Changes in thyroid function and evolution of subclinical thyroid disease in older men.

OBJECTIVE: Prevalence of subclinical thyroid disease increases with age, but optimal detection and surveillance strategies remain unclear particularly for older men. We aimed to assess thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations and their longitudinal changes, to determine the prevalence and incidence of subclinical thyroid dysfunction in older men. DESIGN, PARTICIPANTS AND MEASUREMENTS: Longitudinal study of 994 community-dwelling men aged ≥70 years without known or current thyroid disease, with TSH and FT4 concentrations assessed at baseline and follow-up (after 8.7 ± 0.9 years). Factors associated with incident subclinical thyroid dysfunction were examined by logistic regression and receiver operating characteristic analyses. RESULTS: At baseline, 85 men (8.6%) had subclinical hypothyroidism and 10 (1.0%) subclinical hyperthyroidism. Among 899 men euthyroid at baseline (mean age 75.0 ± 3.0 years), 713 (79.3%) remained euthyroid, 180 (20.0%) developed subclinical/overt hypothyroidism, and 6 (0.7%) subclinical/overt hyperthyroidism. Change in TSH correlated with baseline TSH (r = .16, p < .05). Change in FT4 correlated inversely with baseline FT4 (r = -0.35, p < .05). Only higher age and baseline TSH predicted progression from euthyroid to subclinical/overt hypothyroidism (fully-adjusted odds ratio [OR] per year=1.09, 95% confidence interval [CI] = 1.02-1.17, p = .006; per 2.7-fold increase in TSH OR = 65.4, CI = 31.9-134, p < .001). Baseline TSH concentration ≥2.34 mIU/L had 76% sensitivity and 77% specificity for predicting development of subclinical/overt hypothyroidism. CONCLUSIONS: In older men TSH concentration increased over time, while FT4 concentration showed little change. Subclinical or overt hypothyroidism evolved in one fifth of initially euthyroid men, age and higher baseline TSH predicted this outcome. Increased surveillance for thyroid dysfunction may be justified in older men, especially those with high-normal TSH.

The relationship between serum HDL-cholesterol, cardiovascular disease and mortality in community-based people with type 2 diabetes: the Fremantle Diabetes Study phase 2.

BACKGROUND: Older general population-based studies found an inverse association between serum HDL-cholesterol and both cardiovascular disease (CVD) events and mortality, but more recent data have suggested a U-shaped relationship. Whether this applies to type 2 diabetes is uncertain. The aim of this study was to assess the prognostic significance of serum HDL-cholesterol concentrations in representative, community-based participants from the Fremantle Diabetes Study Phase II (FDS2). METHODS: We followed 1,479 FDS2 participants with confirmed type 2 diabetes (713 females, mean age 65.6 years; 763 males, mean age 65.9 years) from entry (2008-2011) to death/end-2021. Major adverse cardiovascular events (non-fatal myocardial infarction (MI), non-fatal stroke, cardiovascular death; 3-point MACE), and all-cause mortality were ascertained from prospectively collected data and validated administrative databases. Independent associates of 3-point MACE by sex, excluding participants with prior MI/stroke, were assessed using Cox and competing risk models with sex-specific quintiles of HDL-cholesterol added to the most parsimonious models. Predictors of all-cause mortality were identified using Cox proportional hazards modelling. RESULTS: In females, with baseline serum HDL-cholesterol quintile 2 (1.04-1.22 mmol/L) as reference, both quintiles 1 (< 1.04 mmol/L) and 5 (> 1.59 mmol/L) were significant independent predictors of 3-point MACE (P < 0.027) and all-cause death (P < 0.019) after adjustment for a full range of demographic, clinical and laboratory variables. In males, serum HDL-cholesterol quintile did not add to the most parsimonious model for 3-point MACE, but quintile 1 (< 0.90 mmol/L) was a significant predictor of death (P = 0.026 versus quintile 4 (1.15-1.31 mmol/L) as reference) after adjustment. Competing risk analyses for 3-point MACE showed similar results to the Cox models for both sexes. CONCLUSION: There was a significant U-shaped relationship between serum HDL-cholesterol and both 3-point MACE and all-cause death in females with type 2 diabetes after adjustment for confounders. There was no such relationship for 3-point MACE in males but a low HDL-cholesterol was associated with all-cause mortality. These data have sex-specific implications for assessment of serum lipid profiles in the clinical management of type 2 diabetes.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

Subclinical thyroid dysfunction and circulating thyroid hormones are not associated with bone turnover markers or incident hip fracture in older men.

