Childhood asthma and cardiovascular morbidity and mortality in adulthood: The Busselton Health Study.

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than respiratory morbidity are lacking. This study examines the associations of childhood asthma and the occurrence of cardiovascular disease (CVD) events and mortality in adulthood. METHODS: A cohort of 4430 school children (aged 17 years) who attended the Busselton Health Study between 1967 and 1983 were analyzed. Self-reported history of doctor-diagnosed asthma was determined based on the questionnaire. Subsequent CVD events (hospital admissions or death) up to 2014 were identified using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on CVD events and mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analyzed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up, 867 participants experienced a CVD event and 22 participants died from CVD. Childhood asthma was not associated with the risk of CVD events in adulthood (HR, 1.12; 95% CI: 0.91-1.39; p = .2833) and this persisted after adjustment for confounders. Childhood asthma was not associated with coronary heart disease events (HR, 0.72; 95% CI: 0.40-1.30; p = .2761), heart failure events (HR, 0.55; 95% CI: 0.07-4.13; p = .5604) or CVD mortality (HR, 0.91; 95% CI: 0.21-3.89; p = .8987) in adulthood. CONCLUSION: Childhood asthma is not associated with the risk of CVD events and mortality in adulthood.

U-Shaped Relationship of Leukocyte Telomere Length With All-Cause and Cancer-Related Mortality in Older Men.

BACKGROUND: Telomeres are essential DNA-protein complexes whose attrition results in cellular dysfunction and senescence. Leukocyte telomere length (LTL) correlates with tissue telomere length, representing a biomarker for biological age. However, its predictive value for mortality risk, and for cardiovascular versus cancer deaths, in older adults remains uncertain. METHOD: We studied 3608 community-dwelling men aged 77.0 ± 3.6 years. Leukocyte telomere length was measured using multiplex quantitative PCR, expressed as amount of telomeric DNA relative to single-copy control gene (T/S ratio). Deaths from any cause, cardiovascular disease (CVD), and cancer were ascertained using data linkage. Curve fitting used restricted cubic splines and Cox regression analyses adjusted for age, cardiometabolic risk factors, and prevalent disease. RESULTS: There was a U-shaped association of LTL with all-cause mortality. Men with T/S ratio in the middle quartiles had lower mortality (quartiles, Q2 vs Q1, hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.77-0.97, p = .012; Q3 vs Q1 HR = 0.88, CI 0.79-0.99, p = .032). There was no association of LTL with CVD mortality. There was a U-shaped association of LTL with cancer mortality. Men with LTL in the middle quartiles had lower risk of cancer death (Q2 vs Q1, HR = 0.73, CI 0.59-0.90, p = .004; Q3 vs Q1, HR = 0.75, CI 0.61-0.92, p = .007). CONCLUSIONS: In older men, both shorter and longer LTL are associated with all-cause mortality. A similar U-shaped association was seen with cancer deaths, with no association found for cardiovascular deaths. Further research is warranted to explore the prognostic utility of LTL in ageing.

Childhood asthma increases respiratory morbidity, but not all-cause mortality in adulthood: The Busselton Health Study.

BACKGROUND: Long-term childhood asthma studies that investigate adult outcomes other than lung function are lacking. This study examines the associations of childhood asthma and the occurrence of respiratory events and all-cause mortality in adulthood. METHODS: A cohort of 4430 school children (aged to 17 years) who attended the Busselton Health Study between 1967 and 1983 were analysed. Self-reported history of asthma was determined using questionnaires. Participants were followed until 2014 for respiratory disease-related events (hospital admissions or death) and all-cause mortality using the Western Australia Data Linkage System. Cox regression models were used to investigate the impact of childhood asthma on respiratory events and all-cause mortality in adulthood. A subgroup of 2153 participants who re-attended a survey in young adulthood was also analysed. RESULTS: A total of 462 (10%) of the cohort had childhood asthma. During follow-up 791 participants experienced a respiratory event and 140 participants died. Childhood asthma was associated with an increased risk of respiratory events in adulthood (unadjusted HR 1.84, 95% CI 1.52 to 2.23; P < 0.0001). The result remained significant after adjusting for adult-onset asthma, FEV1, body mass index, smoking, dusty job, hay fever, and respiratory symptoms (adjusted HR 1.68, 95% CI 1.07 to 2.64; P = 0.0247). Childhood asthma was not associated with all-cause mortality in adulthood (unadjusted HR 1.08, 95% CI 0.63 to 1.84; P = 0.7821). CONCLUSION: Childhood asthma is associated with increased risk of respiratory disease-related hospital admissions and death but not all-cause mortality in adulthood.

