David J Handelsman

University of Sydney, Sydney, New South Wales, Australia

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Publications (460)2325.98 Total impact

  • David J. Handelsman ·

    Endocrinology: Adult and Pediatric, 01/2016: pages 441-454.e4; , ISBN: 9780323189071
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    PLoS ONE 11/2015; 10(11):e0143555. DOI:10.1371/journal.pone.0143555 · 3.23 Impact Factor

  • Psychoneuroendocrinology 11/2015; DOI:10.1016/j.psyneuen.2015.11.012 · 4.94 Impact Factor
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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.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 10/2015; DOI:10.1093/gerona/glv181 · 5.42 Impact Factor
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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.
    Biology of Reproduction 10/2015; 93(5). DOI:10.1095/biolreprod.115.132241 · 3.32 Impact Factor
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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.
    Proceedings of the Royal Society B: Biological Sciences 10/2015; 282(1816-1816):20151351. DOI:10.1098/rspb.2015.1351 · 5.05 Impact Factor
  • 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.
    Annals of Clinical Biochemistry 10/2015; DOI:10.1177/0004563215610589 · 2.34 Impact Factor
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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.
    Endocrine Related Cancer 10/2015; 22(5):687-701. DOI:10.1530/ERC-15-0203 · 4.81 Impact Factor
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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? Summary answer: While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have no or minimal adverse impact. What is known already: The majority of previous attempts to develop valid reference populations for spermatogenesis have relied on potentially biased sources such as recruits from infertility clinics, self-selected volunteer sperm donors for research or artificial insemination or once-fertile men seeking vasectomy. It is well known that studies requiring semen analysis have low recruitment rates which consequently question their validity. However, there has been some concern that a surprisingly high proportion of young men may have semen variables that do not meet all the WHO reference range criteria for fertile men, with some studies reporting that up to one half of participants have not meet the reference range for fertile men. Reported median sperm concentrations have ranged from 40 to 60 million sperm/ml. Study design, size and duration: The Western Australian Pregnancy Cohort (Raine) was established in 1989. At 20-22 years of age, members of the cohort were contacted to attend for a general follow-up, with 753 participating out of the 913 contactable men. Of these, 423 men (56% of participants in the 20-22 years cohort study, 46% of contactable men) participated in a testicular function study. Of the 423 men, 404 had a testicular ultrasound, 365 provided at least one semen sample, 287 provided a second semen sample and 384 provided a blood sample. Participants/materials, setting, methods: Testicular ultrasound examinations were performed at King Edward Memorial Hospital, Subiaco, Perth, for testicular volume and presence of epididymal cysts and varicoceles. Semen samples were provided and analysed by standard semen assessment and a sperm chromatin structural assay (SCSA) at Fertility Specialists of Western Australia, Claremont, Perth. Serum blood samples were provided at the University of Western Australia, Crawley, Perth and were analysed for serum luteinizing hormone (LH), follicular stimulating hormone (FSH), inhibin B, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), estradiol, estrone and the primary metabolites of DHT: 5α-androstane-3α,17β-diol (3α-diol) and 5-α androstane-3-β-17-beta-diol (3β-diol). Serum steroids were measured by liquid chromatography, mass spectrometry and LH, FSH and inhibin B were measured by ELISA assays. Main results and the role of chance: Cryptorchidism was associated with a significant reduction in testicular (P = 0.047) and semen (P = 0.027) volume, sperm concentration (P = 0.007) and sperm output (P = 0.003). Varicocele was associated with smaller testis volume (P < 0.001), lower sperm concentration (P = 0.012) and total sperm output (P = 0.030) and lower serum inhibin B levels (P = 0.046). Smoking, alcohol intake, herniorrhaphy, an epididymal cyst, medication and illicit drugs were not associated with any significant semen variables, testicular volume or circulating reproductive hormones. BMI had a significantly negative correlation with semen volume (r = -0.12, P = 0.048), sperm output (r = -0.13, P = 0.02), serum LH (r = -0.16, P = 0.002), inhibin B (r = -0.16, P < 0.001), testosterone (r = -0.23, P < 0.001) and DHT (r = -0.22, P < 0.001) and a positive correlation with 3αD (r = 0.13, P = 0.041) and DHEA (r = 0.11, P = 0.03). Second semen samples compared with the first semen samples in the 287 participants who provided two samples, with no significant bias by Bland-Altman analysis. Testis volume was significantly correlated positively with sperm concentration (r = 0.25, P < 0.001) and sperm output (r = 0.29, P < 0.001) and inhibin B (r = 0.42, P < 0.001), and negatively correlated with serum LH (r = -0.24, P < 0.001) and FSH (r = -0.32, P < 0.001). SCSA was inversely correlated with sperm motility (r = -0.20, P < 0.001) and morphology (r = -0.16, P = 0.005). WHO semen reference criteria were all met by only 52 men (14.4%). Some criteria were not met at first analysis in 15-20% of men, including semen volume (<1.5 ml, 14.8%), total sperm output (<39 million, 18.9%), sperm concentration (<15 million/ml, 17.5%), progressive motility (<32%, 14.4%) and morphologically normal sperm (<4%, 26.4%), while all five WHO criteria were not met in four participants (1.1%). Limitations and reasons for caution: This was a large cohort study; however, potential for recruitment bias still exists. Men who did not participate in the testicular evaluation study (n = 282) did not differ from those who did (n = 423) with regard to age, weight, BMI, smoking or circulating reproductive hormones (LH, FSH, inhibin B, T, DHT, E2, E1, DHEA, 3α-diol, 3β-diol), but were significantly shorter (178 versus 180 cm, P = 0.008) and had lower alcohol consumption (P = 0.019) than those who did participate. Wider implications of the findings: This study demonstrated the feasibility of establishing a birth cohort to provide a relatively unbiased insight into population-representative sperm output and function and of investigating its determinants from common exposures. While varicocele, cryptorchidism and obesity may impact on human testicular function, most common drug exposures and the presence of epididymal cysts appear to have little adverse impact, and this study suggests that discrepancies from the WHO reference ranges are expected, due to its derivation from non-population-representative fertile populations. Study funding/competing interests: This study was supported by Australian NHMRC Grant Number 634457 and received support from the Raine Medical Research Foundation, The Telethon Kids institute, The University of Western Australia, Women and Infant Research Foundation, Curtin University and Edith Cowan University. R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. D.A.D., M.L.W., J.A.K., J.E.D., J.E.D., N.E.S. and D.J.H. have no competing interests. RIM is a shareholder in the Monash IVF Group. RJN is a shareholder in FertilitySA.
    Human Reproduction 09/2015; DOI:10.1093/humrep/dev244 · 4.57 Impact Factor
  • 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.
    European Journal of Endocrinology 09/2015; DOI:10.1530/EJE-15-0380 · 4.07 Impact Factor
  • Kirsty A Walters · David J Handelsman ·

