David J Handelsman

University of Sydney, Sydney, New South Wales, Australia

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Publications (479)2365.96 Total impact

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    David J Handelsman · David F Gerrard · Alvin Matsumoto

    Full-text · Dataset · Jan 2016
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    ABSTRACT: Context: Advancing age is accompanied by accumulation of ill-health and shortening of chromosomal telomeres signifying biological ageing. Testosterone (T) is metabolised to dihydrotestosterone (DHT) by 5|ga-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro. Objectives: To establish whether circulating T or its metabolites DHT or E2, and single nucleotide polymorphisms (SNPS) in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men. Participants and methods: Early morning serum T, DHT and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 snps and LTL analysed by PCR in 980 men from the Western Australian Busselton Health Survey. LTL was expressed as the T/S ratio. Results: Men were aged (mean±SD) 53.7±15.6 years. LTL decreased linearly with age, from T/S ratio 1.89±0.41 at <30 years to 1.50±0.49 at 70 to <80 years (r=-0.225, p<0.0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT r=0.069, p=0.030; E2 r=0.068, p=0.034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2 59.3 vs 68.6 pmol/L, p<0.0001; T/S ratio 1.54 vs 1.62, p=0.045), rs10046 C (60.5 vs 68.1 pmol/L, p=0.0005, 1.54 vs 1.62, p=0.035) and rs700518 A (59.9 vs 68.9 pmol/L, p<0.0001, 1.54 vs 1.63, p=0.020). A single copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL. Conclusions: In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include 3 dominant alleles which are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo thus warranting further studies to examine whether hormonal interventions might slow biological ageing in men.
    Full-text · Article · Jan 2016 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Aims: To describe the natural history of non-neurogenic overactive bladder (OAB) and urgency incontinence in community-dwelling older men. Methods: A representative sample of 1,705 community-dwelling men aged 70 and older in a defined geographic area of Sydney, Australia, had their urinary symptoms assessed using the International Prostate Symptom Scores (IPSS) and the International Consultation of Incontinence Questionnaire (ICIQ) at baseline, 2-year follow-up, and 5-year follow-up. Four hundred and eighty-eight men without neurological diseases or prostate cancer during follow-up, or history of urological treatment at baseline were included in the analysis. Urgency incontinence was defined as leakage of urine occurring more than weekly in the above-defined population. OAB was defined as either urgency or urgency incontinence according to 2002 International Continence Society consensus. Results: Of the men with OAB at baseline, 29% received treatment for OAB or benign prostatic enlargement over 5 years. Of the remaining men, 33% had sustained remission at 2-year and 5-year follow-ups without treatment. Of the men with OAB at 2-year follow-up, remission rate at 5-year follow-up was 53% in men without OAB at baseline and 27% in men with OAB at baseline (P = 0.23). No statistically significant difference was found in baseline characteristics between men with sustained remission and men with persistent symptoms. Conclusions: One in three older men with non-neurogenic OAB had sustained remission of symptoms without medical or surgical interventions. No significant predictor of sustained remission was identified. Neurourol. Urodynam. © 2016 Wiley Periodicals, Inc.
    No preview · Article · Jan 2016 · Neurourology and Urodynamics
  • David J. Handelsman

    No preview · Chapter · Jan 2016
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    ABSTRACT: To investigate the effects of number of medications and Drug Burden Index (DBI) on transitions between frailty stages and death in community-dwelling older men. Cohort study. Sydney, Australia. Community-dwelling men aged 70 and older (N = 1,705). Self-reported questionnaires and clinic visits were conducted at baseline and 2 and 5 years. Frailty was assessed at all three waves according to the modified Fried frailty phenotype. The total number of regular prescription medications and DBI (a measure of exposure to sedative and anticholinergic medications) were calculated over the three waves. Data on mortality over 9 years were obtained. Multistate modeling was used to characterize the transitions across three frailty states (robust, prefrail, frail) and death. Each additional medication was associated with a 22% greater risk of transitioning from the robust state to death (adjusted 95% confidence interval (CI) = 1.06–1.41). Every unit increase in DBI was associated with a 73% greater risk of transitioning from the robust state to the prefrail state (adjusted 95% CI = 1.30–2.31) and a 2.75 times greater risk of transitioning from the robust state to death (adjusted 95% CI = 1.60–4.75). There was no evidence of an adjusted association between total number of medications or DBI and the other transitions. Although the possibility of confounding by indication cannot be excluded, additional medications were associated with greater risk of mortality in robust community-dwelling older men. Greater DBI was also associated with greater risk of death and transitioning from the robust state to the prefrail state.
    No preview · Article · Jan 2016 · Journal of the American Geriatrics Society
  • Y. Lam · L. Leece · S. Yuen · D. Handelsman · R. Karas · M. Ng