OBJECTIVE: Overt thyroid dysfunction is a risk factor for osteoporosis and fractures. Subclinical hyperthyroidism has also been associated with fracture. It remains unclear whether variation in thyroid hormones within the euthyroid range modulates bone health, particularly among older men. We assessed whether thyroid stimulating hormone (TSH) and free thyroxine (FT4) are associated with bone turnover markers (BTMs) and predict hip fracture risk in community-dwelling older men without known thyroid disease. DESIGN: Prospective cohort study. PATIENTS: Four thousand two hundred forty-eight men aged 70-89 years. MEASUREMENTS: Baseline blood samples were assayed for TSH, FT4, total osteocalcin (TOC), undercarboxylated osteocalcin (ucOC), N-terminal propeptide of type I collagen (P1NP) and collagen type I C-terminal cross-linked telopeptide (CTX). Incidence of hip fracture events was ascertained to 2012. Associations of TSH and FT4 with BTMs were analysed at baseline using Pearson correlation coefficients, and with incident hip fracture using Cox proportional hazards regression. RESULTS: After excluding men with pre-existing thyroid or bone disease, there were 3, 338 men for analysis. Of these, 3, 117 were euthyroid, 135 had subclinical hypothyroidism, and 86 had subclinical hyperthyroidism. Men with subclinical thyroid disease were older, and those with subclinical hyperthyroidism had lower creatinine than the other groups. After multivariate analysis, there were no associations found between FT4, TSH or subclinical thyroid dysfunction and BTMs at baseline. Neither subclinical thyroid dysfunction, TSH nor FT4 were predictive of incident hip fracture in our study population. CONCLUSIONS: In euthyroid older men, TSH and FT4 were not associated with BTMs or incident hip fracture. Our findings differ from those previously described in postmenopausal women.

Progressive impairment of testicular endocrine function in ageing men: Testosterone and dihydrotestosterone decrease, and luteinizing hormone increases, in men transitioning from the 8th to 9th decades of life.

CONTEXT: Sex hormone trajectories in ageing men and their health implications remain unclear. We examined longitudinal trajectories and associations of testosterone (T), dihydrotestosterone (DHT), oestradiol (E2), luteinizing hormone (LH) and sex hormone-binding globulin (SHBG) in oldest old men. DESIGN: Prospective cohort study. PARTICIPANTS: We studied 1025 community-dwelling men median age 75.1 years at baseline with 8.6 years of follow-up. MEASUREMENTS: Baseline and follow-up T, DHT and E2 were assayed using mass spectrometry. Physical performance was assessed at follow-up. Correlations and covariate-adjusted P-values were determined. RESULTS: Longitudinal change in T was -2.0%/year, DHT -7.2%/year, LH +7.5%/year, SHBG +5.6%/year while E2 remained stable. Annualized increases in LH correlated with decreases in T and DHT (r = -.20, P < .0001 and r = -.12, P = .0035, respectively). Higher baseline T correlated with better physical performance at follow-up (eg, Step test r = .07, P = .03), as did higher baseline DHT (eg, time to sit-stand [TSS] r = -.07, P = .01). Larger annualized increases in LH predicted poorer physical performance at follow-up (eg, TSS r = .14, P = .001). Higher T at follow-up was associated with better physical performance (eg, TSS r = -.07, P = .04), as were higher DHT and lower LH. At baseline, 24 men (2.4%) had abnormally high LH (>16 IU/L); at follow-up, 175 (17.4%) had high LH of whom 70 had low T (<6.4 nmol/L). CONCLUSIONS: Annualized increases in LH are associated with declines in T and DHT, and predict poorer subsequent physical performance in oldest old men. Men transitioning from 8th to 9th decades exhibit biochemical evidence of progressively impaired testicular endocrine function, warranting further evaluation.

Insulin resistance and depressive symptoms in older men: the health in men study.

