Medicine (Austin & Northern Health) - Research Publications
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ItemThe effects of testosterone on body composition in obese men are not sustained after cessation of testosterone treatment(WILEY, 2017-10)BACKGROUND: Testosterone treatment in obese dieting men augments the diet-associated loss of fat mass, but protects against loss of lean mass. We assessed whether body composition changes are maintained following withdrawal of testosterone treatment. METHODS: We conducted a prespecified double-blind randomized placebo-controlled observational follow-up study of a randomized controlled trial (RCT). Participants were men with baseline obesity (body mass index >30 kg/m2 ) and a repeated total testosterone level <12 nmol/L, previously enrolled in a 56-week testosterone treatment trial combined with a weight loss programme. Main outcome measures were mean adjusted differences (MAD) (95% confidence interval), in body composition between testosