Helman Alfonso

In Older Men an Optimal Plasma Testosterone Is Associated With Reduced All-Cause Mortality and Higher Dihydrotestosterone With Reduced Ischemic Heart Disease Mortality, While Estradiol Levels Do Not Predict Mortality

CONTEXT Testosterone (T) levels decline with age and lower T has been associated with increased mortality in aging men. However, the associations of its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with mortality are poorly defined. OBJECTIVE We assessed associations of T, DHT, and E2 with all-cause and ischemic heart disease (IHD) mortality in older men. PARTICIPANTS Participants were community-dwelling men aged 70 to 89 years who were residing in Perth, Western Australia. MAIN OUTCOME MEASURES Plasma total T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples collected in 2001 to 2004 from 3690 men. Deaths to December 2010 were ascertained by data linkage. RESULTS There were 974 deaths (26.4%), including 325 of IHD. Men who died had lower baseline T (12.8±5.1 vs 13.2±4.8 nmol/L [mean±SD], P=.013), DHT (1.4±0.7 vs 1.5±0.7 nmol/L, P=.002), and E2 (71.6±29.3 vs 74.0±29.0 pmol/L, P=.022). After allowance for other risk factors, T and DHT were associated with all-cause mortality (T: quartile [Q] Q2:Q1, adjusted hazard ratio [HR]=0.82, P=.033; Q3:Q1, HR=0.78, P=.010; Q4:Q1, HR=0.86, P>.05; DHT: Q3:Q1, HR=0.76, P=.003; Q4:Q1, HR=0.84, P>.05). Higher DHT was associated with lower IHD mortality (Q3:Q1, HR=0.58, P=.002; Q4:Q1, HR=0.69, P=.026). E2 was not associated with either all-cause or IHD mortality. CONCLUSIONS Optimal androgen levels are a biomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause, whereas those with higher DHT had lower IHD mortality. Further investigations of the biological basis for these associations including randomized trials of T supplementation are needed.

Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men

CONTEXT Testosterone (T) levels decline with increasing age. Controversy exists over the threshold for classifying T as low vs. normal in older men. The relevance of assessing dihydrotestosterone (DHT) and estradiol (E2) remains unclear. OBJECTIVE We assessed the associations of T, DHT, and E2 in men aged 70 yr or older and established reference ranges for these in healthy older men. PARTICIPANTS Community-dwelling men aged 70-89 yr residing in Perth, Western Australia, Australia, participated in the study. MAIN OUTCOME MEASURES Plasma T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples from 3690 men. RESULTS Increasing age, higher body mass index and waist to hip ratio, dyslipidemia, diabetes, and higher LH were independently associated with lower levels of T and DHT. Increasing age, diabetes, and higher LH were associated with lower E2. In a reference group of 394 men aged 76.1 ± 3.2 yr reporting excellent or very good health with no history of smoking, diabetes, cardiovascular disease, cancer, depression, or dementia, the 2.5th percentile for T was 6.4 nmol/liter (184 ng/dl); DHT, 0.49 nmol/liter; and E2, 28 pmol/liter. Applying these cutoffs to all 3690 men, those with low T or DHT had an increased odds ratio for frailty, diabetes, and cardiovascular disease. Men with both low T and DHT had a higher odds ratio for these outcomes. CONCLUSIONS The 2.5th percentile in a reference group of healthy older men provides age-appropriate thresholds for defining low T, DHT, and E2. Additional studies are needed to test their potential applicability and clinical utility in older men.

Vitamins B12, B6, and folic acid for cognition in older men.

Objective: To investigate whether supplementing older men with vitamins B12, B6, and folic acid improves cognitive function. Methods: The investigators recruited 299 community-representative hypertensive men 75 years and older to a randomized, double-blind controlled clinical trial of folic acid, vitamin B6, and B12 supplementation vs placebo over 2 years. The primary outcome of interest was the change in the cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-cog). A secondary aim of the study was to determine if supplementation with vitamins decreased the risk of cognitive impairment and dementia over 8 years. Results: The groups were well-balanced for demographic and biochemical parameters. There was no difference in the ADAS-cog change from baseline to 24 months between the placebo (0.8, SD 4.0) and vitamins group (0.7, SD 3.4). The adjusted scores in the treatment groups did not differ over time (placebo 0.2 lower, z = 0.71, p = 0.478). There was a nonsignificant 28% decrease in the risk of cognitive impairment (odds ratio 0.72, 95% confidence interval 0.25–2.09) and dementia (hazard ratio 0.72, 95% confidence interval 0.29–1.78) over 8 years of follow-up. Conclusions: The daily supplementation of vitamins B12, B6, and folic acid does not benefit cognitive function in older men, nor does it reduce the risk of cognitive impairment or dementia. Classification of evidence: This study provides Class I evidence that vitamin supplementation with daily doses of 400 μg of B12, 2 mg of folic acid, and 25 mg of B6 over 2 years does not improve cognitive function in hypertensive men aged 75 and older.