OBJECTIVE: A positive association between depression and diabetes has been reported, but the direction and nature of this association is unclear. Insulin resistance is a state of reduced responsiveness of target tissues to normal circulating levels of insulin and predisposes to diabetes in the presence of beta cell dysfunction. METHODS: We conducted this cross-sectional and prospective study in a community representative sample of 3,140 older men free of diabetes to determine if insulin resistance was associated with prevalent and incident depressive symptoms. RESULTS: Men with insulin resistance had increased odds of depression cross-sectionally (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.08-2.40), although this was not significant after adjustment for possible confounding (OR: 1.32; 95% CI: 0.85-2.03). In the longitudinal analysis, men with insulin resistance were more likely to develop clinically significant depressive symptoms (adjusted risk ratio [RR]: 2.33; 95% CI: 1.17-4.62), and this risk was greatest for men in the highest quartile of insulin resistance compared with those in the lowest quartile (adjusted RR: 2.54; 95% CI: 1.04-6.18). CONCLUSION: Older men with clinically significant depressive symptoms were more likely to have higher markers of insulin resistance. Additionally, the odds of depression increased with increasing levels of insulin resistance, and insulin resistance increased the risk of developing depression over 5 years later. Because depression is now a leading cause of disability worldwide, addressing the rising challenge of insulin resistance may prove important in improving the future health of our communities.

The inter-relationship between Helicobacter pylori infection, dementia and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase I.

BACKGROUND: Given sparse relevant data, the aim of this study was to determine whether Helicobacter pylori infection, including cytotoxin-associated gene-A (CagA) producing strains, is associated with dementia in type 2 diabetes (T2DM). METHODS: Longitudinal data from 1115 participants in the community-based Fremantle Diabetes Study Phase I (mean age 64.0 years, 48.0 % males; 38.0 % H. pylori seronegative, 24.3 % H. pylori seropositive/CagA seronegative, and 37.7 % H. pylori/CagA seropositive at baseline) were analyzed. RESULTS: During up to 19 years of follow-up, 50.3 % and 83.5 % of participants without and with incident dementia, respectively, died. In Cox proportional hazards models, H. pylori/CagA seropositivity (hazard ratio (95 % CI) 1.68 (1.15, 2.46), P = 0.008), but not H. pylori seropositivity/CagA seronegativity (P = 0.541) was an independent predictor of incident dementia, but neither H. pylori seropositivity/CagA seronegativity nor H. pylori/CagA seropositivity were significant predictors in competing risks models (P ≥ 0.280). CONCLUSIONS: Although CagA seropositivity in T2DM may have a contributory etiologic role in the risk of dementia, this may be through its association with reduced cardiovascular/all-cause mortality.

Lower plasma testosterone or dihydrotestosterone, but not estradiol, is associated with symptoms of intermittent claudication in older men.

OBJECTIVE: In men, testosterone (T) levels decline with age, and lower T predicts all-cause and cardiovascular mortality. However, the associations of T and its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with symptomatic peripheral arterial disease remain unclear. We assessed associations of T, DHT and E2 with lower limb intermittent claudication in older men. DESIGN: Cross-sectional study. PARTICIPANTS: Community-dwelling men aged 70-89 years resident in Perth, Western Australia. MEASUREMENTS: Intermittent claudication was ascertained by the Edinburgh Claudication Questionnaire. Early morning, plasma T, DHT and E2 were assayed using liquid chromatography-tandem mass spectrometry. RESULTS: There were 268 men with intermittent claudication and 2435 without claudication or any leg pain. Men with nonspecific leg pain (n = 986) were excluded. After adjusting for age, smoking, BMI, waist/hip ratio, hypertension, dyslipidaemia, diabetes, creatinine and prevalent cardiovascular disease (CVD), higher T was associated with reduced risk of having claudication (per 1 SD increase, odds ratio [OR] = 0·80, 95% confidence interval [CI] = 0·69-0·94, P = 0·006; quartiles, Q4/Q1, OR = 0·54, 95% CI = 0·36-0·81). Higher DHT was associated with reduced risk of having claudication (per 1 SD increase, OR = 0·86, 95% CI = 0·73-1·00, P = 0·048; Q4/Q1, OR = 0·64, 95% CI = 0·43-0·95). E2 was not associated with claudication (per 1 SD increase, OR = 0·96, 95% CI = 0·83-1·11, P = 0·565; Q4/Q1, OR = 0·88, 95% CI = 0·60-1·29). CONCLUSIONS: Lower T or DHT levels, but not E2, are associated with symptoms of intermittent claudication in older men. Reduced exposure to androgens may represent a causal factor or biomarker for symptomatic peripheral arterial disease. Further studies are needed to examine underlying mechanisms and evaluate therapeutic options in ageing men.

