Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Six-minute walk test distance at time of hospital discharge is strongly and independently associated with all-cause mortality following cardiac surgery.

We investigated the impact of distance covered in the six-minute walk test (6mWT) before being discharged from the hospital after cardiac surgery on the risk of all-cause mortality. Our study included 1127 patients who underwent cardiac surgery and then took part in a standardised physiotherapist-supervised inpatient rehabilitation programme during 2007-2017. The percentage of the predicted 6mWT distance, and the lower limit of normal distance was calculated based on individual patients' age, sex, and body mass index. We used Cox regression with adjustment for confounders to determine multivariable-adjusted hazard ratios (HRs) for mortality. Over a median follow-up period of 6.4 (IQR: 3.5-9.2) years, 15% (n = 169) patients died. We observed a strong and independent inverse association between 6mWT distance and mortality, with every 10 m increase in distance associated to a 4% reduction in mortality (HR: 0.96, 95% CI 0.94-0.98, P < 0.001). Those in the top tertile for predicted 6mWT performance had a 49% reduced risk of mortality (HR: 0.51, 95% CI 0.33-0.79) compared to those in the bottom tertile. Patients who met or exceeded the minimum normal 6mWT distance had 36% lower mortality risk (HR: 0.64, 95% CI 0.45-0.92) compared to those who did not meet this benchmark. Subgroup analysis showed that combined CABG and valve surgery patients walked less in the 6mWT compared to those undergoing isolated CABG or valve surgeries, with a significant association between 6mWT and mortality observed in the isolated procedure groups only. In conclusion, the longer the distance covered in the 6mWT before leaving the hospital, the lower the risk of mortality.

Factors Associated With Circulating Sex Hormones in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements. PURPOSE: To clarify factors associated with variations in sex hormone concentrations. DATA SOURCES: Systematic literature searches (to July 2019). STUDY SELECTION: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry. DATA EXTRACTION: Individual participant data (IPD) (9 studies; n = 21 074) and aggregate data (2 studies; n = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted. DATA SYNTHESIS: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years. LIMITATION: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data. CONCLUSION: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Comparative effect of varenicline and nicotine patches on preventing repeat cardiovascular events.

OBJECTIVE: To determine the comparative effectiveness of postdischarge use of varenicline versus prescription nicotine replacement therapy (NRT) patches for the prevention of recurrent cardiovascular events and mortality and whether this association differs by sex. METHODS: Our cohort study used routinely collected hospital, pharmaceutical dispensing and mortality data for residents of New South Wales, Australia. We included patients hospitalised for a major cardiovascular event or procedure 2011-2017, who were dispensed varenicline or prescription NRT patches within 90day postdischarge. Exposure was defined using an approach analogous to intention to treat. Using inverse probability of treatment weighting with propensity scores to account for confounding, we estimated adjusted HRs for major cardiovascular events (MACEs), overall and by sex. We fitted an additional model with a sex-treatment interaction term to determine if treatment effects differed between males and females. RESULTS: Our cohort of 844 varenicline users (72% male, 75% <65 years) and 2446 prescription NRT patch users (67% male, 65% <65 years) were followed for a median of 2.93 years and 2.34 years, respectively. After weighting, there was no difference in risk of MACE for varenicline relative to prescription NRT patches (aHR 0.99, 95% CI 0.82 to 1.19). We found no difference (interaction p=0.098) between males (aHR 0.92, 95% CI 0.73 to 1.16) and females (aHR 1.30, 95% CI 0.92 to 1.84), although the effect among females deviated from the null. CONCLUSION: We found no difference between varenicline and prescription NRT patches in the risk of recurrent MACE. These results should be considered when determining the most appropriate choice of smoking cessation pharmacotherapy.

Trends and Outcomes for Percutaneous Coronary Intervention and Coronary Artery Bypass Graft Surgery in New South Wales from 2008 to 2019.