    No preview · Article · Dec 2015 · Heart, Lung and Circulation
  • Y. Lam · L. Leece · D. Handelsman · M. Ng

    No preview · Article · Dec 2015 · Heart, Lung and Circulation
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    David J Handelsman · David F Gerrard · Alvin M. Matsumoto
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    ABSTRACT: Objective: To review the doping status of dehydroepiandrosterone (DHEA) for female athletes with adrenal insufficiency within the framework of Therapeutic Use Exemption (TUE) applications for this proandrogen, which is included on the World Anti-Doping Agency (WADA)'s Prohibited List. Data sources and main results: Current knowledge of adrenal pathophysiology with a focus on the physiological role and pharmacological effects of DHEA in female athletes including placebo-controlled clinical trials of DHEA and consensus clinical practice and prescribing guidelines. Conclusions: Because there is no convincing clinical evidence to support the use of DHEA replacement therapy in women with adrenal failure, a TUE for DHEA is not justified by definite health benefit for either secondary or primary adrenal failure. This is consistent with the 2014 update of the US Endocrine Society guidelines, meta-analyses of DHEA treatment in women with or without adrenal failure, current WADA TUE guidance document for adrenal insufficiency and recent case law of WADA's Court of Arbitration for Sport.
    Full-text · Article · Dec 2015 · Clinical Journal of Sport Medicine
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    ABSTRACT: Background/Aims The longitudinal relationships of within-individual hormone and anthropometric changes during puberty have not ever been fully described. The objectives of this study were to demonstrate that 3 monthly urine collection was feasible in young adolescents and to utilise liquid chromatography-tandem mass spectrometry assay methods for serum and urine testosterone (T), estradiol (E2) and luteinizing hormone (LH) in adolescents by relating temporal changes in urine and serum hormones over 12 months to standard measures of pubertal development. Methods A community sample of 104 adolescents (57 female) was studied over 12 months with annual anthropometric assessment, blood sampling and self-rated Tanner staging and urine collected every 3 months. Serum and urine sex steroids (T, E2) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and LH by immunoassay. Results A high proportion (92%) of scheduled samples were obtained with low attrition rate of 6.7% over the 12 months. Urine hormone measurements correlated cross-sectionally and longitudinally with age, anthropometry and Tanner stage. Conclusion We have developed a feasible and valid sampling methodology and measurements for puberty hormones in urine, which allows a sampling frequency by which individual pubertal progression in adolescents can be described in depth.
    Full-text · Article · Nov 2015 · PLoS ONE
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    ABSTRACT: Background: Depression in older men has been associated with low circulating testosterone concentration but data from prospective studies are limited. Methods: We conducted a prospective longitudinal study in a community representative cohort of 3179 older men free of clinically significant depressive symptoms at baseline. The main objective of this study was to determine if low serum testosterone, dihydrotestosterone and estradiol concentrations are associated with the development of depressive symptoms. Incident depression was assessed with the Patient Health Questionnaire and via an electronic health record database (The West Australian Data Linkage System). The main exposures of interest were serum testosterone, dihydrotestosterone and estradiol measured by liquid chromatography-mass spectrometry and calculated free testosterone in baseline blood samples (collected between 2001 and 2004). Results: One hundred and thirty five men (4.2%) developed depression over a median follow up time of 9.4 years (range 8.4-10.9). Men with incident depression were older (median age 77.7 vs 76.1 years, z=-3.82, p=0<0.001) and were more likely to have cardiovascular disease (43.0% vs 32.6%, χ(2)=6.32, p=0.012) and diabetes (22.2% vs 13.2%, χ(2)=8.95, p=0.003). Low serum total testosterone (<6.4nmol/L) was associated with incident depression (HR 2.07, 95%CI 1.17-3.68) and this remained significant after adjustment for relevant potential confounding factors (HR 1.86, 95%CI 1.05-3.31). Low serum dihydrotestosterone, estradiol and calculated free testosterone were not associated with risk of depression. Conclusions: Low serum total testosterone, but not calculated free testosterone, was associated with incident depression in this sample of older men.
    No preview · Article · Nov 2015 · Psychoneuroendocrinology
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    ABSTRACT: Background: Comorbidity and multimorbidity are common in older people. Here we used a novel analytic approach called Association Rules together with network analysis to evaluate multimorbidity (two or more disorders) and comorbidity in old age. Methods: A population-based cross-sectional study was undertaken where 17 morbidities were analyzed using network analysis, cluster analysis, and Association Rules methodology. A comorbidity interestingness score was developed to quantify the richness and variability of comorbidities associated with an index condition. The participants were community-dwelling men aged 70 years or older from the Concord Health and Ageing in Men Project, Sydney, Australia, with complete data (n = 1,464). Results: The vast majority (75%) of participants had multimorbidity. Several morbidity clusters were apparent (vascular cluster, metabolic cluster, neurodegenerative cluster, mental health and other cluster, and a musculoskeletal and other cluster). Association Rules revealed unexpected comorbidities with high lift and confidence linked to index diseases. Anxiety and heart failure had the highest comorbidity interestingness scores while obesity, hearing impairment, and arthritis had the lowest (zero) scores. We also performed Association Rules analysis for the geriatric syndromes of frailty and falls to determine their association with multimorbidity. Frailty had a very complex and rich set of frequent and interesting comorbidities, while there were no frequent and interesting sets associated with falls. Conclusions: Old age is characterized by a complex pattern of multimorbidity and comorbidity. Single disease definitions do not account for the prevalence and complexity of multimorbidity in older people and a new lexicon may be needed to underpin research and health care interventions for older people.
    No preview · Article · Oct 2015 · The Journals of Gerontology Series A Biological Sciences and Medical Sciences