Serum bicarbonate concentration and the risk of death in type 2 diabetes: the Fremantle Diabetes Study Phase II.

AIMS: To examine whether all-cause mortality is independently associated with serum bicarbonate concentration below the laboratory reference interval in a representative, well-characterised community-based cohort of people with type 2 diabetes. METHODS: 1478 FDS2 participants with type 2 diabetes (mean age 65.8 years, 51.6% males, median diabetes duration 9.0 years) from the longitudinal, observational Fremantle Diabetes Study Phase II (FDS2) were followed from study entry to death or end-2016. Independent associates of a low baseline serum bicarbonate (< 22 mmol/L) were determined using multiple logistic regression. The role of important covariates in influencing the association between bicarbonate and mortality was assessed by a stepwise Cox regression approach. RESULTS: A low serum bicarbonate was associated with increased all-cause mortality in unadjusted analysis (hazard ratio (HR) 1.90 (95% confidence limits (CL) 1.39, 2.60 per mmol/L). Mortality remained significantly associated with low serum bicarbonate (HR 1.40 (95% CL 1.01, 1.94) per mmol/L) in a Cox regression model with adjustment for factors associated with mortality but not low serum bicarbonate, but inclusion of estimated glomerular filtration rate categories rendered the association non-significant (HR 1.16 (95% CL 0.83, 1.63) per mmol/L). CONCLUSIONS: A low serum bicarbonate is not an independent prognostic marker in people with type 2 diabetes but it may be a manifestation of the pathway between the development of impaired renal function and death.

Prevalence and predictors of sexual problems in men aged 75-95 years: a population-based study.

INTRODUCTION: Hypogonadism is associated with impaired libido and erectile dysfunction in young men, but the causes of sexual dysfunction in older men are less well understood. AIM: To determine the prevalence and predictors of sexual problems in older men. MAIN OUTCOME MEASURE: Sexual problems, as assessed by a self-reported questionnaire. METHODS: This was a population-based, cohort study of 3,274 community-dwelling men aged 75-95 years (mean 82 years) from Perth, Western Australia. Questionnaires in 2001-2004 and 2008-2009 assessed social and medical risk factors. Sex hormones were measured in 2001-2004. Predictors of sexual problems, measured in 2008-2009, were assessed cross-sectionally in the entire sample, and longitudinally in a subset of 1,744 men with sex hormone data. RESULTS: Sexual problems were highly prevalent, with 49.4% (95% confidence interval 47.7% to 51.1%) reporting erectile problems, 47.7% (45.9% to 49.4%) lacking interest in sexual activity, 38.7% (37.0% to 40.3%) unable to climax, and 20.4% (19.1% to 21.8%) anxious about their ability to perform sexually. Painful and unpleasurable sex were less common (<5%). Overall, 72.0% (70.5% to 73.6%) reported at least one problem. In multivariate binary logistic regression analyses, cardiovascular disease, diabetes, depression, prostate disorders, and insomnia were the factors most commonly associated with sexual problems. Low testosterone levels were associated with lack of interest in sex, but not with other complaints. CONCLUSIONS: Sexual problems are common in elderly men. Chronic disease, depression, and insomnia appear to be the main modifiable risk factors. Androgen deficiency is unlikely to be a major cause of sexual problems in this age group.

The relationship between thyroid dysfunction, cardiovascular morbidity and mortality in type 2 diabetes: The Fremantle Diabetes Study Phase II.