Childhood BMI and the occurrence of respiratory disease-related hospital admissions or death in adulthood: the Busselton Health Study.

PURPOSE: Few studies have investigated the association of childhood obesity with respiratory disease-related outcomes in adulthood and findings are inconsistent. The aim of this study was to examine the associations of body mass index (BMI) in childhood with the occurrence of respiratory events in adulthood. METHODS: We analyzed a cohort of 4537 school-aged children who attended the Busselton Health Study. Height and weight were measured and generated BMI z-scores were categorized into four groups. Participants were followed for respiratory disease-related hospital admissions or death using the Western Australia Data Linkage System. The associations between childhood BMI and respiratory events in adulthood were investigated using Cox regression models. A subgroup of 2196 that reattended a survey in young adulthood was also analyzed. RESULTS: During the 122,781 person-years of follow-up, 810 participants experienced a respiratory event. Childhood BMI group was not associated with risk of respiratory event in adulthood (hazard ratio for BMI z ≥ 1 vs. < -1 = 0.90; 95% CI, 0.70-1.17; P = .295) and this persisted after adjustment for selected confounders in the subgroup (hazard ratio 0.80; 95% CI, 0.43-1.48; P = .476). CONCLUSIONS: Childhood BMI is not associated with risk of respiratory events in adulthood.

Associations of plasma IGF1, IGFBP3 and estradiol with leucocyte telomere length, a marker of biological age, in men.

OBJECTIVE: Effects of insulin-like growth factor 1 (IGF1) and its binding proteins (IGFBPs) on ageing, and their interaction with sex hormones, remain uncertain. We examined associations of plasma IGF1, IGFBP1, IGFBP3, estradiol and testosterone, with leucocyte telomere length (LTL), a marker of biological age, in 2999 community-dwelling men aged 70-84 years. METHODS: Plasma IGF1, IGFBP1 and IGFBP3 measured using immunoassay, sex hormones using mass spectrometry. LTL measured by PCR, expressed as ratio of telomeric to single-copy control gene DNA (T/S ratio). Linear regression models adjusted for age and cardio-metabolic risk factors, median splits defined low/high groups. RESULTS: Mean age was 76.7 ± 3.2 years. IGF1 and IGFBP3 showed age-adjusted correlations with LTL (coefficient 0.59, P = 0.001 and 0.45, P = 0.013 respectively), IGFBP1 did not. In multivariable-adjusted models IGF1 and IGFBP3 (but not IGFBP1) were associated with LTL (T/S ratio 0.015 higher per 1 s.d. increase in IGF1, P = 0.007, and 0.011 per 1 s.d. IGFBP3, P = 0.049). IGF1 and estradiol were independently associated with longer telomeres (T/S ratio 0.012 higher per 1 s.d. increase in estradiol, P = 0.027, when included in model with IGF1). Testosterone was not associated with LTL. Men with both high IGF1 (>133 µg/L) and high estradiol (>70 pmol/L) had longer LTL compared to men with lower values (multivariable-adjusted T/S ratio 1.20 vs 1.16, P = 0.018). CONCLUSIONS: Higher IGF1 and IGFBP3 are independently associated with longer telomeres in older men. Additive associations of higher IGF1 and higher estradiol with telomere length are present. Further studies are needed to determine whether these hormonal exposures cooperate to slow biological aging.

Higher circulating androgens and higher physical activity levels are associated with less central adiposity and lower risk of cardiovascular death in older men.

