David J Handelsman

University of Sydney, Sydney, New South Wales, Australia

Are you David J Handelsman?

Claim your profile

Publications (440)2226.21 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. Community-dwelling men, aged ≥70years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR=0.40 (95% CI: 0.21-0.95)] and institutionalization risk (HR=0.31; 95% CI: 0.09-0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    International journal of cardiology 08/2015; 192:49-55. DOI:10.1016/j.ijcard.2015.05.045 · 6.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method is described that employs a novel derivatization reagent for the measurement of serum estradiol (E2), with simultaneous analysis of underivatized testosterone (T) and dihydrotestosterone (DHT). The main advantage of the new derivatization reagent 1,2-dimethylimidazole-5-sulfonyl chloride is its analyte-specific fragmentation that enables monitoring of confirmatory mass transitions with high sensitivity. The reaction mixture can be analyzed without additional purification steps using a 9.5-minute gradient run, and sensitive detection is achieved with a triple quadrupole mass spectrometer using atmospheric pressure photoionization. Method validation was performed with human serum samples, including a comparison with a standard LC-MS/MS method using 120 samples from a clinical study, and analysis of certified E2 serum reference materials BCR-576, BCR-577, and BCR-578. Lower limits of quantification for E2, T, and DHT were 0.5 pg/mL, 25 pg/mL, and 0.10 ng/mL, respectively from a 200-µL sample. Validation results indicated good accuracy and agreement with established, conventional LC-MS/MS assays, demonstrating suitability for analysis of samples containing E2 in the low pg/mL range, such as serum from men, children and post-menopausal women.
    Analytical Chemistry 06/2015; DOI:10.1021/acs.analchem.5b01042 · 5.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Late adolescence in males is a period of increased susceptibility for the onset of schizophrenia, coinciding with increased circulating testosterone. The cognitive deficits prevalent in schizophrenia may be related to unhealthy cortical interneurons, which are trophically dependent on brain derived neurotrophic factor. We investigated, under conditions of depleted (monkey and rat) and replaced (rat) testosterone over adolescence, changes in gene expression of cortical BDNF and TrkB transcripts and interneuron markers and the relationships between these mRNAs and circulating testosterone. Testosterone removal by gonadectomy reduced gene expression of some BDNF transcripts in monkey and rat frontal cortices and the BDNF mRNA reduction was prevented by testosterone replacement. In rat, testosterone replacement increased the potential for classical TrkB signalling by increasing the full length to truncated TrkB mRNA ratio, whereas in the monkey cortex, circulating testosterone was negatively correlated with the TrkB full length/truncated mRNA ratio. We did not identify changes in interneuron gene expression in monkey frontal cortex in response to gonadectomy, and in rat, we showed that only somatostatin mRNA was decreased by gonadectomy but not restored by testosterone replacement. We identified complex and possibly species-specific, relationships between BDNF/TrkB gene expression and interneuron marker gene expression that appear to be dependent on the presence of testosterone at adolescence in rat and monkey frontal cortices. Taken together, our findings suggest there are dynamic relationships between BDNF/TrkB and interneuron markers that are dependent on the presence of testosterone but that this may not be a straightforward increase in testosterone leading to changes in BDNF/TrkB that contributes to interneuron health. Copyright © 2015. Published by Elsevier B.V.
    Schizophrenia Research 06/2015; 85. DOI:10.1016/j.schres.2015.05.040 · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clarifying the relationship of sex hormones to preclinical atherosclerosis could illuminate pathways by which androgens are associated with cardiovascular events and mortality. Our aim was to determine hormone profiles associated with carotid intima-media thickness (CIMT) and carotid atheroma, in men with and without known coronary artery disease (CAD). We included 492 community-based men aged 20-70 years (Group A) and 426 men with angiographically proven CAD aged <60 years (Group B). Fasting early morning sera were assayed for testosterone (T), dihydrotestosterone (DHT) and estradiol (E2) using mass spectrometry. CIMT and carotid plaque were assessed ultrasonographically. Mean (±SD) age was Group A: 53.8±12.6 and Group B: 49.6±5.1 years. Higher T was associated with reduced CIMT (-0.011 mm per 1-SD increase, p=0.042) and lower prevalence of carotid plaque (odds ratio [OR] per 1-SD increase, 0.68, p=0.012) in Group A, but not B. E2 was associated with increased CIMT in Group A (0.013 mm, p=0.011) but not B. Higher DHT and E2 were associated with reduced carotid plaque in Group B (DHT: OR=0.77, p=0.024; E2: OR=0.75, p=0.008), but not A. In community-dwelling men, higher T is associated with favourable CIMT and lower prevalence of carotid plaque, while higher E2 is associated with worse CIMT. In men with CAD, higher DHT or E2 are associated with less carotid plaque. T, DHT and E2 are differentially associated with preclinical carotid atherosclerosis in a cardiovascular phenotype-specific manner. Interventional studies are needed to examine effects of exogenous T and its metabolites DHT and E2, on atherogenesis.
