David J Handelsman

Concord Hospital, Concord, New Hampshire, United States

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Publications (414)2055.67 Total impact

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    ABSTRACT: This study aims to identify the common risk factors for mortality in community-dwelling older men. A prospective population-based study was conducted with a median of 6.7 years of follow-up. Participants included 1705 men aged ≥70 years at baseline (2005-2007) living in the community in Sydney, Australia. Demographic information, lifestyle factors, health status, self-reported history of diseases, physical performance measures, blood pressure, height and weight, disability (activities of daily living (ADL) and instrumental ADLs, instrumental ADLs (IADLs)), cognitive status, depressive symptoms and blood analyte measures were considered. Cox regression analyses were conducted to model predictors of mortality. During follow-up, 461 men (27 %) died. Using Cox proportional hazards model, significant predictors of mortality included in the final model (p < 0.05) were older age, body mass index < 20 kg m(2), high white cell count, anaemia, low albumin, current smoking, history of cancer, history of myocardial infarction, history of congestive heart failure, depressive symptoms and ADL and IADL disability and impaired chair stands. We found that overweight and obesity and/or being a lifelong non-drinker of alcohol were protective against mortality. Compared to men with less than or equal to one risk factor, the hazard ratio in men with three risk factors was 2.5; with four risk factors, it was 4.0; with five risk factors, it was 4.9; and for six or more risk factors, it was 11.4, respectively. We have identified common risk factors that predict mortality that may be useful in making clinical decisions among older people living in the community. Our findings suggest that, in primary care, screening and management of multiple risk factors are important to consider for extending survival, rather than simply considering individual risk factors in isolation. Some of the "traditional" risk factors for mortality in a younger population, including high blood pressure, hypercholesterolaemia, overweight and obesity and diabetes, were not independent predictors of mortality in this population of older men.
    Age (Dordrecht, Netherlands). 12/2014; 36(6):9732.
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    ABSTRACT: Context: In mice undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity, and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesised that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers. Participants: Community-dwelling men aged 70-89 years resident in Perth, Western Australia. Main Outcome Measures: Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP) and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, dihydrotestosterone (DHT) and estradiol (E2) were assayed by mass spectrometry. Results: Excluding men with osteoporosis, on bisphosphonates, glucocorticoids or warfarin, and conditions affecting sex hormones 2,966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase=0.55, p<0.001). Similar results were seen for TOC (OR=0.60, p<0.001), P1NP (OR=0.64, p<0.001) and CTX (OR=0.60, p<0.001) but not ucOC/TOC. When all four markers were included in the fully-adjusted model, higher ucOC (OR=0.56, p<0.001) and CTX (OR=0.76, p=0.008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient -0.04, p=0.031), TOC (-0.05, p=0.001) and CTX (-0.04, p=0.016); and positively with ucOC/TOC (0.05, p=0.002). DHT was inversely associated with ucOC/TOC (-0.04, p=0.040). T was not associated with bone turnover. Conclusions: Higher bone remodelling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodelling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.
    The Journal of clinical endocrinology and metabolism. 11/2014;
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    ABSTRACT: Accurate measurement of testosterone is important for reproductive endocrinology research, but the validity of direct (non-extraction) testosterone immunoassays, developed and validated for human serum, has not been appraised for application to mouse serum or steroidogenic tissue extracts. Testosterone was measured in serum and extracts of testis or ovary from male and female wild-type mice by two commercial direct testosterone immunoassays, with and without pre-assay extraction, and by the liquid chromatography, tandem mass spectrometry (LC-MS) reference method. Results were compared hierarchically by correlation (Kendall's tau), regression (Passing-Bablok) and deviance (Bland-Altman) analysis, under the null hypothesis of perfect agreement between assays (slope=1, intercept and deviation=0). For mouse serum, immunoassays displayed an upward bias with performance better for male vs female sera and, within gender, improved by pre-assay extraction relative to LC-MS. Testosterone was detectable in all serum samples but few (male 54, female 9%) were accurate (within 20% of the reference measurement). For mouse testis extracts, immunoassays were biased upwards and pre-assay extraction improved immunoassay performance. Although testosterone was detectable in all samples, a minority (45%) were accurate. For mouse ovary extracts, all correlations were poor with severe, upward bias and while testosterone was detectable in all samples, virtually none were accurate. We conclude that these direct testosterone immunoassay kits provide relatively, but not absolutely, accurate results with male mouse serum and testis extracts but not with female mouse serum and ovary extracts, with performance improved by pre-assay extraction. Whether relative accuracy is fit for purpose depends on the experimental aims, design and interpretation.