OBJECTIVE: Low endogenous sex hormones and low physical activity (PA) levels have been associated with CVD risk. Whether these interact to influence CVD outcomes remains unclear. We assessed whether sex hormone concentrations and PA were additively associated with lower central adiposity and CVD risk. PATIENTS: 3351 community-dwelling men, mean age 77 years. MEASUREMENTS: Baseline testosterone (T), dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Levels of PA were ascertained by questionnaire. Men were stratified using median splits into high hormone + high PA (H/H), high hormone + low PA (H/L); low hormone + high PA (L/H) and low hormone + low PA (L/L) groups. RESULTS: A total of 865 CVD events and 499 CVD deaths occurred during 10-year mean follow-up. Men with higher T, DHT or SHBG and higher PA had the lowest BMI, waist circumference and risk of metabolic syndrome. Men with higher T had the lowest risk of incident CVD events, irrespective of PA level. Men with higher T or DHT and higher PA had the lowest risk of dying from CVD (eg, hazard ratios for T/PA H/H 0.76 P = 0.031; H/L 0.85 P = 0.222; L/H 0.80 P = 0.075; L/L 1.00). CONCLUSION: Higher circulating androgens and higher PA were associated with less central adiposity at baseline and fewer CVD deaths during follow-up. These findings are consistent with a potential additive effect of androgens and PA on cardiometabolic outcomes in older men.

A 5α-reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone-binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally.

CONTEXT: Pituitary luteinizing hormone (LH) stimulates testicular production of testosterone (T) which is metabolized to dihydrotestosterone (DHT) by 5α-reductase and to oestradiol (E2) by aromatase. How the activity of population variants in these enzymes impacts on gonadal function is unclear. We examined whether polymorphisms in 5α-reductase (SRD5A2) and aromatase (CYP19A1) genes predict circulating sex hormone concentrations. DESIGN: Cross-sectional analysis of 1865 community-dwelling men aged 50.4 ± 16.8 years. MEASUREMENTS: Early morning sera assayed for T, DHT and E2 (mass spectrometry), and SHBG and LH (immunoassay). Two SRD5A2 and eleven CYP19A1 polymorphisms were analysed by PCR. Regression models were adjusted for age and cardiometabolic risk factors. RESULTS: SRD5A2 polymorphism rs9282858 GA vs. GG was associated with higher serum T (+1.5 nmol/L, P < 0.001) and higher SHBG (+3.3 nmol/L, P = 0.001). CYP19A1 polymorphisms were associated with higher serum E2 and lower LH in reciprocal fashion, from which the two-copy haplotype rs10046 = T/rs2899470 = G/rs11575899 = I/rs700518 = G/rs17703883 = T was associated with higher E2 (63.4 vs. 56.5 pmol/L, P = 0.001) and lower LH (3.9 vs. 4.5 IU/L, P = 0.001) compared to null copies. Conversely, rs10046 = C/rs2899470 = T/rs11575899 = D/rs700518 = A/rs17703883 = C was associated with lower E2 (51.8 vs. 62.0 pmol/L, P = 0.001) and higher LH (5.7 vs. 3.9 IU/L, P < 0.001). These haplotypes were associated primarily with differences in E2 in men <65 years and LH in men ≥65 years. CONCLUSIONS: A 5α-reductase polymorphism predicts circulating T and SHBG, while aromatase polymorphisms predict E2 and LH in reciprocal fashion. Age and aromatase polymorphisms interact to affect E2 and LH. How these functional polymorphisms impact on male reproductive and general health outcomes requires further study.

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men.

CONTEXT: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. PARTICIPANTS AND METHODS: We used cross-sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone-binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. RESULTS: Average difference per decade of age was T -0.46 nmol/L, DHT -0.11 nmol/L, E2 -7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) -0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = -0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient -0.013, P = 0.037) associated with T/S ratio. CONCLUSIONS: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing.

Lower Circulating Androgens Are Associated with Overall Cancer Risk and Prostate Cancer Risk in Men Aged 25-84 Years from the Busselton Health Study.