    Endocrine Journal 06/2015; DOI:10.1507/endocrj.EJ15-0196 · 2.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BRCA1 mutations are associated with ovarian cancer. Previous studies reported that murine granulosa cell (GC) Brca1 loss caused ovarian-uterine tumors resembling serous cystadenomas, but the pathogenesis of these tumors may have been confounded by ectopic Brca1 expression and altered estrous cycling. We have used Tg.AMH.Cre conferring proven ovarian and GC-specific Cre activity to selectively target Brca1 disruption, denoted Brca1 GC−/−. Furthermore, ovary-specific Brca1 GC−/− was combined with global Trp53 haploinsufficiency (Trp53 +/−) and transgenic follicle-stimulating hormone (Tg.FSH) overexpression as a multi-hit strategy to investigate additional genetic and hormonal ovarian tumorigenesis mechanisms. However, 12-month-old Brca1 GC−/− mice had no detectable ovarian or uterine tumors. Brca1 GC−/− mice had significantly increased ovary weights, follicles exhibiting more pyknotic granulosa cells, and fewer corpora lutea with regular estrous cycling compared to controls. Isolated Brca1 GC−/− mutation lengthened the estrous cycle and proestrus stage; however, ovarian cystadenomas were not observed, even when Brca1 GC−/− was combined with Trp53 +/− and overexpressed Tg.FSH. Our Brca1 GC−/− models reveal that specific intra-follicular Brca1 loss alone, or combined with cancer-promoting genetic (Trp53 loss) and endocrine (high serum FSH) changes, was not sufficient to cause ovarian tumors. Our findings show that the ovary is remarkably resistant to oncogenesis, and support the emerging view of an extragonadal, multi-hit origin for ovarian tumorigenesis.
    Hormones and Cancer 05/2015; 6(4). DOI:10.1007/s12672-015-0222-5 · 2.15 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The longitudinal relationship between declining levels of reproductive hormones and cognitive function remains unclear in older men. The objective of this study was to examine the temporal relationship between changes in major reproductive hormone levels and cognitive decline over time. Men aged 70 years and older from the Concord Health and Ageing in Men Project (CHAMP) were assessed at baseline (2005-2007, n=1705), 2-years follow-up (2007-2009, n=1367) and 5-years follow-up (2010-2013, n=958). Main Outcomes and Measures: At all assessments, testosterone (T), dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), 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 (MMSE). 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), cFT (β=0.005) and E1 (β=0.009) remained significantly (p<0.05) associated 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. 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.