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    ABSTRACT: While estrogen action is the major driver of uterine development, androgens acting via the androgen receptor (AR) may also promote uterine growth as suggested by uterine phenotype in global AR knockout (ARKO) female mice. As AR is expressed in uterine endometrial glands, we generated (Cre/loxP) uterine gland epithelium (uge) specific AR knockout (ugeARKO) to determine the role of endometrial gland specific androgen actions. However, AR in uterine gland epithelium may not be required for normal uterine development and function as ugeARKO females had normal uterine development and fertility. To determine if exogenous androgens acting via AR can fully support uterine growth in absence of estrogens the ARKO and ugeARKO females were ovariectomized (OVX) and treated with supraphysiological doses of testosterone or dihydrotestosterone (DHT, non-aromatizable androgen). Both DHT and testosterone supported full uterine regrowth in wild-type (WT) females while ARKO females had no regrowth (comparable to OVX only). These findings suggest that androgens acting via AR can promote full uterine regrowth in the absence of estrogens. The ugeARKO had 50% regrowth when compared to intact and histomorphologically, both the endometrial and myometrial areas were significantly (P < 0.05) reduced, suggesting glandular epithelial AR located in endometrium may indirectly modify myometrial development. Additionally, to confirm the Cre function in endometrial glands, we generated uterine glandular epithelium specific PTEN knockout (ugePTENKO) mouse model. The ugePTENKO females developed severe endometrial hyperplasia and therefore present a novel model for future research.
    Full-text · Article · Oct 2015 · Biology of Reproduction
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    ABSTRACT: Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21-24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a 'gender score' was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together (n = 183; r = —0.59), as well as when males (n = 86; r = —0.55) and females (n = 97; r = —0.48) were examined separately (p-values < 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology (n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
    Full-text · Article · Oct 2015 · Proceedings of the Royal Society B: Biological Sciences
  • David J Handelsman · Ken Sikaris · Lam P Ly
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    ABSTRACT: Background: Age-specific trends of serum testosterone (T) and sex hormone binding globulin (SHBG) across the full lifespan have not been reported. Methods: We deduced age-specific trends in serum testosterone and SHBG in males and females between ages 10 and 90 from a large sample of consecutive results from a single large pathology laboratory. Coded results of 110,712 consecutive blood samples requesting serum testosterone over 7 years (2007-13) comprising blood T, SHBG and calculated free T (cFT) together with gender and age were analyzed create smoothed age-specific centiles (2.5%, 5%, 25%, 50%, 75%, 95%, 97.5%) for males and females. Results: These identified the pubertal increases in serum T in males peaking at 20 years of age and remaining stable thereafter until the 8(t) (h) decade. In women circulating T peaked in late adolescence and declined gradually over the next 2 decades but remained stable across menopause and beyond. After early childhood, serum SHBG declines to a nadir in men the age of 20 years and remain stable till the 6(t) (h) decade with a gradual, progressive rise thereafter. In women the SHBG nadir is reached earlier with levels rising gradually and progressively with age thereafter and accelerating after the age of 70 years. Women also exhibit a second SHBG peak during reproductive ages reflected only in upper centiles due to effects of pregnancy and oral contraceptive use in a significant minority of women. Conclusions: This large sample of clinical data provides a comprehensive profile of androgen status across the lifespan from early adolescence to late old age.
    No preview · Article · Oct 2015 · Annals of Clinical Biochemistry
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    ABSTRACT: Haploinsufficient inactivating phosphatase and tensin homolog (Pten) mutations cause Cowden syndrome, an autosomal dominant risk genotype for hormone dependent reproductive cancers. As androgen actions mediated via the androgen receptor (AR) supports uterine growth and may modify uterine cancer risk, we hypothesized that a functional AR may increase PTEN inactivation induced uterine cancer. To test the hypothesis, we compared the PTEN knockout (PTENKO) induced uterine pathology in heterozygous PTENKO and combined heterozygous PTEN and complete AR knockout (PTENARKO) female mice. PTENKO induced uterine pathology was significantly reduced by AR inactivation with severe macroscopic uterine pathology present in 21% of PTENARKO vs 46% of PTENKO at a median age of 45 weeks. This could be due to reduced stroma ERα expression in PTENARKO compared to PTENKO uterus, while AR inactivation did not modify PTEN or P-AKT levels. Unexpectedly, while progesterone (P4) is assumed protective in uterine cancers, serum P4 was significantly higher in PTENKO females compared to WT, ARKO, and PTENARKO females consistent with more corpora lutea in PTENKO ovaries. Serum testosterone and ovarian estradiol were similar between all females. Hence, our results demonstrated AR inactivation mediated protection against PTENKO induced uterine pathology and suggests a potential role for antiandrogens in uterine cancer prevention and treatment. © 2015 Society for Endocrinology.
    Full-text · Article · Oct 2015 · Endocrine Related Cancer
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    ABSTRACT: STUDY QUESTION By investigating a birth cohort with a high ongoing participation rate to derive an unbiased population, what are the parameters and influences upon testicular function for a population not selected with regard to fertility?
    No preview · Article · Sep 2015 · Human Reproduction
  • David J Handelsman · Bu Yeap · Leon Flicker · Sean Martin · Gary Allen Wittert · Lam P Ly
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    ABSTRACT: Context: The age-specific population profiles in men of circulating testosterone (T) and its two bioactive metabolites dihydrotestosterone (DHT) and estradiol (E2) across the adult lifespan and its determinants are not well described. Objective: To deduce smoothed age-specific centiles of circulating testosterone T, DHT and E2 in men using pooled data from population-based studies in 3 Australian cities from liquid chromatography-mass spectrometry (LC-MS) steroid measurements in a single laboratory. Design, setting and participants: Pooled data of 10,904 serum samples (serum T, DHT, E2, age, height, weight) from observational population-based studies in 3 major cities across Australia. Main outcome measures: Age-specific smoothed centiles for serum T, DHT and E2 in men aged 35 to 100 years deduced by large sample data analysis methods. Results: Serum T, DHT and E2 decline gradually from ages 35 onwards with a more marked decline after 80 years of age. Higher weight, body mass index (BMI) and body surface area (BSA) as well as shorter stature are associated with reduced serum T, DHT and E2. Conclusions: Among Australian men, there is gradual progressive population-wide decline in androgen status during male ageing until the age of 80 years after which there is a more marked decline. Obesity and short stature are associated with reduced androgen status. Research into the age-related decline in androgen status should focus on the progressive accumulation of age-related comorbidities to better inform optimal clinical trial design.
    No preview · Article · Sep 2015 · European Journal of Endocrinology
  • David J Handelsman