Androgens, notably testosterone (T), have been implicated in development of several common cancers and prostate cancer; however, precise mechanisms remain unclear. This study assessed prospective associations of serum T, dihydrotestosterone (DHT) and estradiol (E2) with overall cancer (excluding skin cancer), prostate, colorectal and lung cancer risk in 1574 community-dwelling men aged 25-84 years. Sex hormones were assayed using mass spectrometry and men were followed for 20 years with outcomes ascertained using data linkage. Over 20 years, there were 289, 116, 48 and 22 men who developed any cancer, prostate cancer, colorectal cancer and lung cancer, respectively. Androgens in the lowest quartile were associated with an increased overall cancer risk (HR = 1.36, 95% CI 1.05-1.76, p = 0.020 for T; and HR = 1.30, 95% CI 1.00-1.69, p = 0.049 for DHT comparing the lowest vs other quartiles). T in the lowest quartile was associated with an increased risk of prostate cancer (HR = 1.53, 95% CI 1.02-2.29, p = 0.038 comparing the lowest vs other quartiles). The association between androgens and overall cancer risk remained similar after excluding prostate cancer outcomes; however, results were not significant. There were no associations of T, DHT or E2 with colorectal or lung cancer risk; however, LH in the highest quartile was associated with an increased risk of lung cancer (HR = 4.55, 95% CI 1.70-12.19, p = 0.003 for the highest vs other quartiles). Whether T is a biomarker of poor health in men with any cancer or prostate cancer requires further confirmation as does the nature and mechanism of the association of a high LH with future lung cancer.

Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer.

CONTEXT: Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk. OBJECTIVES: To explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers. DESIGN AND SETTING: A prospective cohort study of a community-dwelling population aged 25-84 years in Western Australia. MAIN OUTCOME MEASURES: Archived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression. RESULTS: During 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 IU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55-0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03-1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer. CONCLUSION: In a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.

Greater physical activity and higher androgen concentrations are independently associated with lower cardiometabolic risk in men.

CONTEXT: Male ageing is associated with lower circulating testosterone (T) and increased incidence of cardiovascular disease (CVD). Whether physical activity (PA) interacts with hormones to modify CVD risk is unclear. OBJECTIVE: We assessed whether PA and sex hormone concentrations were independently associated with measures of CVD risk. PARTICIPANTS: A total of 1649 men. METHODS: Leisure, home, work and total PA were ascertained. At baseline, serum T, dihydrotestosterone (DHT) and oestradiol (E2) were assayed. Men were stratified into high PA+high hormone (H/H); low PA+high hormone (L/H); high PA+low hormone (H/L); and low PA+low hormone (L/L). RESULTS: Mean age was 49.8 years at outset with 415 CVD events and 127 CVD deaths occurring during 20-year follow-up. Men with higher PA and higher T or DHT had lower odds of metabolic syndrome (eg leisure H/H vs L/L odds ratio [OR] 0.17 P<.001 for T, 0.26 P<.001 for DHT). Men with higher PA and E2 had lower risk of metabolic syndrome (eg leisure PA H/H vs L/L OR 0.51, P=.001). Men with higher leisure, work or total PA and higher DHT had the lowest risk of CVD death (eg leisure H/H hazard ratio [HR] 0.55 vs L/L, P=.033). Men with lower leisure, home or work PA and higher E2 were at greater risk of CVD death (eg leisure L/H HR 1.60 vs L/L, P=.039). CONCLUSIONS: Considering T, DHT and E2 in the context of PA better informs consideration of cardiovascular risk. A 2×2 factorial RCT assessing PA and androgens would illuminate the scope for preventing CVD in men.

Higher concentrations of serum iron and transferrin saturation but not serum ferritin are associated with cancer outcomes.

