Benjumin Hsu

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 (β = 0.067), DHT (β = 0.394), calculated free T (β = 0.005), and E1 (β = 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.

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.

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.

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.

Associations Between Circulating Reproductive Hormones and SHBG and Prevalent and Incident Metabolic Syndrome in Community-Dwelling Older Men: The Concord Health and Ageing in Men Project

CONTEXT The causal relationship between metabolic syndrome and reproductive hormones is unclear. OBJECTIVE This study sought to examine the cross-sectional, longitudinal, and predictive associations between reproductive hormones and SHBG and metabolic syndrome in older men. DESIGN, SETTING, AND PARTICIPANTS Men ages 70 years and older from the Concord Health and Ageing in Men Project study (n = 1705) were assessed at baseline and 2-year follow-up. At baseline, T, dihydrotestosterone (DHT), estradiol, and estrone were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Metabolic syndrome was defined using the P National Cholesterol Education Program (NCEP) Adult Treatment Panel III criteria. RESULTS In cross-sectional data, significant associations between each of T, SHBG, DHT, and calculated free testosterone (cFT) with the metabolic syndrome remained significant after multivariate adjustment. In longitudinal analyses, however, only lower SHBG was significantly associated with incident metabolic syndrome over the 2-year follow-up (P for linear trend = .04). CONCLUSIONS Although low serum T, DHT, SHBG, and cFT were associated cross-sectionally with metabolic syndrome among community-dwelling older men, over a 2-year follow-up period only SHBG remained significant after multivariate adjustment. This suggests that lowered circulating androgens (T and DHT) may be biomarkers rather than causally related to incident metabolic syndrome.

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 (β = –0.029), FSH (β = –0.065), LH (β = –0.049), E1 (β = 0.019), and cFT (β = 0.033) remained significantly associated with hip BMD. However for femoral neck BMD, only FSH (β = –0.048) and LH (β = –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 (β = 0.060) and hip fracture (β = 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.

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 (2005–2007; 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.

Sexual Function and Mortality in Older Men: The Concord Health and Ageing in Men Project

Background The longitudinal association between progressive temporal change in sexual (dys)function and mortality in older men. Methods Community-dwelling men aged 70 years and older from the Concord Health and Ageing in Men Project were assessed at baseline (2005-2007, n = 1,705), 2-years follow-up (n = 1,367), and 5-years follow-up (n = 958). Self-reported sexual function (erectile function and sexual activity) using standardized questions were analyzed by generalized estimating equations to examine the longitudinal prediction of mortality according to change in sexual function across three time-points. Results Men reported to have erectile dysfunction increased from 64% to 80%, and to be sexually inactive increased from 56% to 59% over the course follow-up. In univariate analyses, erectile dysfunction (hazard ratio: 2.02, 95% confidence interval [CI]: 1.45-2.81) or having no sexual activity (hazard ratio: 2.31, 95% CI: 1.82-2.93) at baseline predicted increased mortality over the subsequent 7 years. Models adjusted for multivariate and major reproductive hormones had negligible impact on mortality prediction, but neither statistically significantly predicted mortality after adjusting for depression. Similarly, change in erectile dysfunction over time was associated with mortality over 7 years in univariate (odds ratio: 1.69, 95% CI: 1.34-2.14) and multivariate analysis, including hormones, but not after adjusting for depression (odds ratio: 1.24, 95% CI: 0.95-1.62). Change in sexual activity was associated with mortality over 7 years in univariate analysis (odds ratio: 2.37, 95% CI: 1.33-4.20) but not after adjusting for age (odds ratio: 1.45, 95% CI: 0.79-2.64). Conclusions Our analyses suggest sexual dysfunction was not an independent risk factor of, but rather may be a biomarker for, all-cause mortality in older men.

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.