    The Journal of Clinical Endocrinology and Metabolism 04/2015; 100(6):jc20151016. DOI:10.1210/jc.2015-1016 · 6.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Anemia and frailty are both common in older people and are associated with adverse health outcomes. There have been some cross-sectional studies of anemia and frailty but no longitudinal studies. The objectives of this study were to examine cross-sectional and longitudinal associations between anemia and frailty in older Australian men. A total of 1666 men aged 70 years and older from the Concord Health and Aging in Men Project were assessed at baseline (2005-2007), 1314 men came for the 2-year follow-up between 2007 and 2009, and of those, 917 men returned for the 5-year follow-up between 2012 and 2013. The main outcome measurement was frailty, assessed using the Cardiovascular Health Study method. Anemia was defined as a hemoglobin levels <13.0 g/dL. Covariates included age, income, body mass index, measures of health, estimated glomerular filtration rate, and inflammatory markers (white cell count and albumin). The prevalence of anemia was 14.6% at baseline, 16.2% at 2-year follow-up, and 19.4% at 5-year follow-up. Prevalence of frailty was 9.1% at baseline and 9.7 % at both 2- and 5-year follow-up. Among men aged 70-74 at baseline, prevalence of frailty was 4.5%, but at 5-year follow-up the prevalence was 9.0%. There were significant cross-sectional associations between anemia and frailty in unadjusted [odds ratio, [OR 5.03 (95% confidence interval, CI 3.50, 7.25, P < .0001)] and in fully adjusted analysis [OR 2.90 (95% CI 1.87, 4.51, P < .0001)]. Generalized estimating equations time-lag models were used to examine the longitudinal associations between repeated measurements of hemoglobin and frailty. There were significant associations between measurements of anemia and frailty in unadjusted [OR 2.51 (95% CI 1.58, 4.00, P < .0001] and in fully adjusted analysis (OR 1.80, 95% CI 1.14, 2.85, P = .01). Anemia was associated with frailty in both cross-sectional and longitudinal analyses, and anemia precedes frailty in men who were nonfrail at baseline. Low hemoglobin levels among patients may alert clinicians to the increased risk of frailty. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
    Journal of the American Medical Directors Association 03/2015; DOI:10.1016/j.jamda.2015.02.014 · 4.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Sarcopenia is associated with an increased risk of adverse outcomes. The aim of this study was to explore the relationship between severity of sarcopenia and incident activities of daily living (ADL) disability, institutionalization, and all-cause mortality among community-dwelling older men participating in the Concord Health and Ageing in Men Project (CHAMP). Longitudinal analysis of 1705 participants aged 70 years or older at baseline (2005-2007) living in the community in Sydney, Australia. The main outcome measures were incident ADL disability, institutionalization, and mortality. Of the 1705 participants who completed the baseline assessments, a total of 1678 men (mean age 77 years) had complete measures by dual-energy x-ray absorptiometry, to assess sarcopenia in terms of low appendicular lean mass (ALM), using the Foundation for the National Institutes of Health (FNIH) criteria. To differentiate between severity of sarcopenia we used low ALM alone (sarcopenia I), low ALM with weakness (sarcopenia II), and sarcopenia with weakness and poor gait speed (sarcopenia III). Cox proportional hazard models and logistic regression models were used to assess the risk of mortality and institutionalization, and incidence of ADL disability. From baseline to follow-up, 103 (11.3%) men had incident ADL disability, 191 (11.2%) men were institutionalized, and 535 (31.9%) had died. At baseline, 14.2% had sarcopenia I, 5.3% had sarcopenia II, and 3.7% had sarcopenia III. Fully adjusted analysis (adjusted for demographics, lifestyle factors, comorbidities and health conditions, and blood measures) showed that sarcopenia I, II, and III were associated with increased risk of disability, institutionalization, and mortality. Associations between sarcopenia I, II, and III and risk of incident disability were as follows: odds ratio (OR) 2.77 95% confidence interval (CI) 1.30-5.87, OR 3.78 95% CI 1.23-11.64, and OR 4.53 95% CI 0.90-22.72; associations with institutionalization were hazard ratio (HR) 1.96 95% CI 1.14-3.35, HR 2.53 95% CI 1.31-4.90, and HR 2.27 95% CI 1.08-4.80; and with mortality were HR 1.65 95% CI 1.30-2.09, HR 1.50 95% CI 1.08-2.08, and HR 1.69 95% CI 1.17-2.44. This study shows that, in community-dwelling older men, sarcopenia defined by the FNIH criteria is associated with increased risk of incident disability, institutionalization, and mortality. Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.
    Journal of the American Medical Directors Association 03/2015; DOI:10.1016/j.jamda.2015.02.006 · 4.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Urinary hormone concentrations are often adjusted to correct for hydration status. We aimed to determine whether first morning void urine hormones in growing adolescents require adjustments and, if so, whether urinary creatinine or specific gravity (SG) are better adjustments. AND: METHODS: : The study population was adolescents aged 10.1 to 14.3 years initially who provided fasting morning blood samples at 0 and 12 months (n=343) and first morning urine every three months (n=644). Unadjusted, creatinine and SG-adjusted hormonal concentrations were compared by Deming regression and Bland-Altman analysis and grouped according to self-rated Tanner stage or chronological age. F-ratios for self-rated Tanner stages and age groups were used to compare unadjusted and adjusted hormonal changes in growing young adolescents. Correlations of paired serum and urinary hormonal concentration of unadjusted and creatinine and SG adjusted were also compared. Fasting first morning void hormone concentrations correlated well and were unbiased between unadjusted or adjusted by either creatinine or SG. Urine creatinine concentration increases with Tanner stages, age and male gender whereas, urine SG was not influenced by Tanner stage, age or gender. Adjustment by creatinine or SG of urinary luteinizing hormone, estradiol, testosterone, dihydrotestosterone and dehydroepiandrosterone concentrations did not improve correlation with paired serum concentrations. Urine steroid and LH concentrations in first morning void samples of adolescents are not significantly influenced by hydration status and may not require adjustments; however, if desired, both creatinine and SG adjustments are equally suitable. © 2015 Sage Publications, Inc.
