%0 Journal Article %~ PubMed %A McNamara, Keely M %A Nakamura, Yasuhiro %A Sasano, Hironobu %A Handelsman, David J %A Simanainen, Ulla %T Prostate epithelial AR inactivation leads to increased intraprostatic androgen synthesis. %B The Prostate %D 2013 %C United States %I John Wiley & Sons, Inc. %V 73 %N 3 %P 316-327 %@ 1097-0045 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Drummond, Eleanor S %A Martins, Ralph N %A Handelsman, David J %A Harvey, Alan R %T Altered expression of Alzheimer's disease-related proteins in male hypogonadal mice. %B Endocrinology %D 2012 %C United States %I The Endocrine Society %V 153 %N 6 %P 2789-2799 %@ 0013-7227 %X Age-related depletion of estrogens and androgens is associated with an increase in Alzheimer''s disease (AD) brain pathology and diminished cognitive function. Here we investigated AD-associated molecular and cellular changes in brains of aged hypogonadal (hpg) male and female mice. hpg Mice have a spontaneous, inactivating genetic mutation in the GnRH gene resulting in life-long deficiency of gonadotropins and gonadal sex hormones. Western blot analysis revealed low levels of amyloid precursor protein and high levels of presenilin 1, amyloid precursor protein C-terminal fragment, and ?-amyloid 42 in brains of aged male, but not female, hpg mice. Changes were confined to the hippocampus and were not evident in the cerebellum or other brain tissues. Male hpg mice tended to have lower levels of IL-1? protein than male littermate controls. Immunohistochemical staining of the basal forebrain revealed that male hpg mice had lower choline acetyltransferase levels per neuron compared with controls. These AD-like changes specific to male hpg mice supports a link between androgen depletion and the development of AD pathology. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Barroso, Osquel %A Handelsman, David J %A Strasburger, Christian %A Thevis, Mario %T Analytical challenges in the detection of peptide hormones for anti-doping purposes. %B Bioanalysis %D 2012 %C United Kingdom %I Future Science Ltd. %V 4 %N 13 %P 1577-1590 %@ 1757-6199 %X %Z FOR Codes: 110306 111599 %0 Journal Article %~ PubMed %A Simanainen, Ulla %A Gao, Yan Ru %A Walters, Kirsty A %A Watson, Geoff %A Desai, Reena %A Jimenez, Mark %A Handelsman, David J %T Androgen Resistance in Female Mice Increases Susceptibility to DMBA-Induced Mammary Tumors. %B Hormones & Cancer %D 2012 %C United States %I Springer New York LLC %V 3 %N 3 %P 113-124 %@ 1868-8500 %X Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation. The effect of AR inactivation and influence of genetic background on 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis was confirmed using two separate ARKO models with different genetic backgrounds. The onset of palpable mammary tumors was significantly faster in ARKO females (median time 22 vs 34 weeks, respectively; (p?=?0.0024; multivariate Cox regression) compared to WT and independent of the mouse genetic background. The cumulative incidence at 9 months was 81?±?10% [mean?±?SE] for ARKO compared to 50?±?13% in WT females. The increased DMBA susceptibility of ARKO females was associated with a higher epithelial proliferation index but not with major structural or receptor (estrogen or progesterone) expression differences between the virgin WT or ARKO female mammary glands. AR inactivation allowed substantial ductal extension in ARKO males while WT males displayed only rudimentary epithelial branches or complete regression of epithelial structures. Yet, DMBA did not induce epithelial mammary tumors in WT or ARKO males, demonstrating that AR inactivation alone is insufficient to promote mammary tumors. These results demonstrate that AR inactivation accelerates mammary carcinogenesis in female mice exposed to the chemical carcinogen DMBA regardless of mouse genetic background but require prior exposure to endogenous ovarian hormones. %Z FOR Codes: 111209 110306 %0 Journal Article %A McGrath, K C Y %A Li, Xiaohong %A Gaus, K %A Williams, Paul %A Celermajer, Danielle %A Handelsman, David %A Heather, A K %T Androgens Rapidly Activate Nuclear Factor-Kappa B via Intracellular Ca2 Signalling in Human Vascular Endothelial Cells %B Journal of Steroids & Hormonal Science %D 2012 %C United States %I OMICS Publishing Group %V S2 %N %P 005 %@ 2157-7536 %X %Z FOR Codes: 60111 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Handelsman, David J %T DNA damage, NF-κB and accelerated aging %B Asian Journal of Andrology %D 2012 %C United States %I Nature Publishing Group %V 14 %N 6 %P 811¿812 %@ 1745-7262 %X %Z FOR Codes: 110308 110306 %0 Journal Article %~ PubMed %A Huhtinen, Kaisa %A Desai, Reena %A StÃ¥hle, Mia %A Salminen, Anu %A Handelsman, David J %A Perheentupa, Antti %A Poutanen, Matti %T Endometrial and Endometriotic Concentrations of Estrone and Estradiol Are Determined by Local Metabolism Rather than Circulating Levels. %B Journal of Clinical Endocrinology and Metabolism %D 2012 %C United States %I The Endocrine Society %V 97 %N 11 %P 4228-4235 %@ 1945-7197 %X %Z FOR Codes: 110306 %0 Journal Article %A Handelsman, David %A Simanainen, Ulla %A Walters, Kirsty %A Allan, Charles %T Estradiol Immunoassays for Mice: Not Fit for Purpose %B Endocrinology %D 2012 %C United States %I The Endocrine Society %V 152 %N %P 1501 %@ 0013-7227 %X %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Gnjidic, D %A Hilmer, S N %A Blyth, F M %A Naganathan, V %A Cumming, R G %A Handelsman, D J %A McLachlan, A J %A Abernethy, D R %A Banks, E %A Le Couteur, D G %T High-risk prescribing and incidence of frailty among older community-dwelling men. %B Clinical pharmacology and therapeutics %D 2012 %C United States %I Nature Publishing Group %V 91 %N 3 %P 521-528 %@ 1532-6535 %X Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men ?70 years of age. High-risk prescribing was defined as polypharmacy (?5 medicines), hyperpolypharmacy (?10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men. %Z FOR Codes: 111702 111503 %0 Journal Article %~ PubMed %A Conway, Ann J %A Hamblin, Julie C %A Handelsman, David J %T Hormone treatment of gender identity disorder in a cohort of children and adolescents. %B Medical Journal of Australia %D 2012 %C Australia %I Australasian Medical Publishing Company Pty. Ltd %V 197 %N 5 %P 273 %@ 1326-5377 %X %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Stanaway, Fiona F %A Cumming, Robert %A Waite, Louise %A Blyth, Fiona %A Naganathan, Vasi %A Handelsman, David J %A Le Couteur, David G %T Mild Cognitive Impairment Predicts Institutionalization among Older Men: A Population-Based Cohort Study. %B PLoS One %D 2012 %C United States %I Public Library of Science %V 7 %N 9 %P e46061 %@ 1932-6203 %X %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Sivananthan, Thilee %A Bathur, Franz %A Jimenez, Mark %A Conway, Ann %A Idan, Amanda %A Handelsman, David %T Objective non-intrusive markers of sperm production and sexual activity. %B Asian Journal of Andrology %D 2012 %C United States %I Nature Publishing Group %V 14 %N 3 %P 476-480 %@ 1745-7262 %X Objective studies of men''s reproductive function are hindered by their reliance on: (i) self-reporting to quantify sexual activity and (ii) masturbation to quantify sperm output rendering both types of estimate vulnerable to unverifiable subjective factors. We therefore examined whether detection of spermatozoa and measurement of prostate-specific antigen (PSA) in urine could provide objective semiquantitative estimates of sperm output and recent ejaculation, respectively, using widely available laboratory techniques. Of 11 healthy volunteers who provided urine samples before and at intervals for 5 days after ejaculation, sperm was present in 2/11 men before, and in all 11/11 samples immediately after ejaculation, but by the second and subsequent void, spermatozoa were present in ???10%. PSA was detectable at high levels in all urine samples, peaking at the first post-ejaculatory sample but returning to baseline levels by the second post-ejaculatory void. We conclude that urinary spermatozoa and PSA are objective biomarkers for sperm production and sexual activity, but only for a short-time window until the first post-ejaculatory urine void. Hence, for a single urine specimen, the presence of spermatozoa and PSA are valid biomarkers, reflecting sperm production and recent ejaculation only until the next micturition, so their measurement should be restricted to the first morning urine void. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Handelsman, David J %T Pharmacoepidemiology of testosterone prescribing in Australia, 1992-2010. %B Medical Journal of Australia %D 2012 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 196 %N 10 %P 642-645 %@ 1326-5377 %X OBJECTIVE: The progressive increase in PBS-subsidised testosterone prescribing without changes in proven medical indications or improvements in diagnosis of pathologically based androgen deficiency are likely to be due to promotion-driven non-compliance with PBS prescribing criteria, indicating that more effective implementation of the criteria is needed. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Hilmer, Sarah N %A Blyth, Fiona M %A Naganathan, Vasi %A Waite, Louise %A Seibel, Markus J %A McLachlan, Andrew J %A Cumming, Robert G %A Handelsman, David J %A Le Couteur, David G %T Polypharmacy cutoff and outcomes: five or more medicines were used to identify community-dwelling older men at risk of different adverse outcomes. %B Journal of Clinical Epidemiology %D 2012 %C United States %I Elsevier Inc. %V 65 %N 9 %P 989-995 %@ 0895-4356 %X OBJECTIVE: This study aimed to determine an optimal discriminating number of concomitant medications associated with geriatric syndromes, functional outcomes, and mortality in community-dwelling older men. STUDY DESIGN AND SETTING: Older men aged ???70 years (n=1,705), enrolled in the Concord Health and Aging in Men Project were studied. Receiver operating characteristic curve analysis using the Youden Index and the area under the curve was performed to determine discriminating number of medications in relation to each outcome. RESULTS: The highest value of the Youden Index for frailty was obtained for a cutoff point of 6.5 medications compared with a cutoff of 5.5 for disability and 3.5 for cognitive impairment. For mortality and incident falls, the highest value of Youden Index was obtained for a cutoff of 4.5 medications. For every one increase in number of medications, the adjusted odds ratios were 1.13 (95% confidence interval [CI]=1.06-1.21) for frailty, 1.08 (95% CI=1.00-1.15) for disability, 1.09 (95% CI=1.04-1.15) for mortality, and 1.07 (95% CI=1.03-1.12) for incident falls. There was no association between increasing number of medications and cognitive impairment. CONCLUSION: The study supports the use of five or more medications in the current definition of polypharmacy to estimate the medication-related adverse effects for frailty, disability, mortality, and falls. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Litchfield, Melisa J %A Cumming, Robert G %A Smith, David P %A Naganathan, Vasi %A Le Couteur, David G %A Waite, Louise M %A Blyth, Fiona M %A Handelsman, David J %T Prostate-specific antigen levels in men aged 70 years and over: findings from the CHAMP study. %B Medical Journal of Australia %D 2012 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 196 %N 6 %P 395-398 %@ 1326-5377 %X To describe values of serum prostate-specific antigen (PSA) in older men without diagnosed prostate cancer, categorised by age and country of birth, and to describe self-reported prostate cancer screening. %Z FOR Codes: 111404 110308 %0 Journal Article %~ PubMed %A Yeap, Bu B %A Alfonso, Helman %A Chubb, S A Paul %A Handelsman, David J %A Hankey, Graeme J %A Norman, Paul E %A Flicker, Leon %T Reference Ranges and Determinants of Testosterone, Dihydrotestosterone, and Estradiol Levels Measured using Liquid Chromatography-Tandem Mass Spectrometry in a Population-Based Cohort of Older Men. %B Journal of Clinical Endocrinology and Metabolism %D 2012 %C United States %I The Endocrine Society %V 97 %N 11 %P 4030-4039 %@ 1945-7197 %X %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Walters, Kirsty A %A Allan, Charles M %A Handelsman, David J %T Rodent models for human polycystic ovary syndrome. %B Biology of Reproduction %D 2012 %C United States %I Society for the Study of Reproduction %V 86 %N 5 %P 149 %@ 1529-7268 %X Polycystic ovary syndrome (PCOS) is the most frequent female endocrine disorder, affecting 5%-10% of women, causing infertility due to dysfunctional follicular maturation and ovulation, distinctive multicystic ovaries and hyperandrogenism, together with metabolic abnormalities including obesity, hyperinsulinism, an increased risk of type 2 diabetes, and cardiovascular disease. The etiology of PCOS is unclear, and decisive clinical studies are limited by ethical and logistic constraints. Consequently treatment