BACKGROUND: Although the carcinogenic potential of iron has been shown, evidence from observational studies that have linked serum iron variables and cancer outcomes has been inconsistent. OBJECTIVE: We investigated whether higher iron concentrations increased risk of cancer outcomes. DESIGN: A prospective examination of iron biomarkers as independent risk factors for cancer was assessed in 1597 men and 1795 women aged 25-79 y who participated in the 1994/1995 Busselton Health Survey and had relevant data, no history of cancer before the survey, and serum ferritin concentrations ≥20 µg/L. Follow-up for incident cancers and death from cancer was available to 2010. Proportional hazards regression modeling was performed to investigate if iron status predicted cancer incidence and mortality. RESULTS: After adjustments for age, smoking, drinking, anthropometric and biochemical variables, or menopausal status (breast cancer), higher serum iron concentrations and transferrin saturation were associated with increased risks of incident nonskin cancer [HR for iron: 1.83 (95% CI: 1.21, 2.76; P < 0.01); HR for transferrin saturation: 1.68 (95% CI: 1.18, 2.38; P < 0.01)] including breast cancer [HR for iron: 2.45 (95% CI:1.12, 5.34; P < 0.05); HR for transferrin saturation: 1.90 (95% CI:1.02, 3.56; P < 0.05)] in women. Transferrin saturation was also associated with a greater risk of cancer death (HR: 2.48; 95% CI: 1.28, 4.82; P < 0.01). In men, higher iron concentrations were associated with reduced risks of incident nonskin cancer (HR: 0.65; 95% CI: 0.42, 0.99; P < 0.05) including colorectal cancer (HR: 0.34; 95% CI: 0.12, 0.95; P < 0.05). There was no association between serum iron and colorectal cancer risk in women. Serum ferritin was not associated with cancer risk or cancer death. CONCLUSIONS: Higher transferrin saturation or serum iron concentrations were associated with increased nonskin cancer risk and increased risk of cancer death. Conversely, in men, higher serum iron concentrations were associated with decreased risk of nonskin cancer. The molecular basis for the observed differences in the association between serum iron and nonskin cancer risk is unclear.

Neutral associations of testosterone, dihydrotestosterone and estradiol with fatal and non-fatal cardiovascular events, and mortality in men aged 17-97 years.

CONTEXT: Lower testosterone (T) is associated with poorer health outcomes in older men, however, the relationship between T, dihydrotestosterone (DHT) and estradiol (E2) with cardiovascular disease (CVD) in younger to middle-aged men remains unclear. OBJECTIVES: We assessed associations between endogenous sex hormones with mortality (all-cause and CVD) and CVD events, in a cohort of men aged 17-97 years. PARTICIPANTS AND METHODS: Sex hormones were assayed using mass spectrometry in 2143 men from the 1994/5 Busselton Health Survey. Outcomes to December 2010 were analysed. RESULTS: Of the 1804 men included in the analysis, mean age was 50·3 ± 16·8 years and 68·9% of men were aged <60. Mean follow-up period was 14·9 years. There were 319 deaths, 141 CVD deaths and 399 CVD events. Compared to the full cohort, men who died had lower baseline T (12·0 ± 4·4 vs 13·6 ± 4·9 nmol/l), free T (181·9 ± 52·9 vs 218·3 ± 63·8 pmol/l) and DHT (1·65 ± 0·64 vs 1·70 ± 0·72 nmol/l), but higher E2 (64·0 ± 32 vs 60·1 ± 30·2 pmol/l). After adjustment for risk factors, T was not associated with mortality (adjusted HR = 0·90, 95% CI 0·79-1·04; P = 0·164 for every increase in 1 SD of T), CVD deaths (adjusted HR = 1·04, 95% CI 0·84-1·29; P = 0·708) or CVD events (adjusted HR = 1·03, 95% CI 0·92-1·15, P = 0·661). No associations were found for free T, DHT or E2. Results were similar for men older and younger than 60 years. CONCLUSIONS: In predominantly middle-aged men, T, DHT and E2 do not influence mortality or CVD outcomes. This neutral association of hormones with CVD contrasts with prior studies of older men.

Epidemiological and Mendelian Randomization Studies of Dihydrotestosterone and Estradiol and Leukocyte Telomere Length in Men.