    Endocrinology 11/2014; · 4.72 Impact Factor
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    ABSTRACT: Context: Older men have lower testosterone (T) levels but whether differences in circulating T, or its metabolites dihydrotestosterone (DHT) or estradiol (E2) contribute to cardiovascular disease remains controversial. Objective: We tested the hypothesis that plasma T, DHT and E2 are differentially associated with incidence of myocardial infarction (MI) and stroke in older men. Participants and methods: Plasma total T, DHT and E2 were assayed using liquid chromatography-mass spectrometry in early morning samples from 3,690 community-dwelling men aged 70-89 years. Outcomes of first hospital admission or death due to MI or stroke were ascertained by data linkage. Results: Mean follow-up was 6.6 years. Incident MI occurred in 344, stroke in 300 and neither in 3,046 men. In multivariate analysis adjusting for age and other risk factors, neither T, DHT nor E2 were associated with incident MI (fully-adjusted hazard ratio [HR] for T in Quartile (Q)4 vs Q1: 0.92, 95% confidence interval [CI]=0.66-1.28; DHT: 0.83, 0.59-1.15; E2: 0.84, 0.62-1.15). Higher T or DHT was associated with lower incidence of stroke (T: Q4:Q1 fully-adjusted HR=0.56, 95% CI=0.39-0.81, p=0.002; DHT: 0.57, 0.40-0.81, p=0.002). E2 was not associated with stroke (HR=0.76, 95% CI=0.54-1.08, p=0.123). Conclusions: Higher plasma T or DHT are biomarkers for reduced risk of stroke but not MI. Androgen exposure may influence outcomes following rather than incidence of MI, while androgens but not E2 are independent predictors of stroke risk. Randomised clinical trials are needed to clarify the impact of modifying T or DHT on the risk of stroke in ageing men.
    The Journal of clinical endocrinology and metabolism. 09/2014;
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    ABSTRACT: Context: The causal relationship between metabolic syndrome and reproductive hormones is unclear. Objective: To examine the cross-sectional, longitudinal and predictive associations between reproductive hormones and SHBG, and metabolic syndrome in older men. Design, Setting, and Participants: 1705 men aged 70 years and older from the CHAMP study were assessed at baseline and 2-year follow-up. At baseline, testosterone (T), dihydrotestosterone, estradiol (E2), and estrone (E1) were measured by liquid chromatography-tandem mass spectrometry, and SHBG, LH, and FSH by immunoassay. Outcome Measures: Metabolic syndrome was defined using the NCEP ATP III criteria. Results: In cross-sectional data, significant associations between each of T, SHBG, DHT, and calculated free testosterone (cFT) with the metabolic syndrome remained significant after multivariate adjustment. In longitudinal analyses, however, only lower SHBG was significantly associated with incident metabolic syndrome over the 2-year follow-up (p for linear trend=0.04). Conclusions: Although low serum T, DHT, SHBG and cFT were associated cross-sectionally with metabolic syndrome among community-dwelling older men, over a 2-year follow-up period only SHBG remained significant after multivariate adjustment. This suggests that lowered circulating androgens (T, DHT) may be biomarkers rather than causally related to incident metabolic syndrome.