is palliative rather than curative and focuses on symptomatic approaches. Hence, a suitable animal model could provide a valuable means with which to study the pathogenesis of the characteristic reproductive and metabolic abnormalities and thereby identify novel and more effective treatments. So far there is no consensus on the best experimental animal model, which should ideally reproduce the key features associated with human PCOS. The prenatally androgenized rhesus monkey displays many characteristics of the human condition, including hyperandrogenism, anovulation, polycystic ovaries, increased adiposity, and insulin insensitivity. However, the high cost of nonhuman primate studies limits the practical utility of these large-animal models. Rodent models, on the other hand, are inexpensive, provide well-characterized and stable genetic backgrounds readily accessible for targeted genetic manipulation, and shorter reproductive life spans and generation times. Recent rodent models display both reproductive and metabolic disturbances associated with human PCOS. This review aimed to evaluate the rodent models reported to identify the advantages and disadvantages of the distinct rodent models used to investigate this complex endocrine disorder. %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Rodriguez, Esequiel %A Weiss, Dana A %A Ferretti, Max %A Wang, Hong %A Menshenia, Julia %A Risbridger, Gail %A Handelsman, David %A Cunha, Gerald %A Baskin, Laurence %T Specific morphogenetic events in mouse external genitalia sex differentiation are responsive/dependent upon androgens and/or estrogens. %B Differentiation %D 2012 %C United Kingdom %I Elsevier Ltd. %V 84 %N 3 %P 269-279 %@ 1432-0436 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Walters, Kirsty A %A Middleton, Linda J %A Joseph, Shai R %A Hazra, Rasmani %A Jimenez, Mark %A Simanainen, Ulla %A Allan, Charles M %A Handelsman, David J %T Targeted loss of androgen receptor signaling in murine granulosa cells of preantral and antral follicles causes female subfertility. %B Biology of Reproduction %D 2012 %C United States %I Society for the Study of Reproduction %V 87 %N 6 %P 151 %@ 1529-7268 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Hazra, Rasmani %A Corcoran, Lisa %A Robson, Mat %A McTavish, Kirsten J %A Upton, Dannielle %A Handelsman, David J %A Allan, Charles M %T Temporal Role of Sertoli Cell Androgen Receptor Expression in Spermatogenic Development. %B Molecular Endocrinology %D 2012 %C United States %I The Endocrine Society %V 27 %N 1 %P 12-24 %@ 1944-9917 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Purves-Tyson, Tertia D %A Handelsman, David J %A Double, Kay L %A Owens, Samantha J %A Bustamante, Sonia %A Weickert, Cynthia Shannon %T Testosterone regulation of sex steroid-related mRNAs and dopamine-related mRNAs in adolescent male rat substantia nigra. %B BMC Neuroscience %D 2012 %C United Kingdom %I BioMed Central Ltd. %V 13 %N 1 %P 95 %@ 1471-2202 %X %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A McNamara, Keely %A Handelsman, David %A Simanainen, Ulla %T The mouse as a model to investigate sex steroid metabolism in the normal and pathological prostate. %B Journal of Steroid Biochemistry and Molecular Biology %D 2012 %C United Kingdom %I Pergamon %V 131 %N 3-5 %P 107-121 %@ 1879-1220 %X Metabolism of sex steroids within the prostate is an important factor affecting its growth and pathology. Mouse models with genetic gain- and especially loss-of-function have characterised different steroid metabolic pathways and their contribution to prostate pathology. With reference to the human prostate, this review aims to summarize the steroidogenic pathways in the mouse prostate as the basis for using the mouse as a model for intraprostatic steroid signalling. In this review we summarize the current information for three main components of the steroid signalling pathway in the mouse prostate: circulating steroids, steroid receptors and steroidogenic enzymes with regard to signalling via androgen, estrogen, progesterone and glucocorticoid pathways. This review reveals many opportunities for characterisation steroid metabolism in various mouse models. The knowledge of steroid metabolism within prostate tissue and in a lobe (rodent)/region (human) specific manner, will give valuable information for future, novel hypotheses of intraprostatic control of steroid actions. This review summarizes knowledge of steroid metabolism in the mouse prostate and its relevance to the human. Article from the Special Issue on "Steroids and cancer". %Z FOR Codes: 111207 111404 %0 Journal Article %~ PubMed %A Steinbeck, Katharine %A Hazell, Philip %A Cumming, Robert G %A Skinner, S Rachel %A Ivers, Rebecca %A Booy, Robert %A Fulcher, Greg %A Handelsman, David J %A Martin, Andrew J %A Morgan, Geoff %A Starling, Jean %A Bauman, Adrian %A Rawsthorne, Margot L %A Bennett, David L %A Chow, Chin Moi %A Lam, Mary K %A Kelly, Patrick %A Brown, Ngiare J %A Paxton, Karen %A Hawke, Catherine %T The study design and methodology for the ARCHER study - adolescent rural cohort study of hormones, health, education, environments and relationships. %B BMC Pediatrics %D 2012 %C United Kingdom %I BioMed Central Ltd. %V 12 %N 1 %P 143 %@ 1471-2431 %X %Z FOR Codes: 111403 111706 %0 Journal Article %~ PubMed %A Handelsman, David J %T An old emperor finds new clothing: rejuvenation in our time. %B Asian Journal of Andrology %D 2011 %C United States %I Nature Publishing Group %V 13 %N 1 %P 125-129 %@ 1745-7262 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Handelsman, David J %T Androgen misuse and abuse. %B Best Practice & Research. Clinical Endocrinology & Metabolism %D 2011 %C United Kingdom %I Bailliere Tindall %V 25 %N 2 %P 377-389 %@ 1532-1908 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Simanainen, Ulla %A McNamara, Keely %A Gao, Yan Ru %A McPherson, Stephen %A Desai, Reena %A Jimenez, Mark %A Handelsman, David J %T Anterior prostate epithelial AR inactivation modifies estrogen receptor expression and increases estrogen sensitivity. %B American journal of physiology. Endocrinology and metabolism %D 2011 %C United States %I American Physiological Society %V 301 %N 4 %P E727-35 %@ 1522-1555 %X Androgens influence prostate growth and development, so androgen withdrawal can control progression of prostate diseases. Although estrogen treatment was originally used to induce androgen withdrawal, more recently direct estrogen effects on the prostate have been recognized, but the nature of androgen-estrogen interactions within the prostate remain poorly understood. To characterize androgen effects on estrogen sensitivity in the mouse prostate, we contrasted models of castration-induced androgen withdrawal in the prostate stromal and epithelial compartments with a prostate epithelial androgen receptor (AR) knockout (PEARKO) mouse model of selective epithelial AR inactivation. Castration markedly increased prostate epithelial estrogen receptor (ER)?? immunoreactivity compared with very low ER?? expression in intact males. Similarly, strong basal and luminal ER?? expression was detected in PEARKO prostate of intact males, suggesting that epithelial AR activity regulated epithelial ER?? expression. ER?? was strongly expressed in intact, castrated, and PEARKO prostate. However, strong clusters of epithelial ER?? positivity coincided with epithelial stratification in PEARKO prostate. In vivo estrogen sensitivity was increased in PEARKO males, with greater estradiol-induced prostate growth and epithelial proliferation leading to squamous metaplasia, featuring markedly increased epithelial proliferation, thickening, and keratinization compared with littermate controls. Our results suggest that ER?? expression in the prostate epithelial cells is regulated by local, epithelia-specific, androgen-dependent mechanisms, and this imbalance in the AR- and ER-mediated signaling sensitizes the mature prostate to exogenous estrogens. %Z FOR Codes: 111207 111404 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Blyth, Fiona M %A Cumming, Robert G %A Naganathan, Vasi %A Handelsman, David J %A Waite, Louise M %A Sambrook, Philip N %A Creasey, Helen M %A Seibel, Markus J %A Le Couteur, David G %T Back pain in older male Italian-born immigrants in Australia: The importance of socioeconomic factors. %B European Journal of Pain %D 2011 %C United Kingdom, Belg %I Elsevier Ltd %V 15 %N 1 %P 70-76 %@ 1532-2149 %X Back pain is common in older people and is associated with functional disability and poor self-rated health. Older persons are under-represented in back pain research, and research on back pain in older persons from ethnic minorities is particularly sparse. We investigated differences in back pain characteristics, effects and medication use in a population-based sample of 335 Italian-born immigrants and 849 Australian-born men aged 70 years and over. There were 189 (62%) Italian-born men and 507 (63%) Australian-born men who reported experiencing back pain in the past 12 months. Despite no difference in the reported prevalence of back pain between the two groups of men, Italian-born men were more likely to report that their pain was frequent, severe and chronic. Italian-born men were also more likely to report having other sites of pain and that they had limited their activities in the past 12 months due to back pain. Despite these differences, the use of analgesic medication was the same in both groups. Multivariate analyses showed that differences in pain characteristics and effects between the two groups of men were explained by socioeconomic factors such as years of education and occupation history. %Z FOR Codes: 111702 %0 Journal Article %~ PubMed %A Travison, Thomas G %A Nguyen, Anh-Hoa %A Naganathan, Vasi %A Stanaway, Fiona F %A Blyth, Fiona M %A Cumming, Robert G %A Le Couteur, David G %A Sambrook, Philip N %A Handelsman, David J %T Changes in Reproductive Hormone Concentrations Predict the Prevalence and Progression of the Frailty Syndrome in Older Men: The Concord Health and Ageing in Men Project. %B Journal of Clinical Endocrinology and Metabolism %D 2011 %C United States %I The Endocrine Society %V 96 %N 8 %P 2464-2474 %@ 1945-7197 %X Frailty, a syndrome of multiple morbidity, weakness, and immobility in aging, is an increasingly urgent threat to public health. Single measures of low serum androgen have been associated with frailty in men, but the contributory role of hormonal changes with time is unassessed. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Handelsman, David J %T Commentary: androgens and "anabolic steroids": the one-headed janus. %B Endocrinology %D 2011 %C United States %I The Endocrine Society %V 152 %N 5 %P 1752-1754 %@ 0013-7227 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Benson, Vicky L %A McMahon, Aisling C %A Blyth, Fiona %A Handelsman, David J %A Seibel, Markus J %A Kennerson, Marina %A Naganathan, Vasi %A Cumming, Robert G %A de Cabo, Rafael %T Determinants of Serum-Induced SIRT1 Expression in Older Men: The CHAMP Study. %B Journals of Gerontology. Series A: Biological Sciences & Medical Sciences %D 2011 %C United States %I Oxford University Press %V 66 %N 1 %P 3-8 %@ 1758-535X %X Circulating factors that have an effect on SIRT1 expression are influenced by caloric restriction. To determine the association between frailty and such circulating factors, we measured serum-induced SIRT1 expression from a nested cohort of frail (n = 77) and robust (n = 82) participants from Concord Health and Ageing in Men Project, a population-based study of community-dwelling men older than 70 years. Serum-induced SIRT1 expression was not different between frail and robust men (103.1 ?? 17.0 versus 100.4 ?? 19.3 ??g/L). However, subsequent analyses showed that men with the lowest values (first quartile) were less likely to be frail (odds ratio = 0.5, 95% confidence interval = 0.2-1.0, p = .04) and had higher total body lean mass (p = .001) than the other participants. Serum-induced SIRT1 expression did not correlate with age, diseases, medications, albumin, fasting glucose, or lipids. Overall, there was no association between frailty and serum-induced SIRT1 expression; however, post hoc analysis suggested that there might be a paradoxical association between low serum-induced SIRT1 expression and robustness. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Handelsman, David J %A Turner, Leo A %A Conway, Ann J %T Doctors breaching patient privacy: Orwell redux. %B The Medical Journal of Australia %D 2011 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 194 %N 8 %P 403-404 %@ 1326-5377 %X Legislative changes made without public discussion allow disclosure without patient consent. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Cumming, Robert G %A Naganathan, Vasi %A Blyth, Fiona M %A Handelsman, David J %A Le Couteur, David G %A Waite, Louise M %A Creasey, Helen M %A Seibel, Markus J %A Sambrook, Philip N %T Ethnicity and falls in older men: low rate of falls in Italian-born men in Australia. %B Age and Ageing %D 2011 %C United Kingdom %I Oxford University Press %V 40 %N 5 %P 595-601 %@ 0002-0729 %X past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts. %Z FOR Codes: 111706 %0 Journal Article %~ PubMed %A Akram, Omar N %A Bursill, Christina %A Desai, Reena %A Heather, Alison K %A Kazlauskas, Rymantas %A Handelsman, David J %A Lambert, Gilles %T Evaluation of androgenic activity of nutraceutical-derived steroids using mammalian and yeast in vitro androgen bioassays. %B Analytical Chemistry %D 2011 %C United States %I American Chemical Society %V 83 %N 6 %P 2065-2074 %@ 1520-6882 %X Androgenic steroids marketed online as nutraceuticals are a growing concern in sport doping. The inability of conventional mass spectrometry (MS)-based techniques to detect structurally novel androgens has led to the development of in vitro androgen bioassays to identify such designer androgens by their bioactivity. The objective of this study was to determine the androgenic bioactivity of novel steroidal compounds isolated from nutraceuticals using both yeast and mammalian cell-based androgen bioassays. We developed two new in vitro androgen bioassays by stably transfecting HEK293 and HuH7 cells with the human androgen receptor (hAR) expression plasmid together with a novel reporter gene vector (enhancer/ARE/SEAP). The yeast ??-galactosidase androgen bioassay was used for comparison. Our new bioassay featuring the enhancer/ARE/SEAP construct (-S) displayed simpler assay format and higher specificity with lower sensitivity compared with the commonly used mouse mammary tumour virus (MMTV)-luciferase. The relative potencies (RP), defined as [EC(50)] of testosterone/[EC(50)] of steroid, of nutraceutical extracts in the yeast, HEK293-S, and HuH7-S, were 34, 333, and 80,000 for Hemapolin; 208, 250, and 80 for Furazadrol; 0.38, 10, and 106 for Oxyguno; 2.7, 0.28, and 15 for Trena; and 4.5, 0.1, and 0.4 for Formadrol, respectively. The wide discrepancies in rank RP of these compounds was reconciled into a consistent potency ranking when the cells were treated with meclofenamic acid, a nonselective inhibitor of steroid metabolizing enzymes. These findings indicate that steroids extracted from nutraceuticals can be converted in vitro into more or less potent androgens in mammalian but not in yeast cells. We conclude that the putative androgenic bioactivity of a new compound may depend on the bioassay cellular format and that mammalian cell bioassays may have an added benefit in screening for proandrogens but sacrifice specificity for sensitivity in quantitation. %Z FOR Codes: 110306 111404 110604 %0 Journal Article %A Handelsman, David %A Allan, Charles %A Walters, Kirsty %A Simanainen, Ulla %T Genetic models for hormonal regulation of reproduction %B Australian Biochemist %D 2011 %C Australia %I Australian Society for Biochemistry and Molecular %V 42 %N 1 %P 4-7 %@ 0000-0000 %X %Z FOR Codes: 111404 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Gnjidic, Danijela %A Blyth, Fiona M %A Le Couteur, David G %A Naganathan, Vasi %A Waite, Louise %A Seibel, Markus J %A Handelsman, David J %A Sambrook, Philip N %A Cumming, Robert G %T How fast does the Grim Reaper walk? Receiver operating characteristics curve analysis in healthy men aged 70 and over. %B BMJ %D 2011 %C United Kingdom %I BMJ Publishing Group %V 343 %N %P d7679 %@ 1468-5833 %X To determine the speed at which the Grim Reaper (or Death) walks. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Birzniece, Vita %A Meinhardt, Udo J %A Umpleby, Margot A %A Handelsman, David J %A Ho, Ken K Y %T Interaction between Testosterone and Growth Hormone on Whole-Body Protein Anabolism Occurs in the Liver. %B The Journal of Clinical Endocrinology and Metabolism %D 2011 %C United States %I The Endocrine Society %V 96 %N 4 %P 1060-1067 %@ 1945-7197 %X Context: GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. Objective: Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. Design: In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. Patients and Intervention: Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. Main Outcome Measures: Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. Results: In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. Conclusions: In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Blyth, F M %A Cumming, R G %A Nicholas, M K %A Creasey, H %A Handelsman, D J %A Le Couteur, D G %A Naganathan, V %A Sambrook, P N %A Seibel, M J %A Waite, L M %T Intrusive pain and worry about health in older men: The CHAMP study. %B Pain %D 2011 %C Netherlands, United States %I Elsevier BV %V 152 %N 2 %P 447-52 %@ 0304-3959 %X The role of anxiety in pain is less well understood than the role of depression. Based on recent conceptual thinking about worry and pain, we explored the relationship between pain status and worry about health and anxiety in 1217 community-dwelling men aged 70 years or older who participated in the baseline phase of the Concord Health and Ageing in Men Project study, a large population-based epidemiological study of healthy ageing based in Sydney, Australia. We hypothesised that worry about health would be associated with having persistent pain, and that the association would be stronger in the presence of co-existing pain-related interference with activities (intrusive pain). Of men in the study, 12.5% had persistent and intrusive pain, 22.4% were worried about their health, and 6.3% had anxiety. We found a strong association between worry about health and pain that was both persistent and intrusive, and that remained after accounting for age, number of comorbidities, depression, self-rated health status, arthritis, and gait speed (adjusted odds ratio 2.9; 95% confidence interval 1.8-4.7), P<0.0001). The corresponding adjusted odds ratio for the association between anxiety and pain was 2.3 (95% confidence interval 1.0-4.8; P=0.0363). These findings suggest that at a population level, subthreshold anxiety and pain are strongly related, and worry about health occurs much more commonly than anxiety itself. To our knowledge, this is the first study to explore, specifically, the relationship between pain status and worry about health in older men. In older community-dwelling men, pain was robustly associated with worry about health, highlighting the potential importance of subthreshold anxiety-related psychological factors. %Z FOR Codes: 111706 170106 %0 Journal Article %~ PubMed %A Simanainen, Ulla %A Brogley, Michele %A Gao, Yan Ru %A Jimenez, Mark %A Harwood, D Tim %A Handelsman, David J %A Robins, Diane M %T Length of the human androgen receptor glutamine tract determines androgen sensitivity in vivo. %B Molecular and cellular endocrinology %D 2011 %C Ireland %I Elsevier Ireland Ltd %V 342 %N 1-2 %P 81-6 %@ 1872-8057 %X A well established functional polymorphism of the human androgen receptor (hAR) is the length of AR''s N-terminal glutamine tract (Q-tract). This tract is encoded by a CAG trinucleotide repeat and varies from 8 to 33 codons in the healthy population. Q-tract length is inversely correlated with AR transcriptional activity in vitro, but whether endogenous androgen action is affected is not consistently supported by results of clinical and epidemiological studies. To test whether Q-tract length influences androgen sensitivity in vivo, we examined effects of controlled androgen exposure in "humanized" mice with hAR knock-in alleles bearing 12, 21 or 48 CAGs. Mature male mice were analyzed before or 2weeks after orchidectomy, with or without a subdermal dihydrotestosterone (DHT) implant to attain stable levels of this non-aromatizable androgen. The validity of this DHT clamp was demonstrated by similar serum levels of DHT and its two primary 3??Diol and 3??Diol metabolites, regardless of AR Q-tract length. Q-tract length was inversely related to DHT-induced suppression of castrate serum LH (p=0.005), as well as seminal vesicle (SV) weight (p=0.005) and prostate lobe weights (p<0.006). This confirms that the hAR Q-tract polymorphism mediates in vivo tissue androgen sensitivity by impacting negative hypothalamic feedback and trophic androgen effects on target organs. In this manner, AR Q-tract length variation may influence numerous aspects of male health, from virilization to fertility, as well as androgen-dependent diseases, such as prostate cancer. %Z FOR Codes: 60699 %0 Journal Article %~ PubMed %A Handelsman, D J %T RFD Award Lecture 2010.Hormonal regulation of spermatogenesis: insights from constructing genetic models. %B Reproduction, fertility, and development %D 2011 %C Australia %I CSIRO Publishing %V 23 %N 4 %P 507-19 %@ 1031-3613 %X %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Nabipour, Iraj %A Sambrook, Philip N %A Blyth, Fiona M %A Janu, Margaret R %A Waite, Louise M %A Naganathan, Vasi %A Handelsman, David J %A Le Couteur, David G %A Cumming, Robert G %A Seibel, Markus J %T Serum uric acid is associated with bone health in older men: A cross-sectional, population-based study. %B Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research %D 2011 %C United States %I Wiley-Blackwell Publishing, Inc. %V %N 5 %P %@ 1523-4681 %X Serum uric acid (UA) is a strong endogenous antioxidant. As oxidative stress has been linked to osteoporosis, we examined the association between serum uric acid levels and bone mineral density (BMD), prevalent vertebral and non-vertebral fractures, and laboratory measures including calcitropic hormones and bone turnover markers. This cross-sectional analysis comprised 1705 community-dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population-based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median as compared to men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (??=0.12-0.14, p<0.001), serum calcium (??=0.11, p=0.001), parathyroid hormone (??=0.09, p=0.002), 25-hydroxy-vitamin D (??=0.09, p=0.005), and was negatively associated with urinary excretion aminoterminal cross-linked telopeptide of type I collagen (??=-0.09, p=0.006). Overall, serum UA accounted for 1.0-1.44% of the variances in BMD (R2=0.10-0.22). In multiple logistic regression analyses, above-median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck (odds ratio [OR]= 0.42, 95% confidence interval [CI] 0.22-0.81; p=0.010), lumbar spine (OR=0.44, 95%CI 0.23-0.86; p=0.016), and a lower prevalence of vertebral (OR=0.62, 95%CI 0.43-0.91; p=0.015) and non-vertebral (OR=0.54, 95% CI 0.31-0.95; p=0.035) fractures. In conclusion, higher serum uric acid levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and non-vertebral fractures in older men. ?? 2010 American Society for Bone and Mineral Research. %Z FOR Codes: 110306 110302 110322 %0 Journal Article %~ PubMed %A Bleicher, Kerrin %A Cumming, Robert G %A Naganathan, Vasikaran %A Travison, Thomas G %A Sambrook, Philip N %A Blyth, Fiona M %A Handelsman, David J %A Le Couteur, David G %A Waite, Louise M %A Creasey, Helen M %A Seibel, Markus J %T The role of fat and lean mass in bone loss in older men: Findings from the CHAMP study. %B Bone %D 2011 %C United States %I Elsevier Inc. %V 49 %N 6 %P 1299-1305 %@ 8756-3282 %X Weight loss is associated with bone loss; however, it is unclear whether loss of fat or loss of lean body mass plays the key role in this relationship. The aim of this longitudinal analysis was to clarify the relationship between hip BMD, hip BMC and whole body BMC with changes in fat and lean tissue mass in older men. %Z FOR Codes: 110308 %0 Journal Article %~ PubMed %A Allan, Charles M %A Handelsman, David J %T The skeleton gets a (reproductive) life. %B Asian Journal of Andrology %D 2011 %C United States %I Nature Publishing Group %V 13 %N 5 %P 651-652 %@ 1745-7262 %X %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Sieveking, Daniel P %A Lim, Patrick %A Chow, Renée W Y %A Dunn, Louise L %A Bao, Shisan %A McGrath, Kristine C Y %A Heather, Alison K %A Handelsman, David J %A Celermajer, David S %A Ng, Martin K C %T A sex-specific role for androgens in angiogenesis. %B The Journal of Experimental Medicine %D 2010 %C United States %I Rockefeller University Press %V 207 %N 2 %P 345-352 %@ 1540-9538 %X Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men. %Z FOR Codes: 104 %0 Journal Article %~ PubMed %A Ly, Lam P %A Sartorius, Gideon %A Hull, Laura %A Leung, Andrew %A Swerdloff, Ronald S %A Wang, Christina %A Handelsman, David J %T Accuracy of Calculated Free Testosterone Formulae In Men. %B Clinical endocrinology %D 2010 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 73 %N 3 %P 382-8 %@ 0300-0664 %X As reference laboratory methods for measuring free testosterone (FT) by equilibrium dialysis (ED) are laborious, costly and nonautomatable, FT levels are often calculated (cFT) rather than measured. However, the predictive accuracy of such estimates in routine use relative to laboratory measurements is not well defined. We provide a large-scale evaluation of the predictive accuracy for different FT formulae compared with laboratory ED measurement and an analysis of clinical factors that may influence accuracy. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Handelsman, David J %A Cooper, Trevor G %T Afterword to Semen Analysis in 21st Century Medicine special issue in Asian Journal of Andrology. %B Asian Journal of Andrology %D 2010 %C United States, China %I Nature Publishing Group %V 12 %N 1 %P 118-123 %@ 1745-7262 %X %Z FOR Codes: 110306 111404 %0 Book Section %A Handelsman, David %T Androgen Physiology, Pharmacology and Abuse %B Endocrinology 6th Edition %D 2010 %C United States %I Elsevier Inc %V %N %P 2469-2498 %@ 9781416055839 %E Jameson, J. Larry %E De Groot, Leslie J. %X %Z FOR Codes: 111404 111602 111502 %0 Journal Article %~ PubMed %A Maclean, Helen E %A Moore, Alison J %A Sastra, Stephen A %A Morris, Howard A %A Ghasem-Zadeh, Ali %A Rana, Kesha %A Axell, Anna-Maree %A Notini, Amanda J %A Handelsman, David J %A Seeman, Ego %A Zajac, Jeffrey D %A Davey, Rachel A %T DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females. %B The Journal of Endocrinology %D 2010 %C United Kingdom %I Society for Endocrinology %V 206 %N 1 %P 93-103 %@ 1479-6805 %X We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females; 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males; 3) determine the contribution of genomic AR-mediated actions to these gender differences; and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Stanaway, Fiona F %A Cumming, Robert G %A Naganathan, Vasi %A Blyth, Fiona M %A Creasey, Helen M %A Waite, Louise M %A Handelsman, David J %A Seibel, Markus J %T Depressive symptoms in older male Italian immigrants in Australia: the Concord Health and Ageing in Men Project. %B The Medical Journal of Australia %D 2010 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 192 %N 3 %P 158-162 %@ 0025-729X %X OBJECTIVE: To describe the prevalence of depressive symptoms in older male Italian-born Australian immigrants. DESIGN, PARTICIPANTS AND SETTING: Cross-sectional study of 335 Italian-born and 849 Australian-born men aged 70 years and over who completed written questionnaires and were interviewed in the baseline phase of the Concord Health and Ageing in Men Project (CHAMP). MAIN OUTCOME MEASURES: Depressive symptoms assessed by the short (15-item) form of the Geriatric Depression Scale; associations between depressive symptoms and country of birth. RESULTS: The prevalence of depressive symptoms in Italian-born men was 18%, almost twice the prevalence of 10% in Australian-born men (odds ratio [OR], 1.9; 95% CI, 1.2-3.0). After adjusting for socioeconomic and health factors, the relationship between country of birth and depressive symptoms was attenuated and no longer statistically significant (OR, 1.7; 95% CI, 0.9-3.0). The strongest confounders of the relationship between country of birth and depressive symptoms were source of income and satisfaction with social support. CONCLUSION: Male Italian-born immigrants aged over 70 years report more depressive symptoms than their Australian-born counterparts. This association appears to be explained by increased reliance on a government pension as the sole source of income and lower satisfaction with social support among Italian-born men. However, these findings need to be confirmed longitudinally. %Z FOR Codes: 111702 111706 %0 Journal Article %~ PubMed %A Holden, Carol A %A McLachlan, Robert I %A Pitts, Marian %A Cumming, Robert %A Wittert, Gary %A Ehsani, Johnathon P %A de Kretser, David M %A Handelsman, David J %T Determinants of male reproductive health disorders: the Men in Australia Telephone Survey (MATeS). %B BMC Public Health %D 2010 %C United Kingdom %I BioMed Central Ltd. %V 10 %N %P 96 %@ 1471-2458 %X The relationship between reproductive health disorders and lifestyle factors in middle-aged and older men is not clear. The aim of this study is to describe lifestyle and biomedical associations as possible causes of erectile dysfunction (ED), prostate disease (PD), lower urinary tract symptoms (LUTS) and perceived symptoms of androgen deficiency (pAD) in a representative population of middle-aged and older men, using the Men in Australia Telephone Survey (MATeS). %Z FOR Codes: 111404 %0 Book Section %A Brinkworth, Martin H. %A Handelsman, David %T Environmental influences on male reproductive health %B Andrology - Male Reproductive Health and Dysfunction %D 2010 %C Germany %I Springer-Verlag %V %N %P 365-390 %@ 9783540783541 %E Nieschlag, Eberhard %E Behre, Hermann M. %E Nieschlag, Susan %X %Z FOR Codes: 111404 %0 Journal Article %~ PubMed %A Mitchell, Sarah J %A Kirkpatrick, Carl M J %A Le Couteur, David G %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Blyth, Fiona M %A Waite, Louise M %A Handelsman, David J %A Cumming, Robert G %A Hilmer, Sarah N %T Estimation of lean body weight in older community-dwelling men. %B British Journal of Clinical Pharmacology %D 2010 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 69 %N 2 %P 118-127 %@ 1365-2125 %X WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? * Lean mass decreases with age while total body fat increases, leading to changes in the pharmacokinetics and pharmacodynamics of drugs. * Dual-energy X-ray absorptiometry (DXA) is a useful reference method to measure lean body weight but may not be readily utilized clinically. * Limited methods for measurement of lean body weight using easily obtainable participant characteristics, such as height and weight, have been validated for use in people aged > or =65 years. WHAT THIS STUDY ADDS * This study has shown that lean body weight can be estimated using three different equations from easily obtainable participant characteristics with results comparable to DXA-derived estimates. * These equations may be useful tools to estimate lean body weight in situations where DXA is not practical. AIMS Lean body weight (LBW) decreases with age while total body fat increases, altering drug pharmacokinetics. The aim of this study was to evaluate the ability of the LBW equation to predict dual-energy X-ray absorptiometry (DXA)-derived fat free mass (FFM(DXA)) in older community-dwelling males compared with that of two existing FFM equations: the Heitmann and Deurenberg equations. METHODS Data were obtained from 1655 older men enrolled in the Concord Health and Ageing in Men Project. The predictive performance of the LBW and FFM equations to predict FFM(DXA) accurately was assessed graphically using Bland-Altman plots and quantitatively for precision and bias using the method of Sheiner and Beal in all participants and in frailty and body mass index (BMI) subgroups. RESULTS The LBW and Heitmann equations consistently overestimated FFM(DXA) for all frailty and BMI subgroups with a mean difference [95% confidence interval (CI)] of 5.5 kg (-0.65, 11.63 kg) and 3.34 kg (-2.84, 9.64 kg), respectively. The Deurenberg equation overestimated FFM(DXA) for overweight participants but underestimated FFM(DXA) for not-frail participants, with a mean difference (95% CI) of 1 kg (-7.23, 5.25 kg) for all participants. CONCLUSION LBW and FFM estimated using these equations give results comparable to DXA-derived FFM. The LBW and Heitmann equations provide a more consistent estimate of FFM(DXA) in all frailty and BMI groups despite the Deurenberg equation having the smallest mean difference. Further studies to determine whether the LBW equation is a clinically useful substitute for weight when determining drug dose in older people appear warranted. %Z FOR Codes: 111502 110308 %0 Journal Article %~ PubMed %A Allan, Charles M %A Couse, John F %A Simanainen, Ulla %A Spaliviero, Jenny %A Jimenez, Mark %A Rodriguez, Karina %A Korach, Kenneth S %A Handelsman, David J %T Estradiol Induction of Spermatogenesis Is Mediated via an Estrogen Receptor-{alpha} Mechanism Involving Neuroendocrine Activation of Follicle-Stimulating Hormone Secretion. %B Endocrinology %D 2010 %C United States %I The Endocrine Society %V 151 %N 6 %P 2800-10 %@ 0013-7227 %X Both testosterone and its nonaromatizable metabolite dihydrotestosterone (DHT) induce spermatogenesis in gonadotropin-deficient hpg mice. Surprisingly, because aromatization is not required, estradiol (E2) also induces spermatogenesis and increases circulating FSH in hpg mice, but the mechanism remains unclear. We studied E2-induced spermatogenesis in hpg mice on an estrogen receptor (ER)-alpha (hpg/alphaERKO) or ERbeta (hpg/betaERKO) knockout or wild-type ER (hpg/WT) background treated with subdermal E2 or DHT implants for 6 wk. In hpg/WT and hpg/betaERKO, but not hpg/alphaERKO mice, E2 increased testis and epididymal weight, whereas DHT-induced increases were unaffected by ERalpha or ERbeta inactivation. E2 but not DHT treatment increased serum FSH (but not LH) in hpg/WT and hpg/betaERKO but not hpg/alphaERKO hpg mice. DHT or E2 alone increased (premeiotic) spermatogonia and (meiotic) spermatocytes without significant change in Sertoli cell numbers. DHT alone increased postmeiotic spermatids, regardless of ER presence, compared with variable ERalpha-dependent E2 postmeiotic responses. An ERalpha-mediated effect was confirmed by treating hpg mice for 6 wk by subdermal selective ER-alpha (16alpha-LE(2)) or ERbeta (8beta-VE(2)) agonist implants. ERalpha (but not ERbeta) agonist increased testis and epididymal weight, Sertoli cell, spermatogonia, meiotic, and postmeiotic germ cell numbers. Only ERalpha agonist markedly increased serum FSH, whereas either agonist induced small rises in serum LH. Administration of ERalpha agonist or E2 in the presence of functional ERalpha induced prominent gene expression of specific Sertoli (Eppin, Rhox5) and Leydig cell (Cyp11a1, Hsd3b1) markers. We conclude that E2-induced spermatogenesis in hpg mice involves an ERalpha-dependent neuroendocrine mechanism increasing blood FSH and Sertoli cell function. %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Sartorius, Gideon %A Fennell, Carolyn %A Spasevska, Sasa %A Turner, Leo %A Conway, Ann J %A Handelsman, David J %T Factors influencing time course of pain after depot oil intramuscular injection of testosterone undecanoate. %B Asian Journal of Andrology %D 2010 %C United States, China %I Nature Publishing Group %V 12 %N 2 %P 227-233 %@ 1745-7262 %X Pain following depot intramuscular (IM) injection of oil vehicle-based drugs has been little studied. This study aimed to determine prospectively the prevalence, determinants, severity and functional consequences of pain during the week after IM injection of 1 000 mg testosterone undecanoate (TU) in a 4-mL castor oil vehicle. Androgen-deficient men receiving regular T replacement therapy at an academic andrology clinic were recruited to report pain scores using a coloured visual linear analogue scale at seven times over the first day and daily for a week after a deep IM gluteal injection. The time course and covariables influencing pain scores were analysed by mixed model analysis of variance (ANOVA). Following 168 injections in 125 men, pain was reported by 80% of men, peaking immediately after injection, reaching only moderate severity, lasting 1-2 days and returning to baseline by day 4. The pain required little analgesic use and produced minimal interference in daily activities. The time course of pain scores was reproducible in the 43 men who underwent two consecutive injections. Pain was more severe in men who had an earlier painful injection, but less severe in older and more obese men. There were negligible differences in post-injection pain experience between experienced nurses administering injections. Deep IM gluteal injection of depot TU in 4-mL castor oil is well tolerated and post-injection pain is influenced by earlier painful injection experience, as well as age and obesity. %Z FOR Codes: 110306 111502 111404 %0 Journal Article %~ PubMed %A Allan, Charles M %A Kalak, Robert %A Dunstan, Colin R %A McTavish, Kirsten J %A Zhou, Hong %A Handelsman, David J %A Seibel, Markus J %T Follicle-stimulating hormone increases bone mass in female mice. %B Proceedings of the National Academy of Sciences of the United States of America %D 2010 %C United States %I National Academy of Sciences %V 107 %N 52 %P 22629-34 %@ 0027-8424 %X Elevated follicle-stimulating hormone (FSH) activity is proposed to directly cause bone loss independent of estradiol deficiency in aging women. Using transgenic female mice expressing human FSH (TgFSH), we now reveal that TgFSH dose-dependently increased bone mass, markedly elevating tibial and vertebral trabecular bone volume. Furthermore, TgFSH stimulated a striking accrual of bone mass in hypogonadal mice lacking endogenous FSH and luteinizing hormone (LH) function, showing that FSH-induced bone mass occurred independently of background LH or estradiol levels. Higher TgFSH levels increased osteoblast surfaces in trabecular bone and stimulated de novo bone formation, filling marrow spaces with woven rather than lamellar bone, reflective of a strong anabolic stimulus. Trabecular bone volume correlated positively with ovarian-derived serum inhibin A or testosterone levels in TgFSH mice, and ovariectomy abolished TgFSH-induced bone formation, proving that FSH effects on bone require an ovary-dependent pathway. No detectable FSH receptor mRNA in mouse bone or cultured osteoblasts or osteoclasts indicated that FSH did not directly stimulate bone. Therefore, contrary to proposed FSH-induced bone loss, our findings demonstrate that FSH has dose-dependent anabolic effects on bone via an ovary-dependent mechanism, which is independent of LH activity, and does not involve direct FSH actions on bone cells. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Handelsman, David J %A Cooper, Trevor G %T Foreword to Semen Analysis in 21st Century Medicine special issue in Asian Journal of Andrology. %B Asian Journal of Andrology %D 2010 %C United States, China %I Nature Publishing Group %V 12 %N 1 %P 7-10 %@ 1745-7262 %X %Z FOR Codes: 111404 %0 Journal Article %~ PubMed %A Rochat, Stephane %A Cumming, Robert G %A Blyth, Fiona %A Creasey, Helen %A Handelsman, David %A Le Couteur, David G %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Waite, Louise %T Frailty and use of health and community services by community-dwelling older men: the Concord Health and Ageing in Men Project. %B Age and Ageing %D 2010 %C United Kingdom %I Oxford University Press %V 39 %N 2 %P 228-233 %@ 0002-0729 %X BACKGROUND: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. METHODS: the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. RESULTS: overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. CONCLUSION: frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions. %Z FOR Codes: 110308 %0 Journal Article %A Donat, R. %A Lalaka, A. %A Lin, Betty %A Mitterdorfer, A.J. %A Handelsman, David %T How Useful Is Semen Cytology in the Non-Invasive Diagnosis of Prostate Cancer? %B Current Urology %D 2010 %C Switzerland %I S. Karger AG %V 4 %N 3 %P 119-124 %@ 1661-7649 %X %Z FOR Codes: 111202 %0 Journal Article %~ PubMed %A Bleicher, K %A Cumming, R G %A Naganathan, V %A Seibel, M J %A Sambrook, P N %A Blyth, F M %A Le Couteur, D G %A Handelsman, D J %A Creasey, H M %A Waite, L M %T Lifestyle factors, medications, and disease influence bone mineral density in older men: findings from the CHAMP study. %B Osteoporosis International %D 2010 %C United Kingdom %I Springer UK %V 22 %N 9 %P 2421-2437 %@ 1433-2965 %X Aging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Idan, Amanda %A Griffiths, Kaye A %A Harwood, D Tim %A Seibel, Markus J %A Turner, Leo %A Conway, Ann J %A Handelsman, David J %T Long-Term Effects of Dihydrotestosterone Treatment on Prostate Growth in Healthy, Middle-Aged Men Without Prostate Disease: A Randomized, Placebo-Controlled Trial. %B Annals of Internal Medicine %D 2010 %C United States %I American College of Physicians %V 153 %N 10 %P 621-632 %@ 0003-4819 %X Background: Benign prostatic hypertrophy increases with age and can result in substantially decreased quality of life for older men. Surgery is often required to control symptoms. It has been hypothesized that long-term administration of a nonamplifiable pure androgen might decrease prostate growth, thereby decreasing or delaying the need for surgical intervention. Objective: To test the hypothesis that dihydrotestosterone (DHT), a nonamplifiable and nonaromatizable pure androgen, reduces late-life prostate growth in middle-aged men. Design: Randomized, placebo-controlled, parallel-group trial. (Australian New Zealand Clinical Trials Registry number: ACTRN12605000358640) Setting: Ambulatory care research center. Participants: Healthy men (n = 114) older than 50 years without known prostate disease. Intervention: Transdermal DHT (70 mg) or placebo gel daily for 2 years. Measurements: Prostate volume was measured by ultrasonography; bone mineral density (BMD) and body composition were measured by dual-energy x-ray absorptiometry; and blood samples and questionnaires were collected every 6 months, with data analyzed by mixed-model analysis for repeated measures. Results: Over 24 months, there was an increase in total (29% [95% CI, 23% to 34%]) and central (75% [CI, 64% to 86%]; P ??0.2). Dihydrotestosterone treatment decreased spinal BMD (1.4% [CI, 0.6% to 2.3%]; P ??0.2) and increased serum aminoterminal propeptide of type I procollagen in the second year of the study compared with placebo. Dihydrotestosterone increased serum DHT levels and its metabolites (5??-androstane-3??,17??-diol and 5??-androstane-3??,17??-diol) and suppressed serum testosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone levels. Dihydrotestosterone increased hemoglobin levels (7% [CI, 5% to 9%]), serum creatinine levels (9% [CI, 5% to 11%]), and lean mass (2.4% [CI, 1.6% to 3.1%) but decreased fat mass (5.2% [CI, 2.6% to 7.7%]) (P <0.001 for all). Protocol-specific discontinuations due to DHT were asymptomatic increased hematocrit (n = 8), which resolved after stopping treatment, and increased prostate-specific antigen levels (n = 3; none with prostate cancer) in the DHT group. No serious adverse effects due to DHT occurred. Limitation: Negative findings on prostate growth cannot exclude adverse effects on the natural history of prostate cancer. Conclusion: Dihydrotestosterone treatment for 24 months has no beneficial or adverse effect on prostate growth but causes a decrease in spinal but not hip BMD. These findings have important implications for the wider use of nonsteroidal pure androgens in older men. Primary Funding Source: BHR Pharma. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Simanainen, Ulla %A Lampinen, Anita %A Henneicke, Holger %A Brennan, Tara C %A Heinevetter, Uta %A Harwood, D Tim %A McNamara, Keely %A Herrmann, Markus %A Seibel, Markus J %A Handelsman, David J %A Zhou, Hong %T Long-Term corticosterone treatment induced lobe-specific pathology in mouse prostate. %B The Prostate %D 2010 %C United States %I John Wiley & Sons, Inc %V 71 %N %P 289-97 %@ 1097-0045 %X Glucocorticoids influence prostate development and pathology, yet the underlying mechanisms including possible direct glucocorticoid effect on the prostate are not well characterized. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Hairi, Noran N %A Cumming, Robert G %A Naganathan, Vasi %A Handelsman, David J %A Le Couteur, David G %A Creasey, Helen %A Waite, Louise M %A Seibel, Markus J %A Sambrook, Philip N %T Loss of Muscle Strength, Mass (Sarcopenia), and Quality (Specific Force) and Its Relationship with Functional Limitation and Physical Disability: The Concord Health and Ageing in Men Project. %B Journal of the American Geriatrics Society %D 2010 %C United States %I Wiley-Blackwell Publishing, Inc. %V 58 %N 11 %P 2055-2062 %@ 0002-8614 %X OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. DESIGN: Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). SETTING: Elderly men living in a defined geographical region in Sydney, Australia. PARTICIPANTS: One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. MEASUREMENTS: Upper and lower extremity strength were measured using dynamometers for grip and quadriceps strength. Appendicular skeletal lean mass was assessed using dual X-ray absorptiometry. Muscle quality was defined as the ratio of strength to mass in upper and lower extremities. For each parameter, subjects in the lowest 20% of the distribution were defined as below normal. Functional limitation was assessed according to self-report and objective lower extremity performance measures. Physical disability was measured according to self-report questionnaire. RESULTS: After adjusting for important confounders, the prevalence ratio (PR) for poor quadriceps strength and self-reported functional limitation was 1.91 (95% confidence interval (CI)=1.10-2.40); for performance-based functional limitation the PR was 1.81 (95% CI=1.45-2.24). The adjusted PR for poor grip strength and physical disability in instrumental activities of daily living (IADLs) was 1.37 (95% CI=1.20-1.56). The adjusted PR for low skeletal lean mass (adjusted for fat mass) and physical disability in basic activities of daily living was 2.08 (95% CI=1.37-3.15). For muscle quality, the PR for lower extremity specific force and functional limitation and physical disability was stronger than upper extremity specific force. CONCLUSION: Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation. %Z FOR Codes: 111702 %0 Book Section %A Handelsman, David %T Male contraception %B Endocrinology 6th Edition %D 2010 %C United States %I Elsevier Inc %V %N %P 2580-2591 %@ 9781416055839 %E Jameson, J. Larry %E De Groot, Leslie J. %X %Z FOR Codes: 111404 %0 Journal Article %~ PubMed %A McNamara, K M %A Harwood, D T %A Simanainen, U %A Walters, K A %A Jimenez, M %A Handelsman, D J %T Measurement of sex steroids in murine blood and reproductive tissues by liquid chromatography-tandem mass spectrometry. %B The Journal of steroid biochemistry and molecular biology %D 2010 %C United Kingdom %I Pergamon %V 121 %N 3-5 %P 611-8 %@ 1879-1220 %X Accurate measurement of sex steroids is essential to evaluate mouse models for human reproductive development and disorders. The recent advent of liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays that match the sensitivity of steroid immunoassay could overcome problems arising from the limited specificity of steroid immunoassay. In this current study we validate a LC-MS/MS assay for the measurement of key sex steroids from murine serum and reproductive tissues. The assay gave excellent dilutional linearity (r(2)> or =0.98) and reproducibility (CV< or =10% of replicate samples) in serum and reproductive tissues with sensitive quantitation limits; testosterone (T; 2pg), dihydrotestosterone (DHT; 10pg), 5alpha-androstane-3alpha,17beta-diol (3alphaDiol; 40pg), 5alpha-androstane-3beta,17beta-diol (3betaDiol; 40pg), estradiol (E2; 0.5pg) and estrone (E1; 0.3pg). Using 0.1mL sample, T was the only consistently detectable steroid (detection limit 20pg/ml) in both male and female mouse serum. In the testis, T and DHT were quantifiable as were both diols at relatively high levels. Prostatic T levels were low and DHT was determined to be the most abundant androgen in this tissue. Uterine and ovarian levels of E2, E1 and T were measurable, with levels varying according to estrous cycle stage. Hence, we demonstrate that this LC-MS/MS method has the sensitivity, specificity and multi-analyte capability to offer accurate steroid profiling in mouse serum and reproductive tissues. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Chow, Renee W Y %A Handelsman, David J %A Ng, Martin K C %T Minireview: Rapid Actions of Sex Steroids in the Endothelium. %B Endocrinology %D 2010 %C United States %I The Endocrine Society %V 151 %N 6 %P 2411-22 %@ 0013-7227 %X The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades. %Z FOR Codes: 110306 110201 %0 Journal Article %~ PubMed %A Walters, K A %A Simanainen, U %A Handelsman, D J %T Molecular insights into androgen actions in male and female reproductive function from androgen receptor knockout models. %B Human reproduction update %D 2010 %C United Kingdom, Belg %I Oxford University Press %V 16 %N 5 %P 543-58 %@ 1460-2369 %X Androgens and the androgen receptor (AR) have well known roles in male reproduction, and recent genetic mouse models inactivating the Ar gene have conclusively defined a role for androgens in female reproduction. In males, AR gene inactivation severely disrupts spermatogenesis by interrupting completion of meiosis, thereby eliminating production of mature sperm leading to male sterility. These effects have overshadowed the study of additional post-meiotic androgen effects required for the production of fully functional spermatozoa, as well as the production of females with complete androgen insensitivity which cannot be produced by natural breeding. However, these limitations have been overcome by the creation of global and cell-specific AR knockout (ARKO) mouse models using Cre-LoxP genetic engineering. %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Bleicher, Kerrin %A Naganathan, Vasi %A Cumming, Robert G %A Seibel, Markus J %A Sambrook, Philip N %A Blyth, Fiona M %A Le Couteur, David G %A Handelsman, David J %A Waite, Louise M %A Creasey, Helen M %T Prevalence and treatment of osteoporosis in older Australian men: findings from the CHAMP study. %B The Medical Journal of Australia %D 2010 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 193 %N 7 %P 387-391 %@ 0025-729X %X OBJECTIVE: To determine the proportion of older Australian men who meet the Pharmaceutical Benefits Scheme (PBS) criteria for osteoporosis treatment and are receiving effective treatment. DESIGN AND SETTING: A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study focusing on the health of older men. Data were collected through questionnaires and clinical assessments. Bone mineral density (BMD) of the hip and spine was measured by dual x-ray absorptiometry (DXA). Vertebral deformities were identified from DXA lateral vertebral fracture assessment images. The study was conducted at Concord Hospital, Sydney, between January 2005??and May 2007. PARTICIPANTS: 1705??community-dwelling men aged 70??years or over from a defined geographical region around Concord Hospital. MAIN OUTCOME MEASURES: Prevalence of vertebral deformities; previous minimal trauma fractures; BMD T-scores ??? - 3; falls in the previous 12??months; use of bisphosphonates and calcium and vitamin D supplements. RESULTS: Of the 1705??men seen at baseline, 1626??completed all DXA scans and 401??