AIMS: It is uncertain whether subclinical thyroid dysfunction is associated with cardiovascular disease (CVD) events and mortality in people with type 2 diabetes. The aim of this study was to determine whether undetected thyroid disease increases the risk of incident CVD and death in type 2 diabetes. METHODS: One thousand two hundred fifty participants with type 2 diabetes (mean age 65.3 years, 56.5% males, median diabetes duration 8.0 years) without known thyroid disease and not taking medications known to affect thyroid function were categorised, based on baseline serum free thyroxine (FT4) and thyrotropin (TSH) concentrations, as euthyroid, overt hypothyroid (increased TSH, low FT4), subclinical hypothyroid (increased TSH, normal FT4), overt thyrotoxic (decreased TSH, raised FT4) or subclinical thyrotoxic (decreased TSH, normal FT4). Incident myocardial infarction, incident stroke, all-cause and cardiovascular mortality were ascertained during a mean 6.2-6.7 years of follow-up. RESULTS: Most participants with newly-detected thyroid dysfunction had subclinical hypothyroidism (77.2%) while overt/subclinical thyrotoxicosis was infrequent. Compared to participants with TSH 0.34-2.9 mU/L, those with TSH > 5.1 mU/L were not at increased risk of incident myocardial infarction (adjusted hazard ratio (95% confidence limits) 1.77 (0.71, 2.87)), incident stroke (1.66 (0.58, 4.78)), all-cause mortality (0.78 (0.44, 1.37)) or cardiovascular mortality (1.16 (0.38, 3.58)). Independent baseline associates of subclinical hypothyroidism included estimated glomerular filtration rate and systolic blood pressure. CONCLUSIONS: Subclinical hypothyroidism was not independently associated with CVD events or mortality in community-dwelling people with type 2 diabetes despite its associations with CVD risk factors, questioning strategies to identify and/or treat mild thyroid dysfunction outside usual care.

Thyroid hormones and depression: the Health in Men study.

CONTEXT: Current practice guidelines suggest that thyroid function tests should be an integral part of the assessment of adults presenting with a depressive episode, although there is a paucity of data available to support such a recommendation. OBJECTIVE: To determine if biochemical markers of thyroid dysfunction are associated with prevalent and incident clinically significant depressive symptoms. DESIGN: Cross-sectional and cohort studies. PATIENTS: Community-dwelling sample of 3,932 men age 69 to 87 free of overt thyroid disease. MAIN OUTCOME MEASURES: We used the 15-item Geriatric Depression Scale to ascertain the presence of prevalent clinically significant depressive symptoms, and the Western Australia Data Linkage System to establish the onset of a depressive episode according to the International Classification of Diseases. RESULTS: The serum concentration of thyroid-stimulating hormone and free thyroxine (fT4) did not affect the odds of prevalent or the hazard of incident depression. The odds of prevalent depression were 0.8 (95% CI: = 0.5-1.3) for men with subclinical hypothyroidism and 1.4 (95% CI: = 0.3-5.8) for those with subclinical hyperthyroidism. The hazard ratio of incident depression associated with subclinical hypothyroidism was 0.7 (95% CI: = 0.3-1.9). No men with subclinical hyperthyroidism developed depression during the follow-up period of 5.5 ± 1.4 years. CONCLUSIONS: Subclinical thyroid disease is not associated with prevalent or incident depression in older men. These findings do not support the routine screening of subclinical thyroid dysfunction among older adults with depression.

Prevalence of sexual activity and associated factors in men aged 75 to 95 years: a cohort study.

BACKGROUND: Knowledge about sexuality in elderly persons is limited, and normative data are lacking. OBJECTIVE: To determine the proportion of older men who are sexually active and to explore factors predictive of sexual activity. DESIGN: Population-based cohort study. SETTING: Community-dwelling men from Perth, Western Australia, Australia. PARTICIPANTS: 3274 men aged 75 to 95 years. MEASUREMENTS: Questionnaires from 1996 to 1999, 2001 to 2004, and 2008 to 2009 assessed social and medical factors. Sex hormones were measured from 2001 to 2004. Sexual activity was assessed by questionnaire from 2008 to 2009. RESULTS: A total of 2783 men (85.0%) provided data on sexual activity. Sex was considered at least somewhat important by 48.8% (95% CI, 47.0% to 50.6%), and 30.8% (CI, 29.1% to 32.5%) had had at least 1 sexual encounter in the past 12 months. Of the latter, 56.5% were satisfied with the frequency of activity, whereas 43.0% had sex less often than preferred. In cross-sectional analyses, increasing age, partner's lack of interest, partner's physical limitations, osteoporosis, prostate cancer, diabetes, antidepressant use, and ß-blocker use were independently associated with reduced odds of sexual activity. Living with a partner and having a non-English-speaking background were associated with increased odds. In longitudinal analyses, higher testosterone levels were associated with increased odds of being sexually active. Other factors were similar to the cross-sectional model. LIMITATIONS: Response bias may have influenced findings because sexuality can be a sensitive topic. Attrition may have resulted in a healthier-than-average sample of older men. CONCLUSION: One half of elderly men consider sex important, and one third report being sexually active. Men's health problems were associated with lack of sexual activity. Key modifiable risk factors include diabetes, depression, and medication use. Endogenous testosterone levels predict sexual activity, but the role of testosterone therapy remains uncertain. PRIMARY FUNDING SOURCE: National Health and Medical Research Council of Australia.