    The Journal of clinical endocrinology and metabolism. 09/2014;
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    ABSTRACT: Balance training is the most efficacious exercise to prevent falls. This study examined the associations between common sporting activities and the incidence of falls, and whether lower risks can be attributed to the superior balance of sports participants. We studied a population-based cohort of 1,667 older Australian men (mean age = 76.8 years) in the Concord Health and Ageing in Men Project (CHAMP) between 2005 and 2011. Data on incident falls were captured by 12 triannual telephone call cycles per participant and were analyzed using negative binomial regression. The length of follow-up averaged 43.8 months (median, 48 months), during which time 2,662 falls were recorded. In unadjusted models, golfers (n = 160; incidence rate ratio (IRR) = 0.65, 95% confidence interval (CI): 0.47, 0.89) and swimmers (n = 88; IRR = 0.47, 95% CI: 0.30, 0.71) had significantly lower risks of falling. After adjustment for leisure-time physical activity, walking, lifestyle physical activity score (e.g., chores, gardening), and conventional risk factors for falling, swimming was the only activity that was associated with a protective effect (IRR = 0.67, 95% CI: 0.45, 1.00). Swimmers had significantly lower postural sway (β = -5.23 cm(2), P < 0.05) and shorter time to complete a narrow walk test than men who took part in only lifestyle physical activities. Balance indicators were strong predictors of the incidence of falls. The IRR for swimmers was 0.71 (95% CI: 0.48, 1.06) after adding balance measures to the adjusted model.
    American journal of epidemiology. 09/2014;
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    ABSTRACT: Context: Aberrant sex steroid signaling is suggested to promote endometriosis growth by several mechanisms, and the tissue concentrations of sex steroids are key determinants of the hormone action. However, their concentrations are only superficially known in the endometrium and endometriosis lesions. Objective: To evaluate whether the tissue steroid hormone concentrations in endometriosis differ from the endometrium or serum. Main Outcome Measures: Steroid analysis of serum and tissue specimens of women with endometriosis (n=60) and healthy controls (n=16) was measured and supporting data from quantitative RT-PCR for steroidogenic enzymes and explant cultures of a subset of specimens is provided. Results: Endometrial tissue progesterone (P4) concentrations reflected the serum P4 levels during the menstrual cycle, whereas in endometriosis lesions, the cycle dependent change was missing. Remarkably high tissue testosterone (T) concentrations were measured in endometriosis lesions independent of the cycle phase, being 5-19 times higher than the corresponding serum levels. Tissue/serum ratio of T was further increased in patients with contraceptive medication. The altered tissue steroid concentrations in endometriosis were in line with the expression of various steroidogenic enzymes in the lesions, of which HSD3B2 showed constantly high expression, while CYP11A1 expression was low. Furthermore, the high concentration of sex steroids detected in the ovarian lesions involves their production by the lesion and by the adjacent ovarian tissue. Conclusions: Endometriosis lesions present with progestin and androgen metabolism which are different from that of the endometrium, and the lesions are characterized by high tissue T and a loss of cyclical changes in tissue P4 concentration.