Risk profiles are changing for patients who undergo percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). In Australia, little is known of the nature of these changes in contemporary practice and of the impact on patient outcomes. We identified all CABG (n = 40,805) and PCI (n = 142,399) procedures in patients aged ≥18 years in New South Wales, Australia, during 2008 to 2019. Between 2008 and 2019, the age- and gender-standardized revascularization rate increased by 20% (from 267/100,000 to 320/100,000 population) for all revascularizations. The increase in revascularization was particularly driven by a 35% increase (from 194/100,000 to 261/100,000) in PCI, whereas the rate of CABG decreased by 20% (from 73/100,000 to 59/100,000). Mean age and the prevalence of co-morbidities (especially diabetes and atrial fibrillation) increased for patients with PCI in more recent years but remained consistently lower than for patients with CABG. CABGs performed in patients presenting with a non-ST-segment-elevation acute coronary syndrome halved from 34.3% to 18.7% during the study period, whereas PCIs in this group decreased from 36.5% to 29.6%. Risk-adjusted in-hospital mortality decreased by 7.5 deaths/1,000 procedures per month for CABG but remained unchanged for PCI. Risk-adjusted readmission rates were consistently higher for CABG than for PCI and did not change significantly over time. In conclusion, we observed a dramatic shift over time from CABG to PCI as the revascularization procedure of choice, with the patient base for PCI extending to older and sicker patients. There was a large decrease in mortality after CABG, whereas mortality after PCI remained unchanged.

Uptake of prescription smoking cessation pharmacotherapies after hospitalization for major cardiovascular disease.

AIMS: We determined the prevalence of prescription smoking cessation pharmacotherapy (SCP) use after hospitalization for major cardiovascular disease (MCD) among people who smoke and whether this varies by sex. METHODS AND RESULTS: We conducted a population-based cohort study including all people hospitalized in New South Wales, Australia, between July 2013 and December 2018 (2017 for private hospitals) with an MCD diagnosis. For patients who also had a diagnosis of current tobacco use, we used linked pharmaceutical dispensing records to identify prescription SCP dispensings within 90 days post-discharge. We determined the proportion who were dispensed an SCP within 90 days, overall and by type of SCP. We used logistic regression to estimate the odds of females being dispensed an SCP relative to males. Of the 150 758 patients hospitalized for an MCD, 20 162 (13.4%) had a current tobacco use diagnosis, 31% of whom were female. Of these, 11.3% (12.4% of females, 10.9% of males) received prescription SCP within 90 days post-discharge; 3.0% were dispensed varenicline, and 8.3% were dispensed nicotine replacement therapy patches. Females were more likely than males to be dispensed a prescription SCP [odds ratio (OR) 1.16, 95% confidence interval (CI) 1.06-1.27)]; however, this was not maintained after adjusting for potential confounders (adjusted OR 1.04, 95% CI 0.94-1.15). CONCLUSION: Very few females and males who smoke use prescription SCPs after hospitalization for an MCD. The use of varenicline, the SCP with the highest efficacy, was particularly low. This represents a missed opportunity to increase smoking cessation in this high-risk population, thereby reducing their risk of recurrent cardiovascular events.

Psychotropic medicine prescribing and polypharmacy for people with dementia entering residential aged care: the influence of changing general practitioners.