CONTEXT: Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro. OBJECTIVE: The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men. PARTICIPANTS AND METHODS: Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio. RESULTS: Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = -0.225, P < .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P = .030; E2, r = 0.068, P = .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P < .0001; T/S ratio, 1.54 vs 1.62, P = .045), rs10046 C (60.5 vs 68.1 pmol/L, P = .0005, 1.54 vs 1.62, P = .035), and rs700518 A (59.9 vs 68.9 pmol/L, P < .0001, 1.54 vs 1.63, P = .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL. CONCLUSIONS: In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.

Testosterone, dihydrotestosterone and estradiol are differentially associated with carotid intima-media thickness and the presence of carotid plaque in men with and without coronary artery disease.

Clarifying the relationship of sex hormones to preclinical atherosclerosis could illuminate pathways by which androgens are associated with cardiovascular events and mortality. Our aim was to determine hormone profiles associated with carotid intima-media thickness (CIMT) and carotid atheroma, in men with and without known coronary artery disease (CAD). We included 492 community-based men aged 20-70 years (Group A) and 426 men with angiographically proven CAD aged <60 years (Group B). Fasting early morning sera were assayed for testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) using mass spectrometry. CIMT and carotid plaque were assessed ultrasonographically. Mean (±SD) age was Group A: 53.8±12.6 and Group B: 49.6±5.1 years. Higher T was associated with reduced CIMT (-0.011 mm per 1-SD increase, p=0.042) and lower prevalence of carotid plaque (odds ratio [OR] per 1-SD increase, 0.68, p=0.012) in Group A, but not B. E2 was associated with increased CIMT in Group A (0.013 mm, p=0.011) but not B. Higher DHT and E2 were associated with reduced carotid plaque in Group B (DHT: OR=0.77, p=0.024; E2: OR=0.75, p=0.008), but not A. In community-dwelling men, higher T is associated with favourable CIMT and lower prevalence of carotid plaque, while higher E2 is associated with worse CIMT. In men with CAD, higher DHT or E2 are associated with less carotid plaque. T, DHT and E2 are differentially associated with preclinical carotid atherosclerosis in a cardiovascular phenotype-specific manner. Interventional studies are needed to examine effects of exogenous T and its metabolites DHT and E2, on atherogenesis.

Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.

OBJECTIVES: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and oestradiol (E2) are differentially associated with lung function in men. METHODS: Early-morning serum T, DHT and E2 were assayed using mass spectrometry in 1768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, body mass index, respiratory conditions and cardiovascular risk factors were used. RESULTS: Mean age was 50.1 ± 16·8 years. 16·0% were current smokers, 14·1% reported a history of asthma and 2·7% reported chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14·5 vs 13·5 nmol/l, P = 0·002) and higher E2 (65·3 vs 60·1 pmol/l, P = 0·017). In fully adjusted analyses, T was associated with FEV1 (51 ml per 1 SD increase, P < 0·001) as was DHT (62 ml, P < 0·001), E2 was not (P = 0·926). Similar results were seen for FVC (T: 76 ml, P < 0·001; DHT: 65 ml, P < 0·001; E2 P = 0·664). Higher DHT was marginally associated with the ratio FEV1/FVC (0·3% per 1 SD increase, P = 0·047). CONCLUSIONS: Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men.

Higher ferritin levels, but not serum iron or transferrin saturation, are associated with Type 2 diabetes mellitus in adult men and women free of genetic haemochromatosis.