    The Journal of clinical endocrinology and metabolism. 08/2014;
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    ABSTRACT: Although there is a conflicting evidence for an association between low serum 25-hydroxyvitamin D (25D) levels and pain, the relationship between pain and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25D), has not been investigated. The aim of this study was to examine the associations between serum vitamin D metabolites: 25D and 1,25D with intrusive or chronic pain in community-living men aged ≥70 years.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 08/2014; · 4.31 Impact Factor
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    ABSTRACT: Objectives To examine the associations between serum 25-hydroxyvitamin D (25OHD) levels and the active vitamin D metabolite, 1,25-hydroxyvitamin D (1,25OHD), with type 2 diabetes mellitus (DM) in community-living men aged 70 and older.DesignCross-sectional.SettingA population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study conducted in Sydney between January 2005 and May 2007.ParticipantsCommunity dwelling men aged 70 and older taking part in CHAMP (N = 1,659).MeasurementsSerum 25OHD and 1,25OHD levels, presence of DM, age, country of birth, season of blood collection, sun exposure, body mass index, vitamin D supplement use, statin use, income, measures of health, depression, activity of daily living disabilities, parathyroid hormone, estimated glomerular filtration rate, phosphate, and calcium.ResultsThe prevalence of DM was 20.0%. There was a significant association between low 25OHD and 1,25OHD levels and DM that remained after adjustment for a wide range of confounders and covariates of clinical significance such as comorbidity, renal function, calciotropic hormones, and medications.Conclusion25OHD and 1,25OHD levels were associated with DM. The independent association between serum 25OHD and 1,25OHD concentrations and DM raises the question of whether each of the two vitamin D metabolites may influence DM through different biological mechanisms and pathways.
    Journal of the American Geriatrics Society 08/2014; · 4.22 Impact Factor
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    ABSTRACT: The androgen receptor (AR) is widely expressed in mammary cells of female mammals including humans and mice, indicating a possible role for AR-mediated androgen actions in breast development, function and pathology although the specific mechanisms remain unclear. To elucidate the mechanisms of androgen action in mammary gland physiology and development, we used AR knockout (AR(Δ)(ex3)KO) female mice with a universally expressed, transcriptionally inactive AR protein harbouring an in-frame deletion of its second zinc finger. While in sexually mature wild-type (WT) and AR(ex3)(Δ)KO females the mammary epithelial growth was fully extended to the edge of the fat pad, during puberty, AR(ex3)(Δ)KO females exhibit significantly accelerated mammary ductal growth and an increased number of terminal end buds (TEB) compared to wild-type (WT) females. Accelerated AR(ex3)(Δ)KO female mammary growth was associated with significantly increased mammary epithelial ERα expression and activated Wnt/β-catenin signalling as shown by increased Wnt4 expression and accumulation of nuclear β-catenin. These findings are consistent with increased mammary estrogen exposure although ovarian E2 content was unchanged compared with WT females. Furthermore, treatment with the potent pure androgen dihydrotestosterone markedly reduced ductal extension and TEB numbers in WT but not in AR(Δ)(ex3)KO females, further supporting the concept that AR mediated, androgen induced suppression of murine mammary growth is a physiological characteristic of puberty. In summary, our findings reveal an inhibitory role of AR-mediated androgen actions in pubertal mammary gland development by reducing epithelial cell proliferation and could be mediated by regulation of Wnt/β-catenin signalling.
    Endocrinology 07/2014; · 4.72 Impact Factor
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    ABSTRACT: There is a progressive impairment of vascular repair mechanisms with advancing age concomitant with a steady decline in circulating androgen levels in men. Emerging evidence indicates androgens regulate angiogenesis, however little research has focused on the impact of age upon androgen-mediated regulation of angiogenic mechanisms. Human dermal fibroblasts from young (<30yrs) and older (>65yrs) men were incubated with dihydrotestosterone (DHT), with/without androgen receptor antagonist hydroxyflutamide (HF), or phosphoinositide 3-kinase (PI3-kinase) inhibitor. Fibroblast conditioned media was used to stimulate angiogenic functions in human umbilical vein endothelial cells (HUVECs). Nuclear fractionation and fluorescence microscopy were used to study androgen receptor (AR) distribution. Conditioned media from fibroblasts of young men, but not old men, treated with DHT produced a 3-fold increase in HUVEC tubulogenesis and 2-fold increase in migration via increased VEGF expression and secretion, predominantly of VEGF145. DHT-induced VEGF secretion from fibroblasts of young men was AR-dependent and increased AKT phosphorylation, which was abrogated by PI3-kinase inhibition. By contrast, fibroblasts from older men were unresponsive to DHT and lacked androgen-mediated enhancement in VEGF production. These findings were associated with reduced AR nuclear translocation in old fibroblasts. The failure of DHT-induced paracrine stimulation of angiogenesis in fibroblasts from older men is likely due to defective nuclear translocation of AR. This first demonstration of androgen resistance (or insensitivity) acquired by human fibroblasts with aging suggests that pharmacological testosterone therapy for old men may be less effective in enhancing angiogenesis and facilitating tissue regeneration mechanisms reliant on paracrine release of VEGF.