OBJECTIVE: To examine relationships between changing general practitioner after entering residential aged care and overall medicines prescribing (including polypharmacy) and that of psychotropic medicines in particular. DESIGN: Retrospective data linkage study. SETTING, PARTICIPANTS: 45 and Up Study participants in New South Wales with dementia who were PBS concession card holders and entered permanent residential aged care during January 2010 - June 2014 and were alive six months after entry. MAIN OUTCOME MEASURES: Inverse probability of treatment-weighted numbers of medicines dispensed to residents and proportions of residents dispensed antipsychotics, benzodiazepines, and antidepressants in the six months after residential care entry, by most frequent residential care GP category: usual (same as during two years preceding entry), known (another GP, but known to the resident), or new GP. RESULTS: Of 2250 new residents with dementia (mean age, 84.1 years; SD, 7.0 years; 1236 women [55%]), 625 most frequently saw their usual GPs (28%), 645 saw known GPs (29%), and 980 saw new GPs (44%). The increase in mean number of dispensed medicines after residential care entry was larger for residents with new GPs (+1.6 medicines; 95% CI, 1.4-1.9 medicines) than for those attended by their usual GPs (+0.7 medicines; 95% CI, 0.4-1.1 medicines; adjusted rate ratio, 2.42; 95% CI, 1.59-3.70). The odds of being dispensed antipsychotics (adjusted odds ratio [aOR], 1.59; 95% CI, 1.18-2.12) or benzodiazepines (aOR, 1.69; 95% CI, 1.25-2.30), but not antidepressants (aOR, 1.32; 95% CI, 0.98-1.77), were also higher for the new GP group. Differences between the known and usual GP groups were not statistically significant. CONCLUSIONS: Increases in medicine use and rates of psychotropic dispensing were higher for people with dementia who changed GP when they entered residential care. Facilitating continuity of GP care for new residents and more structured transfer of GP care may prevent potentially inappropriate initiation of psychotropic medicines.

Cross-Sectional and Longitudinal Relationships Between Inflammatory Biomarkers and Frailty in Community-dwelling Older Men: The Concord Health and Ageing in Men Project.

BACKGROUND: Previous studies demonstrated associations between IL-6 and frailty, but associations between a wide range of cytokines, chemokines, and growth factors with prevalent and incident frailty has not been studied. METHODS: Community-dwelling men aged more than 75 enrolled in the 5-year and 8-year follow-up of the CHAMP study were assessed. Twenty-seven inflammatory biomarkers were measured using the Bio-Plex Pro Human Cytokine 27-plex Assay kit at 5-year follow-up. Frailty was determined using the Fried frailty phenotype (FP) and Rockwood frailty index (FI) at both time-points. Age, body mass index, smoking, alcohol, and comorbidity were also assessed. RESULTS: In cross-sectional analysis of the 5-year follow-up, the unadjusted odds ratio (OR) for frail versus robust evaluated by the FP showed significant associations for IL-6 (OR: 1.56, 95% confidence interval [CI]: 1.23-1.98) and IL-8 (OR: 1.28, 95% CI: 1.00-1.63). IL-6 remained significantly associated in the age-adjusted (OR: 1.58, 95% CI: 1.21-2.05) and multivariable-adjusted model (OR: 1.54, 95% CI: 1.16-2.05). No associations were observed between pre-frail versus robust. In longitudinal unadjusted analysis, IL-8 (OR: 1.32, 95% CI: 1.03-1.70) and IP-10 (OR: 1.32, 95% CI: 1.03-1.70) at 5-year predicted incident frailty at 8-year follow-up. IL-8 remained longitudinally associated with incident frailty after age (OR: 1.34, 95% CI: 1.03-1.75) but not multivariable (OR: 1.20, 95% CI: 0.98-1.70) adjustment. Similar results were seen using the FI. None of the other biomarkers had significant associations with incident frailty. CONCLUSIONS: Our findings suggest that IL-6 and IL-8 may be cross-sectionally associated with frailty and that all measured inflammatory biomarkers were not causally related to frailty. Together with previous studies, the results suggest that frailty is specifically linked to IL-6 and IL-8 rather than simply representing a nonspecific pan-inflammatory condition.

Temporal associations between sexual function and cognitive function in community-dwelling older men: the Concord Health and Ageing in Men Project.

Background: previous cross-sectional studies have reported bidirectional associations between sexual activity and cognitive function among older people. However, the temporal associations have not been studied. Methods: community-dwelling men aged 70+ from the Concord Health and Ageing in Men Project were assessed. This study was based on 986 men at baseline, 829 men at 2 year and 595 men at 5-year follow-up. Sexual function using a standardised questionnaire (erectile function, sexual activity, sexual satisfaction, sexual desire) was analysed by generalised estimating equations to examine associations between changes in sexual function and changes in mini-mental state examination (MMSE) across three time points over 5 years. Age, BMI, comorbidity, self-rated health, smoking, number of medications, country of birth, education, marital status, depression and reproductive hormones were also measured at all time points. Results: in unadjusted models, declines in erectile function (ß = -0.317) and sexual activity (ß = -0.575) over time were statistically significantly associated with a decline in MMSE over time. The associations observed in the unadjusted models remained after adjusting for a range of covariables. Declines in sexual satisfaction and sexual desire over time were not associated with changes in MMSE. Conclusions: our findings provide evidence of a longitudinal temporal relationship between sexual activity and cognitive function. Further studies are warranted to examine whether maintaining a healthy sexual life has a positive effect on cognitive function in older men.

