between 35 frailty scores and cardiovascular events, cancer, and total mortality in an elderly general population in England: An observational study.

BACKGROUND: Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes. METHODS AND FINDINGS: Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell's C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7-3.3) to 26.2 (95% CI: 15.4-44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6-3.1) to 20.2 (95% CI: 11.8-34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5-1.7) to 8.4 (95% CI: 4.9-14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5-3.2) to 16.5 (95% CI: 7.8-35.0) and from 0.7 (95% CI: 0.4-1.2) to 2.4 (95% CI: 1.0-5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded. CONCLUSION: There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance.

Association of early left ventricular dysfunction with advanced magnetic resonance white matter and gray matter brain measures: The CARDIA study.

INTRODUCTION: Relations between heart failure and clinically manifested stroke are well known, but the associations between heart and brain early abnormalities are not totally clear. AIMS: We explore relations of subclinical brain abnormalities with early cardiac dysfunction in a large healthy middle-aged biracial cohort. METHODS: The CARDIA study enrolled 5115 young adults aged 18-30 years at baseline (1985-1986). We assessed 719 Caucasian and African American participants of the CARDIA study, with echocardiograms and brain MRI at follow-up year 25 (2010-2011). Echocardiography assessed aortic root diameter; LVEF; circumferential, longitudinal, and radial deformation. Cerebral MRI DTI, and, on a subset, ASL perfusion sequences were used to assess white matter fractional anisotropy and gray matter cerebral blood flow (CBF). Linear regression explored relations between cardiac parameters and cerebral measures, adjusting for anthropometrics, risk factors, and brain constitutional variation. RESULTS: Mean age 50 ± 4 years, SBP 118 ± 15 mm Hg; 60% white, and 48% men. Mean CBF was 46 ± 9 mL/100 g/min, and white matter fractional anisotropy was 0.31 ± 0.02. Worse circumferential deformation and larger aortic root were related to worse white matter fractional anisotropy. Worse radial systolic deformation was related to worse CBF in multivariable models. LVEF did not relate to early brain abnormalities. CONCLUSIONS: In spite of no apparent effect of LV ejection fraction, early subclinical cardiac dysfunction and brain abnormalities are present and associated in middle-aged generally healthy individuals.

Malnutrition and Risk of Structural Brain Changes Seen on Magnetic Resonance Imaging in Older Adults.

OBJECTIVES: To study the associations between protein energy malnutrition, micronutrient malnutrition, brain atrophy, and cerebrovascular lesions. DESIGN: Cross-sectional. SETTING: Geriatric outpatient clinic. PARTICIPANTS: Older adults (N = 475; mean age 80 ± 7). MEASUREMENTS: Nutritional status was assessed using the Mini Nutritional Assessment (MNA) and according to serum micronutrient levels (vitamins B1, B6, B12, D; folic acid). White matter hyperintensities (WMHs), global cortical brain atrophy, and medial temporal lobe atrophy on magnetic resonance imaging (MRI) were rated using visual rating scales. Logistic regression analyses were performed to assess associations between the three MNA categories (<17, 17-23.5, ≥23.5) and micronutrients (per SD decrease) and WMHs and measures of brain atrophy. RESULTS: Included were 359 participants. Forty-eight participants (13%) were malnourished (MNA <17), and 197 (55%) were at risk of malnutrition (MNA = 17-23.5). Participants at risk of malnutrition (odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.01-3.71) or who were malnourished (OR = 2.80, 95% CI = 1.19-6.60) had a greater probability of having severe WMHs independent of age and sex than those with adequate nutritional status. Results remained significant after further adjustments for cognitive function, depressive symptoms, cardiovascular risk factors, history of cardiovascular disease, smoking and alcohol use, and micronutrient levels. Lower vitamin B1 (OR = 1.51, 95% CI = 1.11-2.08) and B12 (OR = 1.45, 95% CI = 1.02-2.04) levels were also related to greater risk of severe WMHs, independent of age and sex. Results remained significant after additional adjustments. MNA and vitamin levels were not associated with measures of brain atrophy. CONCLUSION: Malnutrition and lower vitamin B1 and B12 levels were independently associated with greater risk of WMHs. Underlying mechanisms need to be further clarified, and whether nutritional interventions can modify these findings also needs to be studied.

Late-life brain volume: a life-course approach. The AGES-Reykjavik study.