    No preview · Article · Sep 2015 · Medical care
  • Kirsty A Walters · David J Handelsman

    No preview · Article · Aug 2015 · Asian Journal of Andrology
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    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.
    No preview · Article · Aug 2015 · International journal of cardiology

Publication Stats

13k Citations
2,365.96 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
  • 2001-2014
    • Concord Hospital
      Concord, New Hampshire, United States
    • Sydney Orthopaedic Research Institute
      Sydney, New South Wales, Australia
    • University of Turku
      Turku, Varsinais-Suomi, Finland
  • 2004-2013
    • Concord Repatriation General Hospital
      Sydney, New South Wales, Australia
    • University of Helsinki
      Helsinki, Uusimaa, Finland
  • 2009
    • National Measurement Institute
      Sydney, New South Wales, Australia
  • 2007-2009
    • University of Melbourne
      Melbourne, Victoria, Australia
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
  • 1986-2009
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
  • 1980-2009
    • Royal Prince Alfred Hospital
      • • Division of Endocrinology
      • • Department of Medical Oncology
      • • Department of Molecular and Clinical Genetics
      • • Department of Surgery
      Camperdown, New South Wales, Australia
  • 1986-2007
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 2006
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, CA, United States
  • 2005
    • University of Vic
      Vic, Catalonia, Spain
  • 2002
    • Liaoning Research Institute of Family Planning
      Feng-t’ien, Liaoning, China
  • 2000
    • The Endocrine Society of Australia
      Sydney, New South Wales, Australia
  • 1997
    • University of Newcastle
      Newcastle, New South Wales, Australia