    Annals of Clinical Biochemistry 03/2015; DOI:10.1177/0004563215580385 · 2.08 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although sex steroids are known to modulate brain dopamine, it is still unclear how testosterone modifies locomotor behaviour controlled, at least in part, by striatal dopamine in adolescent males. Our previous work suggests that increasing testosterone during adolescence may bias midbrain neurons to synthesise more dopamine. We hypothesised that baseline and amphetamine-induced locomotion would differ in adult males depending on testosterone exposure during adolescence. We hypothesised that concomitant stimulation of estrogen receptor signaling, through a selective estrogen receptor modulator (SERM), raloxifene, can counter testosterone effects on locomotion.
    Hormones and Behavior 03/2015; 70. DOI:10.1016/j.yhbeh.2015.02.005 · 4.51 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objectives of this study were to examine relationships between baseline levels of reproductive hormones in older men and (a) change in bone mineral density (BMD) over 5-years and (b) incident fractures over an average of 6-years follow-up. 1705 men aged 70 years and older from the CHAMP study were assessed at baseline (2005-2007), 2-years follow-up (2007-2009) and 5-year 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 SHBG, LH, and 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 (β = -0.071), FSH (β = -0.085), LH (β = -0.070) and E1 (β = 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 non-vertebral, 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 ageing. This article is protected by copyright. All rights reserved
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2015; DOI:10.1002/jbmr.2493 · 6.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In invertebrates, reproductive output and lifespan are profoundly impacted by dietary macronutrient balance, with these traits achieving their maxima on different diet compositions, giving the appearance of a resource-based tradeoff between reproduction and longevity. For the first time in a mammal, to our knowledge, we evaluate the effects of dietary protein (P), carbohydrate (C), fat (F), and energy (E) on lifespan and reproductive function in aging male and female mice. We show that, as in invertebrates, the balance of macronutrients has marked and largely opposing effects on reproductive and longevity outcomes. Mice were provided ad libitum access to one of 25 diets differing in P, C, F, and E content, with reproductive outcomes assessed at 15 months. An optimal balance of macronutrients exists for reproductive function, which, for most measures, differs from the diets that optimize lifespan, and this response differs with sex. Maximal longevity was achieved on diets containing a P:C ratio of 1:13 in males and 1:11 for females. Diets that optimized testes mass and epididymal sperm counts (indicators of gamete production) contained a higher P:C ratio (1:1) than those that maximized lifespan. In females, uterine mass (an indicator of estrogenic activity) was also greatest on high P:C diets (1:1) whereas ovarian follicle number was greatest on P:C 3:1 associated with high-F intakes. By contrast, estrous cycling was more likely in mice on lower P:C (1:8), and the number of corpora lutea, indicative of recent ovulations, was greatest on P:C similar to those supporting greatest longevity (1:11).