    Asian Journal of Andrology 08/2015; DOI:10.4103/1008-682X.161600 · 2.60 Impact Factor
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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.
    International journal of cardiology 08/2015; 192:49-55. DOI:10.1016/j.ijcard.2015.05.045 · 4.04 Impact Factor
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    Pekka Keski-Rahkonen · Reena Desai · Mark Jimenez · D Tim Harwood · David J Handelsman ·
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    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; 87(14). DOI:10.1021/acs.analchem.5b01042 · 5.64 Impact Factor
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    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 · 3.92 Impact Factor
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    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; 62(9). DOI:10.1507/endocrj.EJ15-0196 · 2.00 Impact Factor
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    ABSTRACT: In 2012, seized capsules containing white powder were analyzed to show the presence of unknown steroid-related compounds. Subsequent gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) investigations identified a mixture of 3α- and 3β- isomers of the novel compound; 3-chloro-17α-methyl-5α-androstan-17β-ol. Synthesis of authentic reference materials followed by comparison of NMR, GC-MS and gas chromatography-tandem mass spectrometry (GC-MS/MS) data confirmed the finding of a new ‘designer’ steroid. Furthermore, in vitro androgen bioassays showed potent activity highlighting the potential for doping using this steroid. Due to the potential toxicity of the halogenated steroid, in vitro metabolic investigations of 3α-chloro-17α-methyl-5α-androstan-17β-ol using equine and human S9 liver fractions were performed. For equine, GC-MS/MS analysis identified the diagnostic 3α-chloro-17α-methyl-5α-androstane-16α,17β-diol metabolite. For human, the 17α-methyl-5α-androstane-3α,17β-diol metabolite was found. Results from these studies were used to verify the ability of GC-MS/MS precursor-ion scanning techniques to support untargeted detection strategies for designer steroids in anti-doping analyses. Copyright © 2015 John Wiley & Sons, Ltd.
    Drug Testing and Analysis 06/2015; DOI:10.1002/dta.1832 · 2.51 Impact Factor
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    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 · 0.02 Impact Factor
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    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 · 6.21 Impact Factor
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    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; 16(7). DOI:10.1016/j.jamda.2015.02.014 · 4.94 Impact Factor
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    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; 16(7). DOI:10.1016/j.jamda.2015.02.006 · 4.94 Impact Factor

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12k Citations
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  • 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
    • Sydney Orthopaedic Research Institute
      Sydney, New South Wales, Australia
    • Concord Hospital
      Concord, New Hampshire, United States
    • University of Turku
      Turku, Varsinais-Suomi, Finland
  • 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
  • 2009
    • National Measurement Institute
      Sydney, New South Wales, Australia
  • 1986-2009
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
    • University of California, Los Angeles
      Los Ángeles, California, United States
  • 1980-2009
    • Royal Prince Alfred Hospital
      • • Division of Endocrinology
      • • Department of Medical Oncology
      • • Department of Molecular and Clinical Genetics
      Camperdown, New South Wales, Australia
  • 2007
    • University of Melbourne
      Melbourne, Victoria, Australia
    • Erasmus Universiteit Rotterdam
      Rotterdam, South Holland, Netherlands
    • Royal Perth Hospital
      Perth City, Western Australia, Australia
  • 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