Bu B. Yeap

Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men

CONTEXT Lower circulating testosterone concentrations are associated with metabolic syndrome, type 2 diabetes, carotid intima-media thickness, and aortic and lower limb arterial disease in men. However, it is unclear whether lower testosterone levels predict major cardiovascular events. OBJECTIVE We examined whether lower serum testosterone was an independently significant risk factor for symptomatic cerebrovascular events in older men. DESIGN This was a prospective observational study with median follow-up of 3.5 yr. SETTING Community-dwelling, stroke-free older men were studied. PARTICIPANTS A total of 3443 men at least 70 yr of age participated in the study. MAIN OUTCOME MEASURES Baseline serum total testosterone, SHBG, and LH were assayed. Free testosterone was calculated using mass action equations. Incident stroke or transient ischemic attack (TIA) was recorded. RESULTS A first stroke or TIA occurred in 119 men (3.5%). Total and free testosterone concentrations in the lowest quartiles (<11.7 nmol/liter and <222 pmol/liter) were associated with reduced event-free survival (P = 0.014 and P = 0.01, respectively). After adjustment including age, waist-hip ratio, waist circumference, smoking, hypertension, dyslipidemia, and medical comorbidity, lower total testosterone predicted increased incidence of stroke or TIA (hazard ratio = 1.99; 95% confidence interval, 1.33-2.99). Lower free testosterone was also associated (hazard ratio = 1.69; 95% confidence interval, 1.15-2.48), whereas SHBG and LH were not independently associated with incident stroke or TIA. CONCLUSIONS In older men, lower total testosterone levels predict increased incidence of stroke or TIA after adjusting for conventional risk factors for cardiovascular disease. Men with low-normal testosterone levels had increased risk. Further studies are warranted to determine whether interventions that raise circulating testosterone levels might prevent cerebrovascular disease in men.

Low Free Testosterone Predicts Frailty in Older Men: The Health in Men Study

CONTEXT The prevalence of frailty increases, whereas testosterone decreases, as men age. Low testosterone may be a risk factor for development of this syndrome. OBJECTIVE Our objective was to determine whether testosterone levels are associated with frailty. DESIGN We conducted a prospective cohort study. SETTING AND PARTICIPANTS Between 2001 and 2004, frailty was assessed in 3616 community-dwelling men aged 70-88 yr. Frailty was reassessed in 1586 men aged 76-93 yr in 2008-2009. MAIN OUTCOME MEASURES Frailty was assessed with the FRAIL scale, comprising five domains: fatigue, difficulty climbing a flight of stairs, difficulty walking more than 100 m, more than five illnesses present, or weight loss greater than 5%. Testosterone, SHBG, and LH were assayed at baseline. Free testosterone was calculated using mass action equations. RESULTS At baseline, 15.2% of men (n = 548) were frail (at least three deficits), increasing to 23.0% (n = 364) at follow-up. At baseline, each 1 sd decrease in total or free testosterone level was associated with increased odds of frailty [odds ratio (OR) = 1.23; 95% confidence interval (CI) = 1.11-1.38, and OR = 1.29; 95% CI = 1.15-1.44 for total and free testosterone, respectively]. Lower LH was associated with reduced odds of frailty (OR = 0.88; 95% CI = 0.81-0.95). Adjustments were made for age, body mass index, smoking, diabetes, social support, and other covariates. At follow-up, only lower free testosterone levels (OR = 1.22; 95% CI = 1.05-1.42) predicted frailty. CONCLUSIONS Lower free testosterone was independently associated with frailty at baseline and follow-up. Randomized trials should explore whether testosterone therapy can prevent the development of frailty.

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Reduced serum total osteocalcin is associated with metabolic syndrome in older men via waist circumference, hyperglycemia, and triglyceride levels

OBJECTIVE Bone-derived undercarboxylated osteocalcin regulates insulin secretion and sensitivity in mice, and reduced serum total osteocalcin (TOC) is associated with diabetes in humans. However, the relationship between TOC levels and other cardiovascular risk factors is uncertain. We sought to determine whether serum TOC is associated with metabolic syndrome and its components in older men. DESIGN Cross-sectional analysis from a population-based cohort of men aged >or=70 years. METHODS Early morning sera were assayed for TOC. Insulin resistance was estimated using a homeostatic model (HOMA2-IR). Metabolic syndrome was defined according to NCEP-ATPIII criteria. RESULTS TOC was assayed in 4047 men. Men who were not fasting and reported having bone fractures, Pagets disease, or bisphosphonate, glucocorticoid, or warfarin use were excluded, leaving 2765 men with metabolic syndrome present in 797 (28.8%). TOC was inversely associated with waist circumference, glucose, and triglyceride levels and HOMA2-IR (all P<0.001), and was lower in men with metabolic syndrome (mean+/-S.E.M.: 20.1+/-0.4 vs 21.4+/-0.2 microg/l, P=0.002). In multivariate analysis, men with TOC of 13.25-16.55 and <13.25 microg/l had 1.5- to 2-fold increased risk of metabolic syndrome compared with men with levels >or=30 microg/l. TOC remained associated with metabolic syndrome after adjustment for individual components, but not after adjusting for both waist circumference and glucose. CONCLUSIONS Increased waist circumference, reduced TOC, elevated glucose, and triglyceride levels are inter-related in aging men. Osteocalcin may lie in the causal pathway between central adiposity and insulin resistance. Further research is required to evaluate whether interventions which raise osteocalcin levels might decrease cardiovascular risk.

Association of Cardiometabolic Multimorbidity With Mortality The Emerging Risk Factors Collaboration

IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy. RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Low Free Testosterone Predicts Mortality from Cardiovascular Disease But Not Other Causes: The Health in Men Study

CONTEXT Low testosterone is associated with all-cause mortality, but the relationship with cause-specific mortality is uncertain. OBJECTIVE Our objective was to explore associations between testosterone and its related hormones and cause-specific mortality. DESIGN This was a population-based cohort study. SETTING AND PARTICIPANTS Demographic and clinical predictors of mortality, and testosterone, SHBG, and LH were measured from 2001-2004 in 3637 community-dwelling men aged 70-88 yr (mean, 77 yr). MAIN OUTCOME MEASURE Cause of death was obtained via electronic record linkage until December 31, 2008. RESULTS During a mean follow-up period of 5.1 yr, there were 605 deaths. Of these, 207 [34.2%; 95% confidence interval (CI) = 30.4-38.1%] were due to cardiovascular disease (CVD), 231 to cancer (38.2%; 95% CI = 34.3-42.1%), 130 to respiratory diseases (21.5%; 95% CI = 18.2-24.8%), and 76 to other causes (12.6%; 95% CI = 9.9-15.2%). There were 39 deaths attributable to both cancer and respiratory diseases. Lower free testosterone (hazard ratio = 1.62; 95% CI = 1.20-2.19, for 100 vs. 280 pmol/liter), and higher SHBG and LH levels were associated with all-cause mortality. In cause-specific analyses, lower free testosterone (sub-hazard ratio = 1.71; 95% CI = 1.12-2.62, for 100 vs. 280 pmol/liter) and higher LH predicted CVD mortality, while higher SHBG predicted non-CVD mortality. Higher total testosterone and free testosterone levels (sub-hazard ratio = 1.96; 95% CI = 1.14-3.36, for 400 vs. 280 pmol/liter) were associated with mortality from lung cancer. CONCLUSIONS Low testosterone predicts mortality from CVD but is not associated with death from other causes. Prevention of androgen deficiency might improve cardiovascular outcomes but is unlikely to affect longevity otherwise.

Low Free Testosterone Concentration as a Potentially Treatable Cause of Depressive Symptoms in Older Men

CONTEXT Serum concentrations of gonadal hormones have been associated with various measures of well-being, but it is unclear whether their association with mood is confounded by concurrent physical morbidity. OBJECTIVE To determine whether the association between serum testosterone concentration and mood in older men is independent of physical comorbidity. DESIGN Cross-sectional study. SETTING Community of Perth, Western Australia. PARTICIPANTS A community sample of men aged 71 to 89 years. MAIN OUTCOME MEASURES We used the 15-item Geriatric Depression Scale (GDS-15) to assess depressed mood. Clinically significant depression was defined a priori as a GDS-15 score of 7 or greater. Physical health was assessed using the weighted Charlson index and the Physical Component Summary score of the 36-Item Short Form Health Survey. RESULTS Of 3987 men included in the study, 203 (5.1%; 95% confidence interval [CI], 4.4%-5.8%) had depression. Participants with depression had significantly lower total and free testosterone concentrations than nondepressed men (P < .001 for both). However, they were also more likely to smoke and to have low educational attainment, a body mass index categorized as obese, a Mini-Mental State Examination score less than 24, a history of antidepressant drug treatment, and greater concurrent physical morbidity. After adjusting for these factors and for age, men with depression were 1.55 (95% CI, 0.91-2.63) and 2.71 (95% CI, 1.49-4.93) times more likely to have total and free testosterone concentrations, respectively, in the lowest quintile. CONCLUSIONS A free testosterone concentration in the lowest quintile is associated with a higher prevalence of depression, and this association cannot be adequately explained by physical comorbidity. A randomized controlled trial is required to determine whether the link between low free testosterone level and depression is causal because older men with depression may benefit from systematic screening of free testosterone concentration and testosterone supplementation.

In men older than 70 years, total testosterone remains stable while free testosterone declines with age. The Health in Men Study

OBJECTIVE An age-related decline in serum total and free testosterone concentration may contribute to ill health in men, but limited data are available for men > 70 years of age. We sought to determine the distribution and associations of reduced testosterone concentrations in older men. DESIGN The Health in Men Study is a community-representative prospective cohort investigation of 4263 men aged > or = 70 years. Cross-sectional hormone data from 3645 men were analysed. METHODS Early morning sera were assayed for total testosterone, sex hormone binding globulin (SHBG) and LH. Free testosterone was calculated using the Vermeulen method. RESULTS Mean (+/- s.d.) serum total testosterone was 15.4 +/- 5.6 nmol/l (444 +/- 162 ng/dl), SHBG 42.4 +/- 16.7 nmol/l and free testosterone 278 +/- 96 pmol/l (8.01 +/- 2.78 ng/dl). Total testosterone correlated with SHBG (Spearmans r = 0.6, P < 0.0001). LH and SHBG increased with age (r = 0.2, P < 0.0001 for both). Instead of declining, total testosterone increased marginally (r = 0.04, P = 0.007) whilst free testosterone declined with age (r = -0.1, P < 0.0001). Free testosterone was inversely correlated with LH (r = -0.1, P < 0.0001). In multivariate analyses, increasing age, body mass index (BMI) and LH were associated with lower free testosterone. CONCLUSIONS In men aged 70-89 years, modulation of androgen action may occur via an age-related increase in SHBG and reduction in free testosterone without a decline in total testosterone concentration. Increasing age, BMI and LH are independently associated with lower free testosterone. Further investigation would be required to assess the clinical consequences of low serum free testosterone, particularly in older men in whom total testosterone may be preserved.

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.