Evaluating Calculated Free Testosterone as a Predictor of Morbidity and Mortality Independent of Testosterone for Cross-sectional and 5-Year Longitudinal Health Outcomes in Older Men: The Concord Health and Ageing in Men Project.

To determine whether calculated free testosterone (cFT) provides prognostic information independent of serum T for predicting morbidity and mortality in older men in cross-sectional and 5-year longitudinal analyses. We studied men aged ≥70 years at baseline (n = 1,705), 2-year and 5-year measuring serum T (liquid chromatography-mass spectrometry), SHBG (immunoassay), cFT (an assumption-free empirical formula) together with 24 morbidity and 4 mortality outcomes. For cross-sectional and longitudinal analyses we employed a joint prediction model using generalized estimating equation models adjusted for age, smoking, comorbidities, and body mass index (BMI) with men having both normal T and normal cFT as referent group. Most morbidity and mortality outcomes were predicted by a combination of low T and cFT (LL). By contrast, only a single morbidity outcome in cross-sectional and none in longitudinal analysis was predicted by low T/normal cFT (LN) or normal T/low cFT (NL) without significant LL associations (isolated discordance). While for the few outcomes that predicted morbidity in men with discordances (LN or NL), these predictions only occurred when LL was also significant. Hence, for morbidity or mortality prediction in older men, discordance between cFT and T is unusual and isolated discordance is rare, so that cFT provides minimal independent prognostic information over serum T.

Total Physical Activity, Exercise Intensity, and Walking Speed as Predictors of All-Cause and Cause-Specific Mortality Over 7 Years in Older Men: The Concord Health and Aging in Men Project.

OBJECTIVE: The study aimed to examine the contemporaneous temporal association between changes in total physical activity, sports intensity, muscle strengthening exercise, and walking speed as predictors of all-cause, cardiovascular, cancer and other cause-specific mortality in older men. DESIGN, SETTING, PARTICIPANTS, MEASUREMENTS: Community-dwelling men aged 70 years and older from Concord Health and Aging in Men Project were assessed at baseline (2005-2007, n = 1705), 2 years (n = 1367), and 5 years follow-up (n = 958). At all time points, Physical Activity Scale for the Elderly questionnaire, walking speed over a 6-m walk, and potential confounders were assessed. Mortality was ascertained through the state death registry with a median follow-up of 7 years. RESULTS: As the Physical Activity Scale for the Elderly score increased by 1 standard deviation over the follow-up period, the relative risk (RR) for mortality was 0.78 [95% confidence interval (CI) 0.69-0.88] for all-cause, 0.66 (95% CI 0.55-0.79) for cardiovascular and 0.75 (95% CI 0.61-0.94) for other cause-specific mortality, but no association was observed in cancer mortality. The RR for undertaking strenuous sports during follow-up was 0.44 (95% CI 0.26-0.72) for all-cause mortality and 0.31 (95% CI 0.13-0.70) for cancer mortality when compared with no sports participation. Increases in walking speed per standard deviation over time were also associated with a decrease in all-cause mortality (RR 0.69, 95% CI 0.61-0.78), with similar associations for cardiovascular (RR 0.60, 95% CI 0.48-0.74), but not cancer mortality. CONCLUSIONS: Older men who engage in strenuous sports and those who increase their walking speed over time may have lower risk of all-cause and some cause-specific mortality.

Longitudinal Associations Between Vitamin D Metabolites and Sarcopenia in Older Australian men: The Concord Health and Aging in Men Project.