    Proceedings of the National Academy of Sciences 03/2015; 112(11). DOI:10.1073/pnas.1422041112 · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lower circulating androgens and poorer lung function are associated with increased cardiovascular risk and mortality in men. The association between androgens and lung function is unclear. We tested the hypothesis that circulating testosterone (T) and its metabolites dihydrotestosterone (DHT) and estradiol (E2) are differentially associated with lung function in men. Early morning serum T, DHT and E2 were assayed using mass spectrometry in 1,768 community-dwelling men from Busselton, Western Australia. Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using spirometry. Linear regression models adjusting for age, height, smoking, exercise, BMI, respiratory conditions and cardiovascular risk factors were used. Mean age was 50.1±16.8 years. 16.0% were current smokers, 14.1% reported a history of asthma and 2.7% chronic obstructive pulmonary disease. Current smokers had higher T compared with never smokers (age-adjusted mean 14.5 vs 13.5 nmol/L, p=0.002) and higher E2 (65.3 vs 60.1 pmol/L, p=0.017). In fully-adjusted analyses, T was associated with FEV1 (51 ml per 1-SD increase, p<0.001) as was DHT (62 ml, p<0.001), E2 was not (p=0.926). Similar results were seen for FVC (T: 76 ml, p<0.001, DHT: 65ml, p<0.001, E2 p=0.664). Higher DHT was marginally associated with the ratio FEV1/FVC (0.3% per 1-SD increase, p=0.047). Both T and DHT were independently associated with higher FEV1 and FVC in predominantly middle-aged community-dwelling men. Androgens may contribute to, or be biomarkers for, better lung function in men. Further research is needed to clarify whether androgens preserve lung function in ageing men. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Clinical Endocrinology 02/2015; DOI:10.1111/cen.12738 · 3.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycystic ovary syndrome (PCOS) is associated with reproductive, endocrine and metabolic abnormalities. As hyperandrogenism is the most consistent PCOS feature, we used wildtype (WT) and androgen receptor (AR) knockout mice (ARKO), together with a mouse model of PCOS, to investigate the contribution of genomic AR-mediated actions in the development of PCOS traits. PCOS features were induced by prenatal exposure to DHT (250μg) or oil vehicle (control) on days 16-18 of gestation in WT, heterozygote and homozygote ARKO mice. DHT treatment of WT mice induced ovarian cysts (100% vs 0%), disrupted estrous cycles (42% vs. 100% cycling) and led to fewer corpora lutea (5.0 ± 0.4 vs. 9.8 ± 1.8). However, diestrus serum LH and FSH, and estradiol-induced negative feedback as well as hypothalamic expression of Kiss1, NKB and Dyn were unaffected by DHT treatment in WT mice. DHT treated WT mice exhibited a >48% increase in adipocyte area, but without changes in body fat. In contrast, heterozygous and homozygous ARKO mice exposed to DHT maintained comparable ovarian (histo)morphology, estrous cycling and corpora lutea numbers, without any increase in adipocyte size. These findings provide strong evidence that genomic AR signaling is an important mediator in the development of these PCOS traits with a dose dependency that allows even AR haplosufficiency to prevent induction by prenatal androgenization of PCOS features in adult life.
    Endocrinology 02/2015; 156(4):en20141887. DOI:10.1210/en.2014-1887 · 4.64 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anaemia and low 25 hydroxyvitamin D (25D) and 1,25 dihydroxyvitamin D (1,25D) levels are common in older people and may adversely affect morbidity and mortality. While there is some evidence for an association between low serum 25D levels and anaemia, there are limited studies among community-dwelling older people. In addition, the relationship between anaemia and the active vitamin D metabolite, 1,25D, has not been investigated. The aim of this study was to examine the associations between serum 25D and 1,25D with anaemia in community-living men aged ≥70 years. Population-based, cross-sectional analysis of the baseline phase and longitudinal analysis of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney among men aged 70 years and older, were performed; 1666 men were seen at baseline (2005-2007), 1314 men at a 2-year follow-up (2007-2009) and 917 at a 5-year follow-up (2012-2013). The main outcome measurement was haemoglobin levels as a continuous measure. Covariates included 25D and 1,25D, estimated glomerular filtration rate, demographic information, lifestyle measures, health conditions and medication information. The prevalence of anaemia (Hb < 13.0 g/dL, WHO definition) was 14.6 %. In cross-sectional analysis, serum 25D concentrations were positively associated with haemoglobin levels in unadjusted analysis (β value 0.004; 95 % confidence interval (CI) 0.0009, 0.007; p = 0.01), but the associations were no longer significant after multivariate adjustment. The association between 1,25D levels and haemoglobin levels was significant in unadjusted analysis (β value 0.003; 95 % CI 0.002, 0.004; p < 0.0001) and remained significant in adjusted analysis (β value 0.001; 95 % CI 0.004, 0.003; p = 0.01). Serum 1,25D (but not 25D) levels at baseline were significantly associated with changes in haemoglobin over 2 and 5 years in unadjusted (β value 0.002; 95 % CI 0.0009, 0.003; p < 0.0001) and in fully adjusted analyses (β value 0.001; 95 % CI 0.0004, 0.002; p = 0.001). Serum 1,25D, but not 25D, concentrations are independently associated with haemoglobin levels in older men in both cross-sectional and longitudinal analyses. This raises the question whether vitamin D metabolites may influence anaemia states, mediated through different biological pathways, or represent a time-dependent biomarker of chronic ill health.