(25%) met one or more of the PBS criteria for osteoporosis treatment. Ninety per cent of the men who met the PBS criteria were unaware they had osteoporosis. Of the men eligible for PBS-subsidised treatment, 39??(10%) reported use of a bisphosphonate, 56??(14%) had taken calcium supplements, and 28??(7%) had taken vitamin D supplements. Only three men had taken calcium, vitamin D and bisphosphonates in combination. CONCLUSIONS: Despite a high prevalence of osteoporosis in elderly Australian men, awareness, diagnosis and treatment of the condition remain very low. %Z FOR Codes: 110322 110306 %0 Journal Article %~ PubMed %A Fennell, Carolyn %A Sartorius, Gideon %A Ly, Lam P %A Turner, Leo %A Liu, Peter Y %A Conway, Ann J %A Handelsman, David J %T Randomized cross-over clinical trial of injectable vs. implantable depot testosterone for maintenance of testosterone replacement therapy in androgen deficient men. %B Clinical endocrinology %D 2010 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 73 %N 1 %P 102-9 %@ 0300-0664 %X Life-long testosterone replacement therapy (TRT) for younger men with organic androgen deficiency is best provided by depot testosterone (T) products. This study compared directly the two long-acting depot T products, subdermal T implants (TI) and injectable T undecanoate (TU) for maintenance of TRT. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Nabipour, I %A Cumming, R %A Handelsman, D J %A Litchfield, M %A Naganathan, V %A Waite, L %A Creasey, H %A Janu, M %A Le Couteur, D %A Sambrook, P N %A Seibel, M J %T Socioeconomic status and bone health in community-dwelling older men: the CHAMP Study. %B Osteoporosis International %D 2010 %C United Kingdom %I Springer UK %V 22 %N 5 %P 1343-1353 %@ 1433-2965 %X The association between socioeconomic status (SES) and bone health, specifically in men, is unclear. Based upon data from the large prospective Concord Health in Ageing Men Project (CHAMP) Study of community-dwelling men aged 70 years or over, we found that specific sub-characteristics of SES, namely, marital status, living circumstances, and acculturation, reflected bone health in older Australian men. %Z FOR Codes: 111702 111706 1117 %0 Journal Article %~ PubMed %A Cawley, Adam %A Collins, Michael %A Kazlauskas, Rymantas %A Handelsman, David J %A Heywood, Robert %A Longworth, Mitchell %A Arenas-Queralt, Andrea %T Stable isotope ratio profiling of testosterone preparations. %B Drug Testing and Analysis %D 2010 %C United Kingdom %I John Wiley & Sons Ltd. %V 2 %N 11-12 %P 557-567 %@ 1942-7611 %X Gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) is the preferred method of confirming the administration of exogenous testosterone by athletes. This relies on synthetic testosterone preparations being depleted in (13) C compared to natural testosterone. There is concern, however, about the existence of synthetic testosterone products that are unexpectedly (13) C-enriched and which may allow athletes to circumvent the current GC-C-IRMS test. Further to the reported studies of legitimate pharmaceutical-grade testosterone products, a detailed analysis of seized materials from border-level seizures was required to obtain intelligence concerning trends in ''black market'' testosterone manufacture and distribution. The sample set collected for this study between 2006 and 2009 inclusive provided a ??(13) C range (n = 266) of -22.9??? to -32.6??? with mean and median values of -28.4??? and -28.6???, respectively. Within this distribution there were 24 samples (9%) confirmed to have ??(13) C values in the range reported for endogenous urinary steroid metabolites (??? -25.8???). The benefit of ??(13) C profiling for testosterone preparations was demonstrated by the ability to identify specific seized products that can be target tested for future intelligence purposes. In addition, the potential of stable hydrogen isotope ratio ((2) H/(1) H; ??(2) H) discrimination to complement ??(13) C analysis was investigated. Methodologies for the determination of ??(2) H values by gas chromatography-thermal conversion-isotope ratio mass spectrometry (GC-TC-IRMS) were developed to provide a ??(2) H range (n = 173) of -177??? to -268??? with mean and median values of -231??? and -234???, respectively. %Z FOR Codes: 110306 111499 110604 %0 Book Section %A Meier, Christian %A Seibel, Markus %A Handelsman, David %T Testicular dysfunction %B Osteoporosis In Men: The Effects of Gender on Skeletal Health %D 2010 %C United States %I Elsevier Academic %V %N %P 423-434 %@ 9780123746023 %E Orwoll, Eric S. %E Bilezikian, John P. %E Vanderschueren, Dirk %X %Z FOR Codes: 111404 %0 Book Section %A Sartorius, Gideon A. %A Handelsman, David %T Testicular dysfunction in systemic disease. %B Andrology - Male Reproductive Health and Dysfunction %D 2010 %C Germany %I Springer-Verlag %V %N %P 339-364 %@ 9783540783541 %E Nieschlag, Eberhard %E Behre, Hermann M. %E Nieschlag, Susan %X %Z FOR Codes: 111404 %0 Journal Article %~ PubMed %A Handelsman, David J %T Testosterone and male ageing: spinning the wheels. %B The Medical Journal of Australia %D 2010 %C Australia %I Australasian Medical Publishing Company Pty. Ltd. %V 193 %N 7 %P 379-380 %@ 0025-729X %X Results of two new trials will drive further research into the "andropause hypothesis". %Z FOR Codes: 110306 110308 %0 Journal Article %~ PubMed %A Le Couteur, David G %A Blyth, Fiona M %A Creasey, Helen M %A Handelsman, David J %A Naganathan, Vasi %A Sambrook, Philip N %A Seibel, Markus J %A Waite, Louise M %A Cumming, Robert G %T The Association of Alanine Transaminase With Aging, Frailty, and Mortality. %B The journals of gerontology. Series A, Biological sciences and medical sciences %D 2010 %C United States %I Oxford University Press %V 65 %N 7 %P 712-7 %@ 1758-535X %X The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53-2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45-5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging. %Z FOR Codes: 111799 110307 %0 Journal Article %~ PubMed %A Ip, Flora %A di Pierro, Irene %A Brown, Ross %A Cunningham, Ilona %A Handelsman, David %A Liu, Peter Y %T Trough serum testosterone predicts the development of polycythemia in hypogonadal men treated for up to 21 years with subcutaneous testosterone pellets. %B European journal of endocrinology / European Federation of Endocrine Societies %D 2010 %C United Kingdom %I BioScientifica Ltd. %V 162 %N 2 %P 385-90 %@ 1479-683X %X Testosterone formulations that have more steady-state pharmacokinetics, such as subcutaneously implanted testosterone pellets, may cause less erythrocytosis than i.m. injections of shorter acting androgen esters. We, therefore, sought to define the prevalence, predictors, and proximate basis (role of erythropoietin) for polycythemia (hematocrit >0.50) in hypogonadal men receiving testosterone implants long term. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Kwong, Po Wan %A Cumming, Robert G %A Chan, Lewis %A Seibel, Markus J %A Naganathan, Vasi %A Creasey, Helen %A Le Couteur, David %A Waite, Louise M %A Sambrook, Philip N %A Handelsman, David %T Urinary incontinence and quality of life among older community-dwelling Australian men: the CHAMP study. %B Age and Ageing %D 2010 %C United Kingdom %I Oxford University Press %V 39 %N 3 %P 349-354 %@ 0002-0729 %X OBJECTIVE: to describe the prevalence and impact on quality of life of urinary incontinence in a population-based cohort of older community-dwelling Australian men. SUBJECTS: the population comprised 1,705 men aged >or=70 years participating in the Concord Health and Ageing in Men Project, a population-based study of urban older Australian men. METHODS: data were collected between January 2005 and June 2007, and the participation rate was 47%. Data on demographics, medical history and from the 12-item Short Form Health Survey (SF-12) and International Consultation on Incontinence Questionnaire were collected. Urinary incontinence was defined as urinary leakage at least two times a week over the past 4 weeks. RESULTS: the prevalence of urinary incontinence was 14.8%, increasing from 12.0% for men aged 70-74 years old to 16.3% for those aged >or=90 years, with urgency incontinence being the most frequent type of urinary incontinence. Daily urine leakage was reported by 3% of men. Men with incontinence had lower overall SF-12 scores with greater impact on the physical (PCS) than the mental (MCS) components of that scale. After adjusting for age, number of co-morbidities, enlarged prostate and prostate cancer, men with incontinence had worse PCS (43.6 vs 45.9) and MCS scores (52.2 vs 54.6) compared with continent men. CONCLUSION: urinary incontinence is common among older community-dwelling men and is associated with worse quality of life with greater impact on physical than mental factors. As the population ages, urinary incontinence prevalence will increase and increased resources will be needed to address this growing problem. %Z FOR Codes: 111702 110312 110308 %0 Journal Article %~ PubMed %A Simanainen, Ulla %A McNamara, Keely %A Gao, Yan Ru %A Handelsman, David J %T Androgen sensitivity of prostate epithelium is enhanced by postnatal androgen receptor inactivation. %B American Journal of Physiology: Endocrinology and Metabolism %D 2009 %C United States %I American Physiological Society %V 296 %N 6 %P E1335-E1343 %@ 0193-1849 %X Postnatal inactivation of epithelial androgen receptor (AR) in prostate epithelial AR knockout (PEARKO) mice results in hindered differentiation but enhanced proliferation of epithelial cells. As this resembles the precancerous proliferative atrophy of human prostates with undifferentiated but intensively replicating epithelial cells, we utilized the PEARKO mice to characterize the epithelial response to castration-induced involution with a focus on identifying the potential role of stromal AR and responsiveness of the androgen-deprived epithelia to the aromatizable androgen testosterone (T) or its nonaromatizable metabolite dihydrotestosterone (DHT). PEARKO and littermate control mice were orchidectomized at 8 wk of age and treated 2 wk later with subdermal implantation of 1-cm Silastic tubing filled with T or DHT for a week. Following castration, the prostatic involution and epithelial apoptosis did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution following castration is mediated primarily via stromal AR-dependent apoptotic signals. Androgen replacement (T/DHT) for 7 days induced significant growth and epithelial proliferation in all prostate lobes in both control and PEARKO, but full regrowth was observed only in controls treated with T. In PEARKO, prostate androgen (T and DHT) treatment induced significant epithelial cell "shedding" into the lumen, with T treatment resulting in acinar disorganization, cyst formation, and aberrant epithelial structures, described as a "gland within a gland." These data suggest that epithelial AR inactivation during postnatal prostate development sensitizes prostate epithelial cells to paracrine signaling mediated by stromal AR activity leading to indirectly androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens. %Z FOR Codes: 111404 110306 111201 %0 Journal Article %~ PubMed %A McRobb, L %A Handelsman, D J %A Heather, A K %T Androgen-induced progression of arterial calcification in apolipoprotein E-null mice is uncoupled from plaque growth and lipid levels. %B Endocrinology %D 2009 %C United States %I The Endocrine Society %V 150 %N 2 %P 841-848 %@ 0013-7227 %X Arterial calcification has prognostic significance for cardiovascular outcomes, but its pathogenesis remains unclear. Calcification increases with age, but its prevalence in men suggests hormonal influence. In this study we analyzed the effect of exogenous androgens on calcification of advanced atherosclerotic lesions in the arterial tree of gonadally intact 34-wk-old male and female apolipoprotein E-null mice. Testosterone (T) increased calcification 3- to 4-fold (P < 0.05) in lesions of the innominate artery and aortic sinus. A nonaromatizable androgen, dihydrotestosterone, also increased lesion calcification in the innominate artery (2.4-fold, P < 0.05) but not the aortic sinus. The androgen-induced effects were independent of sex and occurred despite