B‐vitamins reduce the long‐term risk of depression after stroke: The VITATOPS‐DEP trial

The consumption of certain B‐vitamins through diet or supplementation decreases the total plasma concentration of homocysteine (tHcy) and may enhance response to standard antidepressant treatment. It is unclear if treatment with B‐vitamins can reduce the long‐term prevalence of depression in people at risk, such as stroke survivors. The purpose of this research was to determine if treatment with B‐vitamins reduces the hazard of poststroke depression compared with placebo.

24-month effect of smoking cessation on cognitive function and brain structure in later life

BACKGROUND Observational studies investigating the association between smoking, cognitive decline and dementia have produced conflicting results. We completed this trial to determine if smoking cessation decreases the progression of cognitive decline in later life. METHODS We recruited older smokers (n=229) and never smokers (n=98) and invited smokers to join a smoking cessation trial. The primary outcome of interest was change in Alzheimers Disease Assessment Scale cognitive subscale (ADAS-cog) scores over 24 months. Secondary measures included the Logical Memory test and changes in gray matter density. Successful smoking cessation was defined as a minimum of 547 smoking free days during follow up. RESULTS The ADAS-cog scores of unsuccessful quitters (UQ) increased (i.e., became worse) 1.1±0.3 and 1.2±0.4 points more than the scores of never smokers (NS) (p=0.001) and successful quitters (SQ) (p=0.006) respectively over the 24 months of follow up. Similarly, the scores of UQ declined (i.e., became worse) relative to NS on measures of immediate (p=0.004) and delayed recall (p=0.029). All analyses were adjusted for age, years of education, baseline cognitive performance, alcohol use, depression scores, and the presence of chronic respiratory disease. Thirty-six NS, 18 SQ and 48 UQ completed the imaging substudy. Compared with NS, UQ showed a disproportional loss of gray matter density in the right thalamus, right and left inferior semi-lunar lobule, as well as left superior and inferior parietal lobule over 24 months. SQ showed loss of gray matter compared with NS in the right middle and inferior occipital gyri, right and left culmen, and the left superior frontal gyrus. We did not find any brain regions in which UQ had lost more gray matter than SQ over 2 years. CONCLUSION These results are consistent with the hypothesis that smoking causes cognitive decline and loss of gray matter tissue in the brain over time.

Predicting survival in malignant mesothelioma

Malignant mesothelioma (MM) of the pleura or peritoneum is a universally fatal disease attracting an increasing range of medical interventions and escalating healthcare costs. Changes in survival and the factors affecting survival of all patients ever diagnosed with MM in Western Australia over the past five decades and confirmed by the Western Australian Mesothelioma Registry to December 2005 were examined. Sex, age, date and method of diagnosis, site of disease and histological type were recorded. Date of onset of symptoms and performance status were obtained from clinical notes for a sample of cases. Cox regression was used to examine the association of the clinical variables and the 10-yr periods of disease onset with survival after diagnosis. Survival was inversely related to age, being worse for males (hazard ratio (HR) 1.4, 95% CI 1.2–1.6), and those with peritoneal mesothelioma (HR 1.4, 95% CI 1.1–1.7). Patients with sarcomatoid histology had worse prognosis than patients with epithelioid and biphasic histological subtypes. Survival improved after the 1970s and has made incremental improvements since then. Median (interquartile range) survival by decade, from 1960 until 2005, was 64 (0–198), 177 (48–350), 221 (97–504), 238 (108–502) and 301 (134–611) days; ∼4 weeks of this apparent improvement can be attributed to earlier diagnosis. With increasing resources and treatment costs for MM over the past 40 yrs, there have been modest improvements in survival but no complete remissions.