    Journal of the American Aging Association 02/2015; 37(1):9749. DOI:10.1007/s11357-015-9749-1 · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Injectable testosterone undecanoate (TU) was marketed within the last decade but its safety experience in routine clinical practice is not well defined. To appraise its safety profile, TU injections given in the Andrology Department, Concord Hospital were surveyed prospectively over 3.5 years (3,022 injections given to 347 patients) to estimate the incidence of (a) immediate cough/syncope due to pulmonary oil microembolisation (POME), (b) self-reported post-injection haematoma in patients taking antiplatelet and/or anticoagulant medications and (c) the prevalence of secondary polycythaemia during treatment. POME was observed after 56 injections (66 % mild, 19 % severe; 40 % with onset before injection completed) in 43 patients The incidence of 19 (95 % CI 14-24) per 1000 injections did not differ between 3 experienced nurses but recurrences were more frequent than by chance. No post-injection haematoma was reported including after 269 injections to men taking antiplatelet, anticoagulant or both drugs (upper 95% confidence limit 1%), of whom 56 did not withhold drugs prior to TU administration. Mean haematocrit was 0.44 ± 0.04 (SD) (0.31 - 0.56; 25 (7 %) >0.50, 14 (4 %) >0.52 and 3 (1 %) >0.54. We conclude that TU injections produce a low incidence of POME with injections by experienced nurses but recurrence is more frequent than by chance. Post-injection haematoma was not observed and polycythaemia was a minor problem rarely requires treatment other than optimising inter-injection interval.
    European Journal of Endocrinology 01/2015; 172(5). DOI:10.1530/EJE-14-0891 · 3.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 CHAMP study were assessed at baseline (n=1705) and 2-year follow-up (n=1367) with a total of 1226 men included for the final analyses. Main Outcomes and Measures: At both visits, serum testosterone (T), dihydrotestosterone, estradiol (E2), and estrone (E1) were measured by LC-MS/MS, and SHBG, LH, and FSH 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 were 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%CI: 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. While 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.
    Journal of Clinical Endocrinology &amp Metabolism 01/2015; 100(4):jc20144104. DOI:10.1210/jc.2014-4104 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Men are significantly more susceptible to non-melanoma skin cancers than women, and the androgen receptor (AR) is widely distributed in the skin, suggesting a ro\le for androgens acting via AR. Therefore, we explored the role of androgen action via AR in susceptibility to experimental 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis and in skin structural development of male and female mice. We demonstrate that both the male gender and androgen action via AR modify the susceptibility to carcinogen-induced skin cancer, but the effect depends on the carcinogenesis model used. Following systemic DMBA exposure, males were significantly (p DMBA-induced experimental skin cancer than females and AR inactivation significantly delayed cancer detection in both male (median time to palpable tumours 19 vs. >35 weeks (wild-type [WT] vs. AR knockout [ARKO], p 35 weeks, p = 0.008)) mice. In contrast, following DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced multistage local skin carcinogenesis, AR inactivation protected against formation of DMBA-induced skin cancers in both male and female mice. The skin structure was also affected by gender effect as well as the AR inactivation and could at least partly explain the different responses between the carcinogenesis models (systemic vs. topical). In addition, AR inactivation modified Cox-1 and Cox-2 expression in the skin, suggesting possible molecular mechanism for the AR effect on skin. Finally, some gender differences are observed also in ARKO mice insensitive to androgens, suggesting that factors other than androgens also play a role in gender-dependent skin carcinogenesis.