The "fetal-origins-of-adult-disease" hypothesis proposes that an unfavorable intrauterine environment, estimated from small birth size, may induce permanent changes in fetal organs, including the brain. These changes in combination with effects of (cardiovascular) exposures during adult life may condition the later risk of brain atrophy. We investigated the combined effect of small birth size and mid-life cardiovascular risk on late-life brain volumes. Archived birth records of weight and height were abstracted for 1348 participants of the age, gene/environment susceptibility-Reykjavik study (RS; 2002-2006) population-based cohort, who participated in the original cohort of the RS (baseline 1967). Mid-life cardiovascular risk factors (CVRF) were collected in the RS. As a part of the late-life age, gene/environment susceptibility-RS examination, a brain magnetic resonance imaging was acquired and from it, volumes of total brain, gray matter, white matter, and white matter lesions were estimated. Adjusting for intracranial volume, demographics, and education showed small birth size (low ponderal index [PI]) and increased mid-life cardiovascular risk had an additive effect on having smaller late-life brain volumes. Compared with the reference group (high PI/absence of mid-life CVRF), participants with lower PI/presence of mid-life CVRF (body mass index >25 kg/m(2), hypertension, diabetes, "ever smokers") had smaller total brain volume later in life; B (95% confidence interval) were -10.9 mL (-21.0 to -0.9), -10.9 mL (-20.4 to -1.4), -20.9 mL (-46.9 to 5.2), and -10.8 mL (-19.3 to -2.2), respectively. These results suggest that exposure to an unfavorable intrauterine environment contributes to the trajectory toward smaller brain volume, adding to the atrophy that may be associated with mid-life cardiovascular risk.

Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease.

We investigated whether microbleeds and white matter hyperintensities (WMH) in Alzheimer's disease (AD) associate more with conventional vascular risk factors or with risk factors that reflect amyloid burden. A total of 371 patients with probable AD were included. WMH (Fazekas 2 or 3) were present in 107 (29%) patients and microbleeds were seen in 98 (26%). Patients with both microbleeds and WMH were older and presented more frequently with lacunes and multiple microbleeds than patients with microbleeds in isolation (all p < 0.05). Using multivariate regression models, we found that WMH presence showed independent associations with age, hypertension, current smoking, and lacune presence. Microbleeds were independently associated with male gender, higher blood pressure, lower cerebrospinal fluid Aß42, and apolipoprotein E ε4 homozygosity. Separate analyses for microbleeds according to their location showed that these associations were driven by microbleeds in lobar locations. Our results suggest that, unlike WMH, microbleeds in AD are particularly associated with additional amyloid burden, and as such, may relate to cerebral amyloid angiopathy.

Prevalence and determinants for malnutrition in geriatric outpatients.

BACKGROUND & AIMS: Few data is available on the nutritional status of geriatric outpatients. The aim of this study is to describe the nutritional status and its clinical correlates of independently living geriatric older individuals visiting a geriatric outpatient department. METHODS: From 2005 to 2010, all consecutive patients visiting a geriatric outpatient department in the Netherlands were screened for malnutrition. Nutritional status was assessed by the Mini Nutritional Assessment (MNA). Determinants of malnutrition were categorized into somatic factors (medicine use, comorbidity, walking aid, falls, urinary incontinence), psychological factors (GDS-15 depression scale, MMSE cognition scale), functional status (Activities of Daily Life (ADL), Instrumental ADL (IADL)), social factors (children, marital status), and life style factors (smoking, alcohol use). Univariate and multivariate logistic regression analyses, adjusted for age and sex and all other risk factors were performed to identify correlates of malnutrition (MNA < 17). RESULTS: Included were 448 outpatients, mean (SD) age was 80 (7) years and 38% was men. Prevalence of malnutrition and risk for malnutrition were 17% and 58%. Depression, being IADL dependent, and smoking were independently associated with an increased risk of malnutrition with OR's (95%CI) of 2.6 (1.3-5.3), 2.8 (1.3-6.4), 5.5 (1.9-16.4) respectively. Alcohol use was associated with a decreased risk (OR 0.4 (0.2-0.9)). CONCLUSION: Malnutrition is highly prevalent among geriatric outpatients and is independently associated with depressive symptoms, poor functional status, and life style factors. Our results emphasize the importance of integrating nutritional assessment within a comprehensive geriatric assessment. Future longitudinal studies should be performed to examine the effects of causal relationships and multifactorial interventions.

Sex hormone binding globulin and incident Alzheimer's disease in elderly men and women.

It has been suggested that low levels of estradiol and testosterone increase dementia risk. However, results of the existing observational studies examining associations of endogenous sex hormones with cognition and dementia are conflicting. A possible explanation for these inconsistent findings could be the involvement of sex hormone-binding globulin (SHBG) in regulating sex hormone levels. In the present study, we examined whether SHBG levels were associated with development of AD and overall dementia in a cohort of elderly men and women free of dementia at baseline. We observed that in both men and women higher levels of SHBG were associated with an increased risk for AD and overall dementia. These results were independent of vascular risk factors and bioactive hormone levels. Whether SHBG is causally related to dementia or whether it is a surrogate marker for rate of biological aging and increased risk or for preclinical stage of dementia has to be elucidated.

Sex hormones and cognitive decline in elderly men.

Decline of cognitive function with age may be due, in part, to hormonal changes and it has been hypothesized that higher levels of endogenous sex hormones preserve brain function. The aim of this prospective cohort study was to determine the relative contribution of endogenous sex hormones to cognitive decline in a population-based sample of 242 elderly men aged 73-91 at baseline. Endogenous sex hormone levels were measured at baseline and participants underwent a cognitive assessment at baseline and at follow-up after 4 years. Higher estradiol (total and bioavailable) and estrone levels were associated with an increased risk of cognitive decline in elderly men independent of age, cardiovascular risk factors, atherosclerosis, and APOE genotype. These findings do not support the hypotheses that higher levels of endogenous sex hormones preserve brain function.

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.

Serum sex hormone and plasma homocysteine levels in middle-aged and elderly men.

OBJECTIVE: To investigate whether circulating levels of testosterone (total, bioavailable), estradiol (total, bioavailable), and DHEA sulfate (DHEAS) are associated with fasting plasma homocysteine (tHcy) levels in middle-aged and elderly men. DESIGN: A population-based sample of 400 independently living men between 40 and 80 years of age in a cross-sectional study. METHODS: Total testosterone, sex hormone binding globulin (SHBG), and total estradiol were measured by RIA methods and bioavailable testosterone and estradiol were calculated. DHEAS was measured using an immunometric technique. Fasting homocysteine was measured by fluorescence polarization immunoassay. Anthropometric characteristics were also measured and two standardized questionnaires completed, including life-style factors and diet. Linear regression analysis adjusted for age, body mass index (BMI), creatinine clearance, and mean visceral fat was used to assess the association of endogenous sex hormones and fasting plasma homocysteine levels. RESULTS: After adjustment for age, BMI, creatinine clearance, and mean visceral fat no statistically significant association was observed between testosterone (total, bioavailable), DHEAS, and estradiol (total, bioavailable)levels with natural log tHcy (beta = -2 x 10(-3); 95% confidence intervals (CI) -9 x 10(-3); 5 x 10(-3)), (beta = -4 x 10(-3); 95% CI -18 x 10(-3); 9 x 10(-3)), (beta = 3 x 10(-3); 95% CI -6 x 10(-3); 12 x 10(-3)), (beta = -9.3 x 10(-5); 95% CI -1 x 10(-3); 1 x 10(-3)), and (beta = 0.00; 95% CI -3 x 10(-3); 2 x 10(-3)) respectively. Additional adjustment for smoking, alcohol intake, daily physical activity, diabetes mellitus, and hypertension did not change these findings. CONCLUSION: The results of our study do not support a direct role for circulating sex hormone levels in the regulation of fasting plasma tHcy concentrations in middle-aged and elderly men.

Endogenous sex hormones and metabolic syndrome in aging men.