    Molecular endocrinology (Baltimore, Md.). 07/2014;
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    ABSTRACT: The gonadotropin and sex steroid (testosterone (T) and estradiol (E2)) changes that drive the external manifestations of puberty are well described using cross-sectional data according to age or Tanner staging. Longitudinal data describing the interactions between the changing hormonal milieu and adolescent growth is lacking. Previous studies relied upon older sex steroid immunoassay techniques lacking the sensitivity and specificity of mass spectrometry-based steroid assays. Our aims were to (a) establish and validate liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays for urine T and E2 and an immunoassay for urine LH for a longitudinal study of adolescents (the Adolescent Rural Cohort, Hormones, Health, Education, Environment and Relationships (ARCHER) study (1)) involving frequent (3 monthly) sampling; (b) describe hormone changes over the first year in the first 104 (57 F) participants (of 342 total cohort); (c) describe relationships between changes in urine and serum hormones with standard measures of puberty (anthropometry, Tanner stage). Participants underwent annual physical assessment (height, weight, BMI, foot length), provided self-rated Tanner staging and annual fasting blood samples as well as quarterly urine samples. Urine T and E2 were measured by LC-MS/MS and LH by immunoassay (Immulite) in a single batch and corrected for specific gravity (SG). At baseline, mean ages (SD) were 12.5 (0.93) years for males and 11.8 (0.98) for females. Most scheduled samples were collected (93% serum, 92% urine) with a low participant attrition rate (<3% per annum). Urine E2, T and LH increased according to chronological age and Tanner stage from baseline to 1-year follow-up. Urine and serum hormones correlated with self-rated Tanner stages at both baseline and 1-year follow-up (p<0.01 for all). However, change in self-reported Tanner stage did not exhibit a significant association with change in urine or serum hormones. Changes in foot length were more strongly correlated with urine hormone changes than were other anthropometric or self-rated Tanner stage changes. These preliminary findings demonstrate the feasibility of intensive collection of urine samples together with validated urine assays for sex steroids and LH. These will allow a more accurate and sensitive, individual assessment of puberty timing and tempo. The preliminary findings related to foot length are of potential clinical interest. (1) Steinbeck et al., BMC Pediatr. 2012; 12:143 Nothing to Disclose: BWB, GKS, PJK, KP, CIH, DJH, KSS Sources of Research Support: Sources of research support: The ARCHER study is supported by the Australian National Health and Medical Research Council (NHMRC) Project Grant #1003312 awarded to CIH, KSS
    Endocrine Society's 96th Annual Meeting and Expo, Chicago; 06/2014
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    ABSTRACT: The evidence on the patterns of non-steroidal anti-inflammatory drugs (NSAIDs) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAIDs use according to pain prevalence and concordance with specific clinical guideline recommendations for safe NSAIDs use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n=1696) aged ⩾70 years living in Sydney were studied. 8.2% (n=139) of participants reported regular NSAIDs use compared with 2.9% (n=50) reporting as needed use. The mean treatment duration for regular NSAIDs use was 4.9 years suggesting long-term rather than short-term use as recommended by the guidelines. While guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAIDs users reported PPIs use. Regular NSAIDs users were significantly more likely to report use of opioid analgesics (p<0.0001) compared with non-regular users. In relation to pain prevalence, regular NSAIDs users were significantly more likely to report chronic pain (p<0.0001), recent pain (p=0.0001) and chronic intrusive pain (p<0.0001) compared with non-regular users. The findings of this study indicate that NSAIDs prescribing practices do not align with specific clinical practice guidelines for safe use in older people. This difference between the guideline recommendation and what is happening in the "real world" should be explored further.