BACKGROUND: To explore the associations between serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) levels at baseline and incidence of sarcopenia over time in older Australian community-dwelling older men. METHODS: Of the 1,705 men aged ≥70 years (2005-2007) participating in the Concord Health and Ageing in Men Project, those without sarcopenia at baseline (n = 1,312 for 25D and n = 1,231 for 1,25D), 2 years (n = 1,024 for 25D and n = 956 for 1,25D), and 5-year follow-up (n = 709 for 25D and n = 663 for 1,25D) were included in the study. The main outcome measurement was the incidence of sarcopenia defined as appendicular lean mass adjusted for body mass index <0.789 and grip strength <26.0 kg. Serum 25D and 1,25D levels were measured at baseline by radioimmunoassay (Diasorin, Stillwater, MN) and categorized into quartiles as predictor variables. Covariates included age, income, season of blood collection, physical activity, vitamin D supplement and medication use, measures of health, serum parathyroid hormone (PTH), estimated glomerular filtration rate (eGFR), albumin, and white blood cell count. RESULTS: In this study, incidence of sarcopenia was 3.9% in men at the 2-year follow-up and 8.6% at the 5-year follow-up. In adjusted analysis, men with vitamin D levels in the lowest quartiles (25D <40nmol/L; 1,25D <62 pmol/L) showed significant associations with increased odds of incident sarcopenia compared to those with vitamin D levels in the highest quartiles over 5 years. [25D: odds ratio (OR) 2.53 (95% confidence interval (CI) 1.14, 5.64) p = .02; 1,25D: OR 2.67 (95% CI 1.28, 5.60) p = .01]. After further adjustments for the respective other serum vitamin D measure, (either 25D or 1,25D), the association remained significant [25D: OR 2.40 (95% CI 1.02, 5.64) p = .04; 1,25D: OR 2.23 (95% CI 1.04, 4.80) p = .04]. CONCLUSION: Low serum 1,25D and 25D concentrations at baseline are independently associated with the incidence of sarcopenia over the subsequent 5 years. Although our data do not prove any causal relationship, it is conceivable that maintaining vitamin D sufficiency may reduce the incidence of sarcopenia in ageing men.

Progressive Temporal Change in Serum SHBG, But Not in Serum Testosterone or Estradiol, Is Associated With Bone Loss and Incident Fractures in Older Men: The Concord Health and Ageing in Men Project.

This study aimed to examine progressive temporal relationships between changes in major reproductive hormones across three waves of a cohort study of older men and (1) changes in bone mineral density (BMD) and (2) incident fractures (any, hip or non-vertebral) over an average of 6 years of follow-up. The CHAMP cohort of men aged 70 years and older were assessed at baseline (2005 to 2007, n = 1705), 2-year follow-up (n = 1367), and 5-year follow-up (n = 958). Serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) (by liquid chromatography-tandem mass spectrometry [LC-MS/MS]), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) (by immunoassay) were measured at all time-points, whereas free testosterone (cFT) was calculated using a well-validated formula. Hip BMD was measured by dual-energy X-ray absorptiometry (DXA) at all three time-points, and fracture data were verified radiographically. Statistical modeling was done using general estimating equations (GEEs). For total hip BMD, univariable analyses revealed inverse associations with temporal changes in serum SHBG, FSH, and LH and positive associations for serum E1 and cFT across the three time-points. In models adjusted for multiple covariables, serum SHBG (ß = -0.029), FSH (ß = -0.065), LH (ß = -0.049), E1 (ß = 0.019), and cFT (ß = 0.033) remained significantly associated with hip BMD. However for femoral neck BMD, only FSH (ß = -0.048) and LH (ß = -0.036) remained associated in multivariable-adjusted models. Temporal change in serum SHBG, but not T, E2, or other hormonal variables, was significantly associated with any, nonvertebral or hip fracture incidence in univariable analyses. In multivariable-adjusted models, temporal increase in serum SHBG over time remained associated with any fracture (ß = 0.060) and hip fracture (ß = 0.041) incidence, but not nonvertebral fracture incidence. These data indicate that a progressive increase in circulating SHBG over time predicts bone loss and fracture risk in older men. Further studies are warranted to further characterize changes in circulating SHBG as a mechanism and/or biomarker of bone health during male ageing. © 2016 American Society for Bone and Mineral Research.

Temporal Changes in Androgens and Estrogens Are Associated With All-Cause and Cause-Specific Mortality in Older Men.

CONTEXT: The dynamic temporal relationship between changes in serum reproductive hormones and mortality in men has not been reported. OBJECTIVE: The objective of the study was to examine the relationship between progressive changes in circulating reproductive hormones over time with all-cause and cause-specific mortality in older men. DESIGN, SETTING, AND PARTICIPANTS: Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005-2007, n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). MAIN OUTCOMES AND MEASURES: At all three time-points, T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were determined by immunoassay and calculated free T (cFT) was calculated. Mortality was ascertained through the state death registry. Statistical modeling was by general estimating equations with the Poisson regression. RESULTS: Serum T over time (relative risk [RR] per 1 SD decrease in concentration: 1.18, 95% confidence interval [CI] 1.05-1.32), DHT (RR 1.17, 95% CI 1.05-1.32), and E2 (RR 1.46, 95% CI 1.30-1.63) as well as cFT (RR 1.27, 95% CI 1.13-1.41) was associated with all-cause mortality. After adjusting for multiple covariables, the decline in serum T (RR 1.17, 95% CI 1.03-1.32), DHT (RR 1.17, 95% CI 1.03-1.32), and cFT (RR 1.13, 95% CI 1.08-1.19) remained significantly associated with all-cause mortality. Similar relationships were observed for cancer but not cardiovascular mortality. Progressive decline in serum E2 levels remained significantly associated with all-cause (RR 1.49, 95% CI 1.31-1.69), cancer (RR 1.82, 95% CI 1.45-2.28), and cardiovascular (RR 1.37, 95% CI 1.13-1.66) mortality, even after adjustment for covariables. Serum E1, LH, FSH, and SHBG were not associated with all-cause, cancer, or cardiovascular mortality. CONCLUSION: Dynamic temporal changes in serum T, cFT, DHT, and E2 (but not E1, LH, FSH, and SHBG) in older men are associated with all-cause and cause-specific mortality in distinct patterns.

Temporal Trend in Androgen Status and Androgen-Sensitive Outcomes in Older Men.

CONTEXT: Although androgen status decreases with aging in unselected men, the contemporaneous relationship over time between circulating hormones and androgen-sensitive outcomes has not been reported. OBJECTIVE: To investigate the temporal relationships between age-specific androgen status and muscle (mass, strength), hemoglobin, and prostate-specific antigen (PSA). DESIGN, SETTING AND PARTICIPANTS: Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (2005­2007; n = 1705) and at 2-year (n = 1367) and 5-year follow-up (n = 958). MAIN OUTCOME MEASURES: At all assessments, serum T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and serum SHBG, LH, and FSH were measured by immunoassay together with calculation of free T (cFT). Muscle mass, strength of upper (hand grip) and lower (walking speed) limbs, hemoglobin, and prostate size (serum PSA) were measured. RESULTS: Serum hormones showed longitudinal, within-man decreases in serum T (−2.6%/y), DHT (−2.6%/y), E1 (−3.2%/y), and cFT (−2.8%/y) but increases in serum E2 (2.6%/y), SHBG (1.3%/y), LH (1.9%/y), and FSH (1.8%/y). Significant positive correlation was observed between changes in serum T with muscle mass, strength, and hemoglobin but not with PSA across the three time-points. Changes in serum DHT, cFT, and E1 had significant correlation with muscle mass, strength, and hemoglobin, but not with PSA. CONCLUSIONS: These extended observational data are consistent with the impact of reduced androgen status on some somatic features of male aging. However, they do not exclude reverse causality or independent effects of aging on both androgen status and androgen-sensitive outcomes.

Longitudinal Relationships between Reproductive Hormones and Cognitive Decline in Older Men: The Concord Health and Ageing in Men Project.