corresponding reductions in plaque area, the latter correlating inversely with increased serum high-density lipoprotein cholesterol levels. Androgen-induced calcification in the innominate artery was observed with up-regulation of local androgen receptor (AR) expression in response to T and dihydrotestosterone for both males and females but neither androgen influenced innominate artery estrogen receptor (ER)-alpha or -beta expression in either sex. Conversely, T-induced calcification in the aortic sinus was associated with down-regulation of ERalpha but not ERbeta expression in both sexes, whereas androgen-induced AR expression was increased in female but decreased in male mice. This study demonstrates for the first time that calcification of advanced atherosclerotic lesions is an androgen-sensitive process and postulates potential roles for both AR- and ER-mediated pathways in androgen-induced vascular calcification. We demonstrate a novel direct link between vascular calcification and the major male hormone, T, uncoupled from conventional relationships with plaque growth and lipid levels. %Z FOR Codes: 110299 110306 %0 Journal Article %~ PubMed %A Harwood, D Tim %A Handelsman, David J %T Development and validation of a sensitive liquid chromatography-tandem mass spectrometry assay to simultaneously measure androgens and estrogens in serum without derivatization. %B Clinica Chimica Acta %D 2009 %C Netherlands %I Elsevier BV %V 409 %N 1-2 %P 78-84 %@ 1873-3492 %X BACKGROUND: Immunoassays are widely used to quantify steroid hormones in biological samples. However, they lack specificity, especially at low levels. This study aimed to develop a sensitive LC-MS/MS method to measure serum androgens and estrogens without derivatization within a single run. METHODS: A stable-isotope dilution LC-MS/MS method was established using atmospheric pressure photoionization to quantify testosterone (T), dihydrotestosterone (DHT), estradiol (E2) and estrone (E1) from serum. Sample preparation involved liquid-liquid extraction (LLE) with hexane:ethyl acetate (3:2) containing deuterated internal standards. Accuracy was assessed by spiked recovery of serum pools, and imprecision by quality controls. RESULTS: Using 200 microL serum, limits of quantification were 0.3 pg (1.5 pg/mL) E(1), 0.5 pg (2.5 pg/mL) E(2), 2 pg (10 pg/mL) T and 10 pg (50 pg/mL) DHT. Accuracy (93-110%) and precision (median 4%, all <15%) were determined to be well within acceptable limits for bioanalytical method validation. An analysis time of less than 10 min allowed up to 150 samples (600 analytes) to be processed per day. CONCLUSIONS: The method is sufficiently sensitive and precise to accurately quantify serum T levels in females and E(2) in males, and is readily adapted to tissue and non-human samples. %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Gnjidic, Danijela %A Cumming, Robert G %A Le Couteur, David G %A Handelsman, David J %A Naganathan, Vasi %A Abernethy, Darrell R %A Hilmer, Sarah N %T Drug Burden Index and physical function in older Australian men. %B British Journal of Clinical Pharmacology %D 2009 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 68 %N 1 %P 97-105 %@ 0306-5251 %X AIMS: This study evaluated the associations of physical performance and functional status measures with the Drug Burden Index in older Australian men. The Drug Burden Index is a measure of total exposure to anticholinergic and sedative medications that incorporates the principles of dose-response and maximal effect. METHODS: A cross-sectional survey was performed on community-dwelling older men enrolled in The Concord Health and Ageing in Men Project, Sydney, Australia. Outcomes included chair stands, walking speed over 6 m, 20-cm narrow walk speed, balance, grip strength and Instrumental Activities of Daily Living score (IADLs). RESULTS: The study population consisted of 1705 men (age 76.9 +/- 5.5 years). Of the 1527 (90%) participants who reported taking medications, 21% were exposed to anticholinergic and 13% to sedative drugs. The average Drug Burden Index in the study population was 0.18 +/- 0.35. After adjusting for confounders (sociodemographics, comorbidities, cognitive impairment, depression), Drug Burden Index was associated with slower walking speed (P < 0.05), slower narrow walk speed (P < 0.05), balance difficulty (P < 0.01), grip weakness (P < 0.01) and poorer performance on IADLs (P < 0.05). Associations with physical performance and function were stronger for the sedative than for the anticholinergic component of the Drug Burden Index. CONCLUSIONS: Higher Drug Burden Index is associated with poorer physical performance and functional status in community-dwelling older Australian men. The Drug Burden Index has broad applicability as a tool for assessing the impact of medications on functions that determine independence in older people. %Z FOR Codes: 111503 110308 %0 Journal Article %~ PubMed %A Handelsman, David J %A Goebel, Catrin %A Idan, Amanda %A Jimenez, Mark %A Trout, Graham %A Kazlauskas, Rymantas %T Effects of recombinant human luteinizing hormone and human chorionic gonadotropin on serum and urine LH and androgens in men. %B Clinical endocrinology %D 2009 %C Australia %I Wiley-Blackwell %V 71 %N 3 %P 417-28 %@ 1365-2265 %X The administration of gonadotrophins is prohibited in sport but the effect in men of recently available recombinant hCG and LH on serum and urine concentrations of gonadotrophins and androgens has not been systematically evaluated in the antidoping context. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Liu, Peter Y %A Gordon Baker, H W %A Jayadev, Veena %A Zacharin, Margaret %A Conway, Ann J %A Handelsman, David J %T Induction of spermatogenesis and fertility during gonadotropin treatment of gonadotropin deficient infertile men: predictors of fertility outcome. %B The Journal of clinical endocrinology and metabolism %D 2009 %C US %I The Endocrine Society %V 94 %N 0 %P 801-8 %@ 0021-972X %X The induction of spermatogenesis and fertility with gonadotropin therapy in gonadotropin-deficient men varies in rate and extent. Understanding the predictors of response would inform clinical practice but requires multivariate analyses in sufficiently large clinical cohorts that are suitably detailed and frequently assessed. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Roa, J %A Castellano, J M %A Navarro, V M %A Handelsman, D J %A Pinilla, L %A Tena-Sempere, M %T Kisspeptins and the control of gonadotropin secretion in male and female rodents. %B Peptides %D 2009 %C United States %I Elsevier Inc. %V 30 %N 1 %P 57-66 %@ 0196-9781 %X Kisspeptins, the products of KiSS-1 gene acting via G protein-coupled receptor 54 (GPR54), have recently emerged as fundamental gatekeepers of gonadal function by virtue of their ability to stimulate gonadotropin secretion. Indeed, since the original disclosure of the reproductive facet of the KiSS-1/GPR54 system, an ever-growing number of studies have substantiated the extraordinary potency of kisspeptins to elicit gonadotropin secretion in different mammalian species, under different physiologic and experimental conditions, and through different routes of administration. In this context, studies conducted in laboratory rodents have been enormously instrumental to characterize: (i) the primary mechanisms of action of kisspeptins in the control of gonadotropin secretion; (ii) the pharmacological consequences of acute vs. continuous activation of GPR54; (iii) the roles of specific populations of kisspeptin-producing neurons at the hypothalamus in mediating the feedback effects of sex steroids; (v) the function of kisspeptins in the generation of the pre-ovulatory surge of gonadotropins; and (iv) the influence of sex steroids on GnRH/gonadotropin responsiveness to kisspeptins. While some of those aspects of kisspeptin function will be covered elsewhere in this Special Issue, we summarize herein the most salient data, obtained in laboratory rodents, that have helped to define the physiologic roles and putative pharmacological implications of kisspeptins in the control of male and female gonadotropic axis. %Z FOR Codes: 110101 %0 Journal Article %~ PubMed %A Sartorius, Gideon %A Ly, Lam P %A Sikaris, Ken %A McLachlan, Robert %A Handelsman, David J %T Predictive accuracy and sources of variability in calculated free testosterone estimates. %B Annals of Clinical Biochemistry %D 2009 %C United Kingdom %I Royal Society of Medicine Press Ltd. %V 46 %N Pt 2 %P 137-143 %@ 0004-5632 %X BACKGROUND: Serum free testosterone (FT) concentrations are commonly requested, but because reference FT methods are too laborious various calculational algorithms for FT based on total testosterone (TT) and sex hormone-binding globulin (SHBG) are frequently used. This study provides the first large-scale evaluation of the predictive accuracy and sources of variability for different FT formulae compared with direct laboratory measurements. METHODS: Using a large data-set of direct FT measurements by centrifugal ultrafiltration, the predictive accuracy of five different formulas for cFT (four existing plus a new formula) is evaluated in 3975 consecutive blood samples. In a second data-set of 124 samples from a reference panel of healthy eugonadal young men, we estimate the relative influence of the five algorithms and eight different TT and two SHBG assays including all available commercial total TT and SHBG assays together with a gas chromatography/mass spectrometry T reference method. RESULTS: cFT formulae show wide discrepancies with equilibrium-binding algorithms showing systematic overestimation relative to direct FT measurements, whereas two empirical cFT methods were more concordant. Variations between commercially available TT immunoassays have a strong impact on calculation of FT with TT assays contributing 82.2% of overall variance compared with 13.7% for the cFT algorithms and 4.1% for the SHBG assays. CONCLUSIONS: If FT measurements are requested and direct measurement impractical, cFT formulae using TT and SHBG immunoassays provide an approximation to direct FT measurement that is strongly dependent on the TT, cFT formula used and, to a lesser extent, SHBG immunoassays. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Lim, Patrick %A Robson, Mathew %A Spaliviero, Jenny %A McTavish, Kirsten J %A Jimenez, Mark %A Zajac, Jeffrey D %A Handelsman, David J %A Allan, Charles M %T Sertoli cell androgen receptor DNA binding domain is essential for the completion of spermatogenesis. %B Endocrinology %D 2009 %C Philadelphia %I Saunders Elsevier %V 150 %N 10 %P 4755-65 %@ 0013-7227 %X We examined the biological importance of Sertoli cell androgen receptor (AR) genomic interaction, using a Cre-loxP approach to selectively disrupt the AR DNA-binding domain (AR-DBD). Sertoli cell (SC)-specific transgenic Abpa or AMH promoters targeted Cre-mediated inframe excision of mouse Ar exon-3, encoding the AR-DBD second zinc-finger (ZF2), generating SC-specific mutant AR(DeltaZF2) lines designated Abp.SCAR(DeltaZF2) and AMH.SCAR(DeltaZF2), respectively. Both SCAR(DeltaZF2) lines produced infertile males exhibiting spermatogenic arrest, despite normal SC numbers and immunolocalized SC nuclear AR. Adult homozygous TgCre((+/+)) SCAR(DeltaZF2) or double-TgCre((+/-)) Abp/AMH.SCAR(DeltaZF2) males displayed equivalent small testes 30% of normal size, representing maximal Cre-loxP-disruption of Sertoli AR function. Hemizygous TgCre((+/-)) vs. homozygous TgCre((+/+)) Abp.SCAR(DeltaZF2) testes were larger (47% normal size) with more postmeiotic development, indicating dose-dependent Cre-mediated disruption of SC-specific AR-DBD activity. SCAR(DeltaZF2) males exhibited adult Leydig cell hypertrophy but normal serum testosterone levels. Sertoli cell-specific Rhox5 and Spinlw1 transcription, regulated by divergent or classical androgen-response elements, respectively, were both decreased in postnatal SCAR(DeltaZF2) vs. control testes, demonstrating SC-specific AR-DBD function as early as postnatal d 5. However, Rhox5 expression declined dose-dependently, whereas Spinlw1 expression increased, in adult TgCre((+/-)) and TgCre((+/+)) SCAR(DeltaZF2) testes, revealing differential temporal control for distinct AR-regulated transcripts. Androgen-repressed Ngfr was not up-regulated in SCAR(DeltaZF2) testes, suggesting maintenance of a nonclassical mechanism independent of AR-DBD. Thus, our unique SCAR(DeltaZF2) paradigm provided dose-dependent Cre-mediated disruption of testicular development and gene expression revealing that the AR-DBD is essential for SC function and postmeiotic spermatogenesis. Nongenomic or AR-DBD-independent pathways appear secondary or play no major independent role in SC function. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Walters, K A %A McTavish, K J %A Seneviratne, M G %A Jimenez, M %A McMahon, A C %A Allan, C M %A Salamonsen, L A %A Handelsman, D J %T Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. %B Endocrinology %D 2009 %C United States %I The Endocrine Society %V 150 %N 7 %P 3274-3282 %@ 0013-7227 %X Female androgen receptor (AR) knockout mice (AR(-/-)) generated by an in-frame Ar exon 3 deletion are subfertile, but the mechanism is not clearly defined. To distinguish between extra- and intraovarian defects, reciprocal ovarian transplants were undertaken. Ovariectomized AR(-/-) hosts with wild-type (AR(+/+)) ovary transplants displayed abnormal estrus cycles, with longer cycles (50%, P < 0.05), and 66% were infertile (P < 0.05), whereas AR(+/+) hosts with either AR(-/-) or surgical control AR(+/+) ovary transplants displayed normal estrus cycles and fertility. These data imply a neuroendocrine defect, which is further supported by increased FSH (P <0.05) and estradiol (P <0.05), and greater LH suppressibility by estradiol in AR(-/-) females at estrus (P <0.05). Additional intraovarian defects were observed by the finding that both experimental transplant groups exhibited significantly reduced pups per litter (P < 0.05) and corpora lutea numbers (P < 0.05) compared with surgical controls. All groups exhibited normal uterine and lactation functions. AR(-/-) uteri were morphologically different from AR(+/+) with an increase in horn length (P < 0.01) but a reduction in uterine diameter (P < 0.05), total uterine area (P < 0.05), endometrial area (P < 0.05), and myometrial area (P < 0.01) at diestrus, indicating a role for AR in uterine growth and development. Both experimental transplant groups displayed a significant reduction in uterine diameter (P < 0.01) compared with transplanted wild-type controls, indicating a role for both AR-mediated intraovarian and intrauterine influences on uterine physiology. In conclusion, these data provide direct evidence that extraovarian neuroendocrine, but not uterine effects, as well as local intraovarian AR-mediated actions are important in maintaining female fertility, and a disruption of AR signaling leads to altered uterine development. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A Birzniece, Vita %A Meinhardt, Udo J %A Handelsman, David J %A Ho, Ken K Y %T Testosterone stimulates extra-hepatic but not hepatic fat oxidation (Fox): comparison of oral and transdermal testosterone administration in hypopituitary men. %B Clinical Endocrinology %D 2009 %C United Kingdom %I Wiley-Blackwell Publishing Ltd. %V 71 %N 5 %P 715-721 %@ 0300-0664 %X BACKGROUND: Fat mass is increased in hypogonadal men and the changes are reversed by testosterone replacement. Testosterone administration enhances whole body fat oxidation (Fox). Fat is oxidized in the liver and in extra-hepatic tissues. OBJECTIVE: To determine whether the stimulation of Fox by testosterone arises primarily from the liver or from extra-hepatic tissues. DESIGN/PATIENTS: This was an open-label cross-over study. Thirteen men with hypopituitarism (age 53.1 +/- 4.1 years) with both growth hormone (GH) and testosterone deficiency were studied sequentially after 2 weeks of treatment with transdermal testosterone (5 mg), no treatment, and stepwise incremental doses of oral crystalline testosterone (10, 20, 40 and 80 mg) in the absence of GH replacement. MEASUREMENTS: Serum testosterone, IGF-I, metabolic effects [resting energy expenditure (REE) and Fox], SHBG, and thyroid binding globulin (TBG) as markers of excessive hepatic androgen exposure, were measured at the end of each treatment period. RESULTS: When compared to the no-treatment phase, mean blood testosterone levels rose into the physiological range after transdermal testosterone delivery but did not significantly change after 10, 20, 40 or 80 mg oral testosterone treatment. Blood SHBG and TBG fell significantly with 80 mg oral testosterone dose but were unaffected by any other testosterone treatment. Fox increased significantly with transdermal but not with any dose of oral testosterone. Mean plasma IGF-I and REE were unaffected by testosterone, regardless of the route or dose. CONCLUSIONS: Short-term testosterone administration does not stimulate hepatic fat oxidation but enhances whole body fat oxidation by acting on extra-hepatic tissues. %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Allan, Charles M %A Lim, Patrick %A Robson, Mathew %A Spaliviero, Jenny %A Handelsman, David J %T Transgenic mutant D567G but not wild-type human FSH receptor overexpression provides FSH-independent and promiscuous glycoprotein hormone Sertoli cell signaling. %B American Journal of Physiology: Endocrinology and Metabolism %D 2009 %C United States %I American Physiological Society %V 296 %N 5 %P E1022-E1028 %@ 0193-1849 %X We have characterized the in vivo actions of human wild-type FSH receptor (FSHR) overexpressed in Sertoli cells of transgenic (Tg) mice (TgFSHRwt) compared with transgenic overexpression of the human activated mutant FSHR*D567G (TgFSHR*D567G). Testicular TgFSHRwt expression significantly elevated specific FSH binding (>2-fold, P < 0.01) relative to nontransgenic testes, similar to increased FSH binding in TgFSHR*D567G testes. Isolated TgFSHRwt Sertoli cells exhibited higher FSH-stimulated cAMP levels compared with non-Tg or TgFSHR*D567G cells but did not display the elevated FSH-independent basal cAMP levels found in TgFSHR*D567G Sertoli cells. Furthermore, Sertoli cell overexpression of TgFSHR*D567G but not TgFSHRwt allowed promiscuous cAMP responses to human chorionic gonadotropin (300 IU/ml) and TSH (30 mIU/ml), demonstrating increased constitutive signaling and altered glycoprotein hormone specificity via the intracellular D567G substitution rather than FSHR overexpression. Despite elevating Sertoli cell FSH sensitivity, overexpression of TgFSHRwt had no detectable effect upon normal testis function and did not stimulate Sertoli and germ cell development in testes of gonadotropin-deficient hypogonadal (hpg) mice, in contrast to the increased meiotic and postmeiotic germ cell development in TgFSHR*D567G hpg testes. Increased steroidogenic potential of TgFSHR*D567G hpg testes was demonstrated by elevated Cyp11a1 and Star expression, which was not detected in TgFSHRwt hpg testes. Androgen-regulated and Sertoli cell-specific Rhox5 gene expression was increased in TgFSHR*D567G but not TgFSHRwt hpg testes, providing evidence of elevated LH-independent androgen activity due to mutant FSHR*D567G. Hence, transgenic FSHR overexpression in Sertoli cells revealed that the D567G mutation confers autonomous signaling and steroidogenic activity in vivo as well as promiscuous glycoprotein hormone receptor activation, independently of FSHR overexpression alone. %Z FOR Codes: 110306 111404 %0 Journal Article %~ PubMed %A MacLean, Helen E %A Handelsman, David J %T Unraveling androgen action in muscle: genetic tools probing cellular mechanisms. %B Endocrinology %D 2009 %C United States %I The Endocrine Society %V 150 %N 8 %P 3437-3439 %@ 0013-7227 %X %Z FOR Codes: 110306 %0 Journal Article %~ PubMed %A Handelsman, David J %A Heather, Alison %T Androgen abuse in sports. %B Asian Journal of Andrology %D 2008 %C United States %I Nature Publishing Group %V 10 %N 3 %P 403-415 %@ 1008-682X %X Androgens remain the most effective and widely abused ergogenic drugs in sport. Although androgen doping has been prohibited for over 3 decades with a ban enforced by mass spectrometric (MS)-based urine testing for synthetic and exogenous natural androgens, attempts continue to develop increasingly complex schemes to circumvent the ban. A prominent recent approach has been the development of designer androgens. Such never-marketed androgens evade detection because mass spectrometry relies on identifying characteristic chemical signatures requiring prior knowledge of chemical structure. Although once known, designer androgens are readily detected and added to the Prohibited List. However, until their structures are elucidated, designer androgens can circumvent the ban on androgen doping. To combat this, in vitro androgen bioassays offer powerful new possibilities for the generic detection of unidentified bioactive androgens, regardless of their chemical structure. Another approach to circumvent the ban on androgen doping has been the development of indirect androgen doping, the use of exogenous drugs to produce a sustained increase in endogenous testosterone (T) production. Apart from estrogen blockers, however, such neuroendocrine active drugs mostly provide only transient increases in blood T. Finally the ban on androgen doping must allow provision for rare athletes with incidental, proven androgen deficiency who require T replacement therapy. The Therapeutic Use Exemption mechanism makes provision for such necessary medical treatment, subject to rigorous criteria for demonstrating a genuine ongoing need for T and monitoring of T dosage. Effective deterrence of sports doping requires novel, increasingly sophisticated detection options calibrated to defeat these challenges, without which fairness in sport is tarnished and the social and health idealization of sporting champions devalued. %Z FOR Codes: 110399 111404 %0 Journal Article %~ PubMed %A Walters, K A %A Allan, C M %A Handelsman, D J %T Androgen actions and the ovary. %B Biology of reproduction %D 2008 %C United States %I Society for the Study of Reproduction %V 78 %N 3 %P 380-389 %@ 0006-3363 %X Although androgens and the androgen receptor (AR) have defining roles in male reproductive development and function, previously no role in female reproductive physiology beyond testosterone (T) as the precursor in estradiol (E(2)) biosynthesis was firmly established. Understanding the role and specific mechanisms of androgen action via the AR in the ovary has been limited by confusion on how to interpret results from pharmacological studies, because many androgens can be metabolized in vivo and in vitro to steroids that can also exert actions via the estrogen receptor (ESR). Recent genetic studies using mouse models with specific disruption of the Ar gene have highlighted the role that AR-mediated actions play in maintaining female fertility through key roles in the regulation of follicle health, development, and ovulation. Furthermore, these genetic studies have revealed that AR-mediated effects influence age-related female fertility, possibly via mechanisms acting predominantly at the hypothalamic-pituitary axis in a dose-dependent manner. This review focuses on combining the findings from pharmacological studies and novel genetic mouse models to unravel the roles of ovarian androgen actions in relation to female fertility and ovarian aging, as well as creating new insights into the role of androgens in androgen-associated reproductive disorders such as polycystic ovarian syndrome. %Z FOR Codes: 111404 110306 %0 Journal Article %~ PubMed %A Ho, Lye Lin %A Kench, James G %A Handelsman, David J %A Scheffer, George L %A Stricker, Phillip D %A Grygiel, John G %A Sutherland, Robert L %A Henshall, Susan M %A Allen, John D %A Horvath, Lisa G %T Androgen regulation of multidrug resistance-associated protein 4 (MRP4/ABCC4) in prostate cancer. %B The Prostate %D 2008 %C United States %I John Wiley & Sons %V 68 %N 13 %P 1421-9 %@ 0270-4137 %X MRP4/ABCC4 is an ATP-binding cassette transporter expressed in normal prostate. This study aimed to define the pattern of MRP4/ABCC4 expression in normal and malignant prostate tissue and the relationship of MRP4/ABCC4 expression and function in response to androgen signaling. %Z FOR Codes: 110312 110502 111201 111404 %0 Journal Article %~ PubMed %A Cumming, Robert G %A Handelsman, David %A Seibel, Markus J %A Creasey, Helen %A Sambrook, Philip %A Waite, Louise %A Naganathan, Vasi %A Couteur, David Le %A Litchfield, Melisa %T Cohort profile: The Concord Health and Ageing in Men Project (CHAMP). %B International journal of epidemiology %D 2008 %C GREAT CLARENDON ST, OXFORD, ENGLAND, OX2 6D %I Oxford Univ Press %V 38 %N 0 %P 374-8 %@ 0300-5771 %X %Z FOR Codes: 111706 111404 %0 Journal Article %~ PubMed %A Liu, Peter Y %A Swerdloff, Ronald S %A Anawalt, Bradley D %A Anderson, Richard A %A Bremner, William J %A Elliesen, Joerg %A Gu, Yi-Qun %A Kersemaekers, Wendy M %A McLachlan, Robert I %A Meriggiola, M Cristina %A Nieschlag, Eberhard %A Sitruk-Ware, Regine %A Vogelsong, Kirsten %A Wang, Xing-Hai %A Wu, Frederick C W %A Zitzmann, Michael %A Handelsman, David J %A Wang, Christina %T Determinants of the Rate and Extent of Spermatogenic Suppression during Hormonal Male Contraception: An Integrated Analysis. %B The Journal of Clinical Endocrinology and Metabolism %D 2008 %C United States %I The Endocrine Society %V 93 %N 5 %P 1774-1783 %@ 0021-972X %X Context: Male hormonal contraceptive methods require effective suppression of sperm output. Objective: The objective of the study was to define the covariables that influence the rate and extent of suppression of spermatogenesis to a level shown in previous World Health Organization-sponsored studies to be sufficient for contraceptive purposes (