    Pain 06/2014; · 5.64 Impact Factor
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    ABSTRACT: Polycystic ovary syndrome (PCOS) affects 5-10% of women of reproductive age, causing a range of reproductive, metabolic and endocrine defects including: anovulation, infertility, hyperandrogenism, obesity, hyperinsulinism and an increased risk of type 2 diabetes and cardiovascular disease. Hyperandrogenism is the most consistent feature of PCOS, but its etiology remains unknown, and ethical and logistic constraints limit definitive experimentation in humans to determine mechanisms involved. In this study, we provide the first comprehensive characterization of reproductive, endocrine and metabolic PCOS traits in four distinct murine models of hyperandrogenism, comprising prenatal dihydrotestosterone (DHT, potent non-aromatizable androgen) treatment during days 16-18 of gestation, or long-term treatment (90 days from 21 days of age) with DHT, dehydroepiandrosterone (DHEA), or letrozole (aromatase inhibitor). Prenatal DHT treated mature mice exhibited irregular estrous cycles, oligo-ovulation, reduced preantral follicle health, hepatic steatosis and adipocyte hypertrophy, but lacked overall changes in body fat composition. Long-term DHT treatment induced polycystic ovaries displaying unhealthy antral follicles (degenerate oocyte and/or > 10% pyknotic granulosa cells), as well as anovulation and acyclicity in mature (16 week old) females. Long-term DHT also increased body and fat pad weights, and induced adipocyte hypertrophy and hypercholesterolemia. Long-term letrozole treated mice exhibited absent or irregular cycles, oligo-ovulation, polycystic ovaries containing hemorrhagic cysts atypical of PCOS, and displayed no metabolic features of PCOS. Long-term DHEA treatment produced no PCOS features in mature mice. Our findings reveal that long-term DHT treatment replicated a breadth of ovarian, endocrine and metabolic features of human PCOS, and provides the best mouse model for experimental studies of PCOS pathogenesis.
    Endocrinology 05/2014; · 4.72 Impact Factor
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    ABSTRACT: Glucocorticoids are used as a last resort treatment for prostate cancer but the cell-specific glucocorticoid receptor (GR) mediated actions and the role of endogenous glucocorticoids in prostate are not understood.
    The Prostate 05/2014; · 3.84 Impact Factor
  • Gideon A. Sartorius, Lam P. Ly, David J. Handelsman
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    ABSTRACT: IntroductionMale sexual function is highly androgen dependent but whether aromatization of testosterone (T) to estradiol is required remains contentious.AimThis study aims to investigate the effects of selective estrogen deficiency induced by a nonaromatizable androgen, dihydrotestosterone (DHT), on sexual function of healthy middle-aged and older men.Methods Randomized clinical trial of daily transdermal DHT (70 mg) or placebo gel treatment in 114 healthy middle-aged and older (>50 years, mean 60.5 years) men without known prostate disease maintaining selective estrogen deficiency for 24 months.Outcome Measures and AnalysisThe end points were responses to a psychosexual and mood questionnaire completed before, at 3 months, then at 6 monthly intervals during and 3 months after study. Data were analyzed by mixed model analysis of variance for repeated measures using age and body mass index (BMI) as covariates and including interactions of treatment with age and time-on-study.ResultsDHT treatment increased serum DHT with complete suppression of serum T, luteinizing hormone, follicle stimulating hormone, and estradiol throughout the 24-month study resulting in reduced spinal bone density. There were no spontaneous complaints, or discontinuations for, adverse effects on sexual function during the study. DHT administration had no effects on any of 33 measures of sexual function and mood, apart from a mild, but significant decrease in overall sexual desire, which was reversible after cessation of treatment. Increasing age and less often increasing BMI were associated with significant decreases in most aspects of sexual function.Conclusions We conclude that aromatization plays only a minimal role in maintenance of sexual function in healthy eugonadal middle-aged or older men, but age and obesity are significantly associated with decreases in most aspects of self-reported sexual function and satisfaction. The dependence of male sexual function on aromatization may be conditional on age and obesity and can be overcome by a nonaromatizable androgen. Sartorius GA, Ly LP, and Handelsman DJ. Male sexual function can be maintained without aromatization: Randomized placebo-controlled trial of dihydrotestosterone (DHT) in healthy, older men for 24 months. J Sex Med **;**:**–**.