CONTEXT: The longitudinal relationship between declining levels of reproductive hormones and cognitive function remains unclear in older men. OBJECTIVES: The objective of this study was to examine the temporal relationship between changes in major reproductive hormone levels and cognitive decline over time. DESIGN, SETTING, AND PARTICIPANTS: Men age 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) were assessed at baseline (2005-2007; n = 1705), 2-year followup (2007-2009; n = 1367), and 5-year followup (2010-2013; n = 958). MAIN OUTCOMES AND MEASURES: At all assessments, T, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Dementia was diagnosed at baseline by clinical assessment and review by a specialist panel. Cognitive function was measured at all three assessments by the Mini Mental State Examination. RESULTS: None of the baseline reproductive hormones predicted cognitive decline in men without dementia over 5 years. However, the change in serum hormones over time was associated with cognitive decline. In univariate analysis, change in all the studied hormones, except for E2, was significantly associated with cognitive decline. However, in multivariate-adjusted models accounting for potential confounders, only change in serum T (ß = 0.067), DHT (ß = 0.394), calculated free T (ß = 0.005), and E1 (ß = 0.009) remained significantly associated (P < .05) with cognitive decline. Men who had dementia at baseline had significantly greater decline in serum T levels, but not in other studied hormones, over the 5 years. CONCLUSIONS: Our findings show that decline in androgen status is associated with cognitive decline in older men, but the causality of this association requires further elucidation.

Reproductive Hormones and Longitudinal Change in Bone Mineral Density and Incident Fracture Risk in Older Men: The Concord Health and Aging in Men Project.

The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (1) change in bone mineral density (BMD) over 5 years and (2) incident fractures over an average of 6 years' follow-up. A total of 1705 men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) study were assessed at baseline (2005-2007), 2 years follow-up (2007-2009), and 5 years follow-up (2010-2013). At baseline, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and sex hormone-binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) by immunoassay. Hip BMD was measured by dual X-ray absorptiometry (DXA) at all three time-points. Fracture data were collected at 4-monthly phone calls and verified radiographically. Statistical modeling was by general estimating equations and Cox model regression. Univariate analyses revealed inverse associations for serum SHBG, FSH, and LH and positive association for E1 but not DHT or E2 with BMD loss at the hip across the three time points. Serum levels of SHBG (ß = -0.071), FSH (ß = -0.085), LH (ß = -0.070), and E1 (ß = 0.107) remained significantly associated with BMD loss in multivariate-adjusted models; however, we were unable to identify any thresholds for accelerated BMD loss according to reproductive steroids. Incident fractures (all, n = 171; hip, n = 44; and nonvertebral, n = 139) were all significantly associated with serum SHBG, FSH, and LH levels in univariate models but none remained significantly associated in multivariate-adjusted model. Serum T, DHT, E2, and E1 levels were not associated with incident fractures in univariate or multivariate-adjusted analyses. In older men, lower serum SHBG, FSH, and LH and higher E1 levels protected against loss of BMD without increasing fracture rate. This means these reproductive variables may be considered as novel biomarkers of bone health during male aging.

The longitudinal relationship of sexual function and androgen status in older men: the Concord Health and Ageing in Men Project.

CONTEXT: It is unclear whether declining sexual function in older men is a cause or consequence of reduced androgen status. OBJECTIVE: Longitudinal associations were examined between reproductive hormones and sexual function in older men. DESIGN, SETTING, AND PARTICIPANTS: Men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at baseline (n = 1705) and 2-year follow-up (n = 1367), with a total of 1226 men included in the final analyses. MAIN OUTCOMES AND MEASURES: At both visits, serum testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH were measured by immunoassay. Sexual functions (erectile function, sexual activity, and sexual desire) were self-reported via standardized questions. RESULTS: In longitudinal analyses, although baseline hormones (T, DHT, E2, and E1) did not predict decline in sexual function, the decline in serum T (but not DHT, E2, or E1) over 2 years was strongly related to the change in sexual activity and desire (but not erectile function). For each 1-SD decrease in T from baseline to 2-year follow-up, there was a multivariate-adjusted odds ratio of 1.23 (95% confidence interval, 1.12-1.36) for an additional risk of further decline in sexual activity. However, the magnitude of the decrease in serum T was strikingly small (<10%). Similar associations were found for changes over 2 years in serum T and decline in sexual desire, but not for erectile function. CONCLUSIONS: We found a consistent association among older men followed over 2 years between the decline in sexual activity and desire, but not in erectile function, with a decrease in serum T. Although these observational findings cannot determine causality, the small magnitude of the decrease in serum T raises the hypothesis that reduced sexual function may reduce serum T rather than the reverse.