BACKGROUND: Sex hormone levels in men change during aging. These changes may be associated with insulin sensitivity and the metabolic syndrome. METHODS: We studied the association between endogenous sex hormones and characteristics of the metabolic syndrome in 400 independently living men between 40 and 80 yr of age in a cross-sectional study. Serum concentrations of lipids, glucose, insulin, total testosterone (TT), SHBG, estradiol (E2), and dehydroepiandrosterone sulfate (DHEA-S) were measured. Bioavailable testosterone (BT) was calculated using TT and SHBG. Body height, weight, waist-hip circumference, blood pressure, and physical activity were assessed. Smoking and alcohol consumption was estimated from self-report. The metabolic syndrome was defined according to the National Cholesterol Education Program definition, and insulin sensitivity was calculated by use of the quantitative insulin sensitivity check index. RESULTS: Multiple logistic regression analyses showed an inverse relationship according to 1 sd increase for circulating TT [odds ratio (OR) = 0.43; 95% confidence interval (CI), 0.32-0.59], BT (OR = 0.62; 95% CI, 0.46-0.83), SHBG (OR = 0.46; 95% CI, 0.33-0.64), and DHEA-S (OR = 0.76; 95% CI, 0.56-1.02) with the metabolic syndrome. Each sd increase in E2 levels was not significantly associated with the metabolic syndrome (OR = 1.16; 95% CI, 0.92-1.45). Linear regression analyses showed that higher TT, BT, and SHBG levels were related to higher insulin sensitivity; beta-coefficients (95% CI) were 0.011 (0.008-0.015), 0.005 (0.001-0.009), and 0.013 (0.010-0.017), respectively, whereas no effects were found for DHEA-S and E2. Estimates were adjusted for age, smoking, alcohol consumption, and physical activity score. Further adjustment for insulin levels and body composition measurements attenuated the estimates, and the associations were similar in the group free of cardiovascular disease and diabetes. CONCLUSIONS: Higher testosterone and SHBG levels in aging males are independently associated with a higher insulin sensitivity and a reduced risk of the metabolic syndrome, independent of insulin levels and body composition measurements, suggesting that these hormones may protect against the development of metabolic syndrome.

Vascular risk factors and cognitive function in a sample of independently living men.

Decline of cognitive function with age may be due, in part, to atherosclerotic changes. The aim of the present study was to determine the relative contribution of vascular risk factors to cognitive functioning in a non-clinical sample of men. Cognitive tests were administered to 400 independently living men aged 40-80 years. The measures included short-term memory, speed of information processing, verbal and visual long-term memory, word fluency, cognitive flexibility, an estimate of verbal intelligence, and general cognitive status. Systolic blood pressure, serum cholesterol, glucose levels, smoking, alcohol intake, body mass index, homocysteine and peak expiratory flow rate were entered as independent variables into a multiple regression model, after adjustment for age and education. Hierarchical regression analyses revealed independent contributions of the combination of vascular risk factors in explaining the observed variance in performance on tests of cognitive functioning targeted at information processing capacity and speed and general cognitive status. Of the individual predictor variables, alcohol intake and homocysteine levels were significantly associated with processing capacity and speed, and peak expiratory flow rate was significantly associated with general cognitive status. Our results indicate that the combination of several independent vascular risk factors predicts performance on cognitive tests of information processing capacity and speed in a population-based sample of middle-aged and elderly men.

Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men.

Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 +/- 152 ng/dl (18.6 +/- 5.26 nmol/liter), mean +/- sd]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (beta) after adjustment for age and body mass index, 286 +/- 15.8; P < 0.001] and total E2 (beta = 4.47 +/- 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (beta = -1.78 +/- 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (beta = 32.0 +/- 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (beta = -0.016 +/- 0.002; P < 0.001) or non-SHBG-bound (beta = -0.011 +/- 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.

Endogenous sex hormones and progression of carotid atherosclerosis in elderly men.

BACKGROUND: The burden of atherosclerosis especially afflicts the increasing older segment of the population. Recent evidence has emphasized a protective role of endogenous sex hormones in the development of atherosclerosis in aging men. METHODS AND RESULTS: We studied the association between endogenous sex hormones and progression of atherosclerosis in 195 independently living elderly men. Participants underwent measurements of carotid intima-media thickness (IMT) at baseline in 1996 and again in 2000. At baseline, serum concentrations of testosterone (total and free) and estradiol (total and free E2) were measured. Serum free testosterone concentrations were inversely related to the mean progression of IMT of the common carotid artery after adjustment for age (beta=-3.57; 95% CI, -6.34 to -0.80). Higher serum total and free E2 levels were related to progression of IMT of the common carotid artery after adjustment for age (beta=0.38; 95% CI, -0.11 to 0.86; and beta=0.018; 95% CI, -0.002 to 0.038, respectively). These associations were independent of body mass index, waist-to-hip ratio, presence of hypertension and diabetes, smoking, and serum cholesterol levels CONCLUSIONS: Low free testosterone levels were related to IMT of the common carotid artery in elderly men independently of cardiovascular risk factors.