    Journal of Sexual Medicine 05/2014; · 3.51 Impact Factor
  • Julie D Newman, David J Handelsman
    The Clinical biochemist. Reviews / Australian Association of Clinical Biochemists 05/2014; 35(2):75-9.
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    ABSTRACT: Low-circulating testosterone is associated with development of type 2 diabetes in obese men. In this study, we examined the effects of experimental overfeeding and weight gain on serum levels of sex hormones and skeletal muscle expression of steroidogenic enzymes in healthy men with (FH+) and without (FH-) a family history of type 2 diabetes. Following a 3-day lead in energy balanced diet, FH+ (n=9) and FH- men (n=11) were overfed by 5200kJ/day (45% fat) for 28days. Body weight, fasting glucose, insulin, sex steroid, sex hormone binding globulin (SHBG) levels, insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) and body fat (DXA) were assessed in all individuals at baseline and day28, and sex steroidogenesis-related enzyme expression in vastus lateralis biopsies was examined in a subset (n=11). Body weight, fat mass and fasting insulin levels were increased by overfeeding (P<0.01) and insulin was increased significantly more in FH+ men (P<0.01). Serum sex hormone binding globulin (SHBG) and 5α-dihydrotestosterone (DHT) were reduced with overfeeding (P<0.05), and serum testosterone and DHT were reduced to a greater extent in FH+ men (P<0.05). Overfeeding reduced mRNA expression of 3β-hydroxysteroid dehydrogenase (HSD) and 17βHSD (P≤0.007), independently of group. 5α-Reductase (SRD5A1) mRNA expression was not changed overall, but a time by group interaction was observed (P=0.04). Overfeeding reduced SHBG and muscle expression of enzymes involved in the formation of testosterone in skeletal muscle. Men with a family history of T2DM were more susceptible to deleterious outcomes of overfeeding with greater reductions in serum testosterone and DHT and greater increases in markers of insulin resistance, which may contribute to increased risk of developing type 2 diabetes.
    Diabetes & Metabolism 04/2014; · 2.39 Impact Factor
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    ABSTRACT: Context: Testosterone (T) and nandrolone (N) esters require deep intramuscular injections by medical personnel but these often deposit injectate into subcutaneous fat, so that more convenient subcutaneous self-administration may be feasible. Objective: To investigate the feasibility, and pharmacology of subcutaneous injection of N decanoate in healthy men using dried blood spot (DBS) for frequent blood sampling without clinic visits. Participants, Methods and Outcomes: Healthy male volunteers received 100 mg N decanoate by a single subcutaneous injection. Finger-prick capillary blood was spotted onto filter paper before injection and daily at home for 21 days and stored at room temperature. Venous whole blood was also spotted onto filter paper before and weekly for 3 weeks after injection. DBS were extracted for assay of N and T by liquid chromatography, tandem mass spectrometry (LC-MS/MS) in a single batch with serum concentrations estimated with adjustment for capillary blood sample volume and hematocrit to define peak (N) or nadir (T) time and concentration from individual daily measurements. Results: Daily serum N peaked 2.50 ± 0.25 (SEM) ng/mL at a median (range) of 6 (4-13) days causing a reduction in serum T from 3.50 ± 0.57 ng/mL at baseline to a nadir of 0.38 ± 0.13 (SEM) ng/mL (89 ± 3% suppression) at a median (range) of 8 (5-16) days. Simultaneously sampled capillary, venous whole blood and serum gave almost identical results for serum T and N. Finger-pricks and subcutaneous injections were well tolerated. Conclusions: This study demonstrates that (a) DBS sampling with LC-MS steroid analysis achieves frequent time sampling in the community without requiring clinic visits, venesection or frozen serum storage and (b) androgen esters in an oil vehicle can be delivered effectively by subcutaneous injection avoiding the need for medically supervised deep intramuscular injections.