Depression, Antidepressant Use and Mortality in Later Life: The Health in Men Study

Context Depression is associated with increased mortality, but it is unclear if this relationship is dose-dependent and if it can be modified by treatment with antidepressants. Objective To determine if (1) the association between depression and mortality is independent of other common potential causes of death in later life, (2) there is a dose-response relationship between increasing severity of depression and mortality rates, and (3) the use of antidepressant drugs reduces mortality rates. Methods Cohort study of 5,276 community-dwelling men aged 68–88 years living in Perth, Australia. We used the Geriatric Depression Scale 15-items (GDS-15) to ascertain the presence and severity of depression. GDS-15≥7 indicates the presence of clinically significant depression. Men were also grouped according to the severity of symptoms: “no symptoms” (GDS-15 = 0), “questionable” (1≤GDS-15≤4), “mild to moderate” (5≤GDS-15≤9), and “severe” (GDS-15≥10). Participants listed all medications used regularly. We used the Western Australian Data Linkage System to monitor mortality. Results There were 883 deaths between the study assessment and the 30th June 2008 (mean follow-up of participants: 6.0±1.1 years). The adjusted mortality hazard (MH) of men with clinically significant depression was 1.98 (95%CI = 1.61–2.43), and increased with the severity of symptoms: 1.39 (95%CI = 1.13–1.71) for questionable, 2.71 (95%CI = 2.13–3.46) for mild/moderate, and 3.32 (95%CI: 2.31–4.78) for severe depression. The use of antidepressants increased MH (HR = 1.31, 95%CI = 1.02–1.68). Compared with men who were not depressed and were not taking antidepressants, MH increased from 1.22 (95%CI = 0.91–1.63) for men with no depression who were using antidepressants to 1.85 (95%CI = 1.47–2.32) for participants who were depressed but were not using antidepressants, and 2.97 (95%CI = 1.94–4.54) for those who were depressed and were using antidepressants. All analyses were adjusted for age, educational attainment, migrant status, physical activity, smoking and alcohol use and the Charlson comorbidity index. Conclusions The mortality associated with depression increases with the severity of depressive symptoms and is largely independent of comorbid conditions. The use of antidepressants does not reduce the mortality rates of older men with persistent symptoms of depression.

Maternal cigarette smoking and breastfeeding duration

Aim: To examine the relationship between cigarette smoking and breastfeeding duration at 2 wk, 6 mo, and longer. Methods: Design. A 12‐mo longitudinal study. Setting. Two public maternity hospitals in the Perth metropolitan area (Western Australia). Subjects. Eligible mothers of healthy newborn infants. Interventions. Participants completed a self‐administered baseline questionnaire while in hospital or shortly after discharge. All women regardless of their chosen infant feeding method were followed up by telephone interview at 4, 10, 16, 22, 32, 40 and 52 wk postpartum. Main outcome measures. Prevalence of breastfeeding at 2 wk, 2 wk to 6 mo and >6 mo in women who smoked during pregnancy, and breastfeeding duration. Results: Women who smoked during pregnancy had a lower prevalence and shorter duration of breastfeeding than non‐smoking mothers (28 vs 11 wk, 95% CI 8.3–13.7). This effect remained even after adjustment for age, education, income, fathers smoking status, mothers country of birth, intended duration of breastfeeding >6 mo and birthweight (risk ratio 1.59, 95% CI 1.22–2.08).

Higher serum undercarboxylated osteocalcin and other bone turnover markers are associated with reduced diabetes risk and lower estradiol concentrations in older men.

CONTEXT In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers. PARTICIPANTS PARTICIPANTS were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia. MAIN OUTCOME MEASURES Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry. RESULTS Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, P = .031), TOC (-0.05, P = .001) and CTX (-0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (-0.04, P = .040). T was not associated with bone turnover. CONCLUSIONS Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.

The Built Environment and Depression in Later Life: The Health in Men Study

OBJECTIVE This study examined the impact of built environment (BE) attributes on depression in older men to determine whether associations were independent of neighborhood composition factors and sociodemographic, psychosocial, and health factors at the individual level. METHODS The authors used geocoded data from the Health in Men Study collected in Western Australia in 2001 (N = 5,218). Depression was measured using the self-rated 15-item Geriatric Depression Scale. Geographic Information Systems were used to objectively measure BE attributes. Univariate logistic regressions were applied to select relevant covariates. Multivariate logistic regressions were conducted to examine BE attributes both separately and conjointly. RESULTS Higher degrees of land-use mix were associated with higher odds of depression independent of other factors, including street connectivity and residential density (odds ratio = 1.54, 95% confidence interval [CI] = 1.10-2.16, and odds ratio = 1.52, 95% CI = 1.08-2.14 for the second and third tertiles, respectively). Further examination showed that retail availability was associated with a 40% increase in the odds of depression (95% CI = 4%-90%) independent of other factors, including availability of other land uses. CONCLUSIONS The BE is independently associated with depression through land-use mix, and specifically through retail availability. Although local retail facilitates walking, our findings suggest that it may increase the odds of depression in older men. This requires further exploration but suggests the need for careful planning of retail in residential environments, particularly near housing for older adults.