    01/2015; 6(1). DOI:10.1007/s12672-014-0210-1
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aims to identify the common risk factors for mortality in community-dwelling older men. A prospective population-based study was conducted with a median of 6.7 years of follow-up. Participants included 1705 men aged ≥70 years at baseline (2005-2007) living in the community in Sydney, Australia. Demographic information, lifestyle factors, health status, self-reported history of diseases, physical performance measures, blood pressure, height and weight, disability (activities of daily living (ADL) and instrumental ADLs, instrumental ADLs (IADLs)), cognitive status, depressive symptoms and blood analyte measures were considered. Cox regression analyses were conducted to model predictors of mortality. During follow-up, 461 men (27 %) died. Using Cox proportional hazards model, significant predictors of mortality included in the final model (p < 0.05) were older age, body mass index < 20 kg m(2), high white cell count, anaemia, low albumin, current smoking, history of cancer, history of myocardial infarction, history of congestive heart failure, depressive symptoms and ADL and IADL disability and impaired chair stands. We found that overweight and obesity and/or being a lifelong non-drinker of alcohol were protective against mortality. Compared to men with less than or equal to one risk factor, the hazard ratio in men with three risk factors was 2.5; with four risk factors, it was 4.0; with five risk factors, it was 4.9; and for six or more risk factors, it was 11.4, respectively. We have identified common risk factors that predict mortality that may be useful in making clinical decisions among older people living in the community. Our findings suggest that, in primary care, screening and management of multiple risk factors are important to consider for extending survival, rather than simply considering individual risk factors in isolation. Some of the "traditional" risk factors for mortality in a younger population, including high blood pressure, hypercholesterolaemia, overweight and obesity and diabetes, were not independent predictors of mortality in this population of older men.
    Journal of the American Aging Association 12/2014; 36(6):9732. DOI:10.1007/s11357-014-9732-2 · 3.45 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is currently the most frequent, fatal cancer of women in western countries. While estrogens have a widely understood involvement in breast cancer, a significant but not yet fully understood role for androgens has also been suggested. The principal androgen, testosterone, is the obligate steroidal precursor of estradiol, but can equally be metabolized into dihydrotestosterone, a more potent, pure androgen. Both androgens exert their distinctive biological effects via the androgen receptor, which is coexpressed with estrogen receptor alpha in 80 to 90% of breast cancers. The hormonal control of breast development and pathology has been examined experimentally through the use of animal models, notably mice and rats. This review summarizes the data from experimental rodent models on the effects of androgens in experimental breast cancer, aiming to address the importance of androgens and the androgen receptor in the origins and pathogenesis of breast cancers, as well as to discuss potential biomarker and therapeutic opportunities arising from novel insights based on the experimental research.
    Breast Cancer Research 11/2014; 16(6). DOI:10.1186/s13058-014-0483-x · 5.33 Impact Factor

Publication Stats

10k Citations
2,226.21 Total Impact Points

Institutions

  • 1979–2015
    • University of Sydney
      • • School of Public Health
      • • ANZAC Research Institute
      • • Centre for Education and Research on Ageing
      • • Discipline in Obstetrics and Gynaecology
      Sydney, New South Wales, Australia
  • 2014
    • Universiti Teknologi MARA
      • Faculty of Pharmacy
      Shah Alam, Selangor, Malaysia
  • 2001–2014
    • Sydney Orthopaedic Research Institute
      Sydney, New South Wales, Australia
    • Concord Hospital
      Concord, New Hampshire, United States
  • 2013
    • Hong Kong SAR Government
      Hong Kong, Hong Kong
  • 2004–2013
    • Concord Repatriation General Hospital
      Sydney, New South Wales, Australia
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 2011
    • Australian Society for Biochemistry and Molecular Biology
      Sydney, New South Wales, Australia
  • 2009
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • Heart Research Institute
      • Free Radical Group
      Newtown, New South Wales, Australia
    • National Measurement Institute
      Sydney, New South Wales, Australia
  • 1981–2009
    • Royal Prince Alfred Hospital
      • • Division of Endocrinology
      • • Department of Medical Oncology
      • • Department of Molecular and Clinical Genetics
      Camperdown, New South Wales, Australia
  • 2008
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2007
    • University of Melbourne
      Melbourne, Victoria, Australia
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 2005
    • University of Vic
      Vic, Catalonia, Spain
  • 2003
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2002
    • Liaoning Research Institute of Family Planning
      Feng-t’ien, Liaoning, China
  • 1994–2001
    • University of Turku
      Turku, Varsinais-Suomi, Finland
  • 1997
    • University of Newcastle
      Newcastle, New South Wales, Australia
    • Royal North Shore Hospital
      Sydney, New South Wales, Australia