Longitudinal relationships of circulating reproductive hormone with functional disability, muscle mass, and strength in community-dwelling older men: the Concord Health and Ageing in Men project.

CONTEXT: The relationship between functional disability and reproductive hormones and whether it is mediated by muscle mass and strength in older men are unclear. OBJECTIVES: The objective of the study was to identify the relationships between hormones and change in functional disability over a 2-year follow-up and to examine whether muscle mass and strength explain any of the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: A total of 1318 men aged 70 years and older from the Concord Health and Ageing in Men Project study were assessed at both baseline and 2-year follow-up. T, DHT, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. OUTCOME MEASURES: Functional disability was measured by basic Activities of Daily Living scale at both time points. Grip and quadricep strength were measured using dynamometers and lean (muscle) mass was determined by dual X-ray absorptiometry. RESULTS: All hormones were significantly associated with functional decline in univariate analyses. Only T, E2, E1, and calculated free T remained associated in multivariate analyses. Men in the lowest T quartile (vs the highest quartile) had an increased risk functional decline (odds ratio 1.96, 95% confidence interval 1.01-3.82). Similar associations were observed in E2, E1, and calculated free T. When muscle variables were added into the multivariate model, the associations between these hormones and functional decline were no longer statistically significant. CONCLUSION: Low T, E2, and E1 were significantly associated with prospective functional decline over 2 years. This relationship was no longer significant when muscle mass or strength were added, suggesting that the hormonal associations are mediated through their sequential effect on muscle mass and strength.

Longitudinal and cross-sectional relationships of circulating reproductive hormone levels to self-rated health and health-related quality of life in community-dwelling older men.

CONTEXT: Self-rated health and health-related quality of life are inversely associated with increased morbidity and mortality; however, the temporal relationship with reproductive hormones is poorly understood. OBJECTIVES: The objective of the study was to examine relationships between reproductive hormones, self-rated health, and quality of life in older men at baseline as well as changes over a 2-year follow-up. DESIGN, SETTING, AND PARTICIPANTS: One thousand six hundred thirty-seven men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline and 1316 men returned for the 2-year follow-up. Serum T, dihydrotestosterone, estradiol, and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry and SHBG, LH, and FSH by immunoassay. Logistic regression and multivariate linear regression models were performed. OUTCOME MEASURES: Self-rated health and health-related quality of life measures (12-Item Short Form Health Survey) were determined. RESULTS: In the cross-sectional baseline data, univariate analyses revealed significant associations between many of the hormones and quality-of-life scores and self-rated health. In a multivariable analysis, the associations between T, E1, and calculated free T and self-rated health remained statistically significant. Compared with men in the highest T quartile, men in the lowest T quartile had an odds ratio of 1.47 (95% confidence interval 1.04-2.06) for reporting fair, poor, or very poor health vs excellent or good health. The findings for E1 and calculated free T were similar. In the longitudinal data, the only significant relationship was that between E1 and self-rated health. Compared with those in the highest E1 quartile, those in the lowest quartile experienced deterioration in self-rated health: adjusted odds ratio of 1.84 (95% confidence interval 1.10-3.06). CONCLUSION: Low serum T and E1 are associated with poorer self-rated health in older men, whereas lower serum levels of E1 are predictive of subsequent deterioration in self-rated health over time. Therefore, serum E1 is a novel potential risk factor for poor self-rated health in older men that warrants further investigation.