CONTEXT: Iron overload predisposes to diabetes and higher ferritin levels have been associated with diabetes. However, it is unclear whether ferritin reflects differences in iron-related parameters between diabetic and nondiabetic persons. We examined associations of serum ferritin, iron and transferrin saturation with Type 2 diabetes in adults without genetic predisposition to iron overload. DESIGN, PARTICIPANTS AND MEASUREMENTS: Cross-sectional analysis of community-dwelling men and women aged 17-97 years from the Busselton Health Survey, Western Australia. Men and women carrying genotypes associated with haemochromatosis (C282Y/C282Y or C282Y/H63D) were excluded. Serum ferritin, iron and transferrin saturation were assayed. RESULTS: There were 1834 men (122 with diabetes, 6·6%) and 2351 women (141 with diabetes, 6%). In men, higher serum ferritin was associated with diabetes after adjusting for age, smoking, alcohol, cardiovascular history, body mass index (BMI), waist, blood pressure, lipids, C-reactive protein (CRP), adiponectin, alanine transaminase (ALT) and gamma-glutamyl transpeptidase (GGT) [odds ratio (OR): 1·29 per 1 unit increase log ferritin, 95% confidence interval (CI) = 1·01-1·65, P = 0·043]. In women, higher serum ferritin was associated with diabetes [fully adjusted OR: 1·31 per 1 unit increase log ferritin, 95% CI = 1·04-1·63, P = 0·020; 1·84 for tertile (T) 3 vs T1, 95% CI = 1·09-3·11]. Neither iron levels nor transferrin saturation were associated with diabetes risk in men or women. Higher ferritin was not associated with insulin resistance in nondiabetic adults. CONCLUSIONS: In adults, higher ferritin levels are independently associated with prevalent diabetes while iron and transferrin saturation are not. Ferritin is a robust biomarker for diabetes risk, but further investigation is needed to clarify whether this relationship is mediated via iron metabolism.

Leisure time physical activity and long-term cardiovascular and cancer outcomes: the Busselton Health Study.

The study aimed to investigate whether meeting leisure time physical activity recommendations was associated with reduced incident and fatal cancer or cardiovascular disease (CVD) in a community-based cohort of middle- to late-aged adults with long-term follow-up. At baseline, 2,320 individuals were assessed on a large number of lifestyle and clinical parameters including their level of physical activity per week, other risk factors (e.g. smoking and alcohol use) various anthropometric measures, blood tests and medical history. Individuals were linked to hospital and mortality registry data to identify future cancer and cardiovascular events (fatal and non-fatal) out to 15 years of follow-up. Cox regression analyses adjusted for relevant confounders identified a priori were used to estimate risk for all-cause, cancer-specific and CVD-specific mortality. In the full cohort an estimated 21 % decreased risk for all-cause mortality (HR 0.79; 95 % CI 0.66-0.96) and 22 % decreased risk for fatal/non-fatal CVD events (HR 0.78; 95 % CI 0.66-0.92) was associated with baseline self-reported physical activity levels of 150 min or more. After exclusion of those with chronic co-morbidities (CVD, cancer, diabetes, chronic obstructive pulmonary disease, hypertension treatment) at baseline, lower risk for fatal/non-fatal CVD events remained significantly associated with 150 min or more of physical activity (HR 0.77; 95 % CI 0.62-0.96). Results from this well established prospective community-based cohort study support the role of leisure time physical activity in reducing all-cause mortality and CVD events (fatal/nonfatal) in the broader population studied. The data also suggest that physical activity associated reductions in risk for CVD events (fatal/nonfatal) were not overly impacted by prevalent key non-communicable diseases.

A longitudinal analysis of the influence of the neighborhood built environment on walking for transportation: the RESIDE study.

The purpose of the present analysis was to use longitudinal data collected over 7 years (from 4 surveys) in the Residential Environments (RESIDE) Study (Perth, Australia, 2003-2012) to more carefully examine the relationship of neighborhood walkability and destination accessibility with walking for transportation that has been seen in many cross-sectional studies. We compared effect estimates from 3 types of logistic regression models: 2 that utilize all available data (a population marginal model and a subject-level mixed model) and a third subject-level conditional model that exclusively uses within-person longitudinal evidence. The results support the evidence that neighborhood walkability (especially land-use mix and street connectivity), local access to public transit stops, and variety in the types of local destinations are important determinants of walking for transportation. The similarity of subject-level effect estimates from logistic mixed models and those from conditional logistic models indicates that there is little or no bias from uncontrolled time-constant residential preference (self-selection) factors; however, confounding by uncontrolled time-varying factors, such as health status, remains a possibility. These findings provide policy makers and urban planners with further evidence that certain features of the built environment may be important in the design of neighborhoods to increase walking for transportation and meet the health needs of residents.