Changes in the Epidemiology of Hepatobiliary Disease Complicating Type 2 Diabetes over 25 Years: The Fremantle Diabetes Study.

OBJECTIVE: To determine whether the incidence/outcome of hepatobiliary disease (HBD) has increased over recent decades in community-based Australians with and without type 2 diabetes (T2D). METHODS: Longitudinal data from the Fremantle Diabetes Study Phase I (FDS1; recruitment 1993-1996; n = 1291 with T2D) and Phase II (FDS2; 2008-2011; n = 1509) were analyzed. Participants with T2D from both Phases were age-, sex-, and postcode-matched 1:4 to people without diabetes. Incident HBD and associated mortality were ascertained from hospitalization, cancer registration, and/or death certification codes. Incidence rates (IRs) and IR ratios (IRRs) for those with versus without diabetes in FDS1 and FDS2 were calculated. RESULTS: HBD IRs for people without diabetes did not change between Phases. The IRR (95% CI) for people with T2D in FDS2 versus FDS1 was 1.30 (1.01-1.68) with the highest IRRs in participants aged <65 years. Non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) events were 54% greater in FDS2 than FDS1 in the presence of greater abdominal adiposity. NAFLD/NASH was coded in one in 11 HBD events in FDS2 and in 10% of HBD deaths (<4% of total mortality). CONCLUSIONS: HBD is more frequent in people with versus without T2D and this discrepancy is increasing. Hospitalizations/deaths due to NAFLD/NASH remain uncommon.

U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men.

PURPOSE: Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. PARTICIPANTS AND METHODS: Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. RESULTS: Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] 0.51-0.94, P = .020; Q3: HR 0.59, 95% CI 0.42-0.83, P = .002) and hip fracture (Q2 versus Q1: HR 0.60, 95% CI 0.37-0.93, P = .043; Q3: HR 0.52, 95% CI 0.31-0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: HR 1.76, 95% CI 1.05-2.96, P = .033). CONCLUSIONS: Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

Healthier lifestyle predicts higher circulating testosterone in older men: the Health In Men Study.

OBJECTIVE: Circulating testosterone declines during male ageing, and low testosterone may predispose to ill health. We sought to determine whether greater participation in healthy behaviours predicted reduced risk of subsequent lower circulating testosterone in older men. DESIGN: Cross-sectional analysis of a population-based follow-up study. PARTICIPANTS: A total of 3453 men aged 65-83 years. MEASUREMENTS: Lifestyle score, a tally of eight prudent health-related behaviours, was determined during 1996-99. Early morning sera collected in 2001-04 were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using mass action equations. RESULTS: Mean (+/- SD) time between collection of lifestyle data and blood sampling was 5.7 +/- 0.9 years. Lifestyle score correlated with subsequent total testosterone (r = 0.06, P < 0.001) and SHBG (r = 0.07, P < 0.001), but not free testosterone (r = 0.03, P = 0.08) or LH (r = -0.03, P = 0.12). In multivariate analyses, higher lifestyle scores (4 and above) predicted reduced risk of total testosterone and SHBG in the lowest quartile of values. For the highest category (>or= 7), odds ratio (95% CI) for total testosterone and SHBG in the lowest quartile were 0.37 (0.18-0.77) and 0.26 (0.13-0.54), respectively. Lower lifestyle scores including and excluding body mass index predicted higher risk of total testosterone and SHBG in the lowest quartiles. CONCLUSIONS: In men > 65 years old, higher lifestyle score reflecting greater engagement in healthy behaviours predicts higher subsequent total testosterone and SHBG levels. This relationship appears cumulative and may reflect interaction between lifestyle and insulin sensitivity. Successfully promoting healthy behaviours in older men could ameliorate the age-related decline in circulating testosterone.

Luteinizing hormone levels are positively correlated with plasma amyloid-beta protein levels in elderly men.

Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated with increased risk of cognitive decline and developing dementia. Compared to controls, men with Alzheimer's disease (AD) have been shown to have lower serum testosterone levels and higher serum luteinizing hormone (LH) levels. As serum free testosterone concentration is negatively correlated with LH in older men, the independent contributions of these hormones to the pathogenesis of AD warrants further clarification. To explore this notion, we measured plasma amyloid-beta (Abeta), serum testosterone, serum LH and other biochemical parameters in 40 cognitively normal elderly men. Multiple linear regression analysis revealed that serum LH concentration is the only parameter that significantly correlates with plasma Abeta levels in these men (r=0.5, p=0.041). These results suggest that increased serum LH concentration, rather than lower serum free testosterone, is associated with the accumulation of Abeta in plasma. Larger, longitudinal human studies are needed to determine the significance of LH in the pathogenesis of AD.

Higher serum free testosterone is associated with better cognitive function in older men, while total testosterone is not. The Health In Men Study.

OBJECTIVE: To determine the relationship of total and free serum testosterone to cognitive performance in older men. DESIGN: Cross-sectional study of a population-based sample. Participants A total of 2932 men aged 70-89 years. MEASUREMENTS: Cognitive function was assessed using the Standardized Mini-Mental State Examination (SMMSE). Early morning sera were assayed for total testosterone, SHBG and LH. Free testosterone was calculated using the Vermeulen method. RESULTS: There were weak positive correlations between SMMSE score and serum free testosterone (Spearman's rho = 0.06, P = 0.001) and total testosterone (r = 0.04, P = 0.027), and a weak negative correlation with LH (r = -0.07, P < 0.001). Men with SMMSE scores in the top quintile had higher serum free testosterone compared with those in the lowest quintile [median (interquartile range, IQR): 278 (228-335) vs. 262 (212-320) pmol/l, P = 0.003], but similar total testosterone [15.2 (11.9-18.8) vs. 14.8 (11.6-18.3) nmol/l, P = 0.118]. Increasing age, non-English-speaking background, lower educational attainment, presence of clinically significant depressive symptoms, and cardiovascular morbidity were associated with the lowest cognitive performance quintile. After their effects were taken into account in a multivariate analysis, serum free testosterone > or = 210 pmol/l was associated with reduced likelihood of poor cognitive performance on the SMMSE [odds ratio (OR) 0.71, 95% confidence interval (CI) 0.52-0.97]. CONCLUSIONS: In community-dwelling older men, serum free testosterone > or = 210 pmol/l is associated with better cognitive performance. In this context, calculated free testosterone seems to be a more informative measure of androgen status than total testosterone. Studies examining the contribution of androgens to age-related cognitive decline should incorporate an assessment of free testosterone concentration.

Clinical utility of bone turnover markers in the management of common metabolic bone diseases in adults.

Bone turnover marker (BTMs) concentrations in blood and urine reflect bone-remodelling activity, and may be useful adjuncts in the diagnosis and management of metabolic bone diseases. Newer biomarkers, mainly bone regulatory proteins, are currently being investigated to elucidate their role in bone metabolism and disease and may in future be useful in clinical diagnosis and management of metabolic bone disease. BTM concentrations increase around menopause in women, and at a population level the degree of increase in BTMs reflect bone loss. However, lack of adequate data precludes their use in individual patients for fracture risk assessment in clinical practice. The rapid and large changes in BTMs following anti-resorptive and anabolic therapies for osteoporosis treatment indicate they may be useful for monitoring therapy in clinical practice. The offset of drug effect on BTMs could be helpful for adjudicating the duration of bisphosphonate drug holidays. BTMs may offer useful additional data in skeletal diseases that are typically characterised by increased bone remodelling: chronic kidney disease (CKD), primary hyperparathyroidism (PHPT) and Paget's disease. In CKD, bone specific alkaline phosphatase (bAP) is currently endorsed for use for the assessment of mineral bone disease. The role of BTMsin predicting the bone mineral density response to successful parathyroidectomy in PHPT shows some utility but the data are not consistent and studies are limited in size and/or duration. In Paget's disease of bone, BTMs are used to confirm diagnosis, evaluate extent of disease or degree of activity and for monitoring the response to bisphosphonate treatment. Whilst BTMs are currently used in specific clinical practice instances when investigating or managing metabolic bone disease, further data are needed to consolidate their clinical use where evidence of utility is limited.

A 10-Year Prospective Study of Bone Mineral Density and Bone Turnover in Males and Females With Type 1 Diabetes.

Context: In a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD. Objective: To determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers. Design: Longitudinal observational study. Setting: Urban community. Patients: Forty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later. Main Outcome Measures: BMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers. Results: After adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies. Conclusions: There is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.