    The Journal of Clinical Endocrinology and Metabolism 03/2014; · 6.31 Impact Factor
  • Christian M Girgis, Ivan Kuo, David J Handelsman
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    ABSTRACT: Background: Although the illicit use of synthetic androgens is common amongst amatuer body-builders in Australia, the toxicology of these drugs is largely limited to case reports while the health effects are not well understood. Furthermore, combined use with off-label prescription drugs carries undefined medical risks.Method: We describe a 35-year-old male amateur body-builder who developed acute hepatitis with accompanying fever.Results: This phenomenon occured several weeks after he commenced high-dose methandrostenolone, a non-marketed 17-alpha-alkylated synthetic androgen available over the internet or in gyms, in combination with anti-oestrogen drugs to purportedly prevent gynaecomastia and diuretics to lower body weight prior to a body-building competition.Conclusion: In the absence of infection, this is the first reported case of acute hepatitis occuring in association with fever secondary to the use of a 17-alpha-alkylated androgen. This case also serves to increase public, physician and health authority awareness of this prevalent form of drug abuse and toxicity.
    Endocrine Practice 03/2014; · 2.49 Impact Factor

Publication Stats

8k Citations
2,055.67 Total Impact Points

Institutions

  • 2001–2014
    • Concord Hospital
      Concord, New Hampshire, United States
  • 1979–2014
    • University of Sydney
      • • Faculty of Pharmacy
      • • School of Public Health
      • • Eye disease Research Program
      • • Centre for Education and Research on Ageing
      • • Discipline in Obstetrics and Gynaecology
      Sydney, New South Wales, Australia
  • 2013
    • The George Institute for Global Health
      • Musculoskeletal Division
      Sydney, New South Wales, Australia
    • Hong Kong SAR Government
      Hong Kong, Hong Kong
    • Universiti Teknologi MARA
      Shah Alam, Selangor, Malaysia
  • 2009–2013
    • Garvan Institute of Medical Research
      • Cancer Research Program
      Darlinghurst, New South Wales, Australia
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • National Measurement Institute
      Sydney, New South Wales, Australia
  • 2011
    • Boston University
      • Section of Endocrinology, Diabetes, Nutrition
      Boston, Massachusetts, United States
  • 2001–2011
    • Sydney Orthopaedic Research Institute
      Sydney, New South Wales, Australia
  • 2010
    • Monash University (Australia)
      Melbourne, Victoria, Australia
  • 2004–2010
    • Heart Research Institute
      • Free Radical Group
      Newtown, New South Wales, Australia
  • 2001–2010
    • Concord Repatriation General Hospital
      Sydney, New South Wales, Australia
  • 1981–2010
    • Royal Prince Alfred Hospital
      • Division of Endocrinology
      Camperdown, New South Wales, Australia
  • 1997–2009
    • Royal North Shore Hospital
      Sydney, New South Wales, Australia
    • University of Newcastle
      Newcastle, New South Wales, Australia
  • 2008
    • Universitätsspital Basel
      Bâle, Basel-City, Switzerland
  • 2005
    • Flinders Medical Centre
      Tarndarnya, South Australia, Australia
  • 2003
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2002
    • Liaoning Research Institute of Family Planning
      Feng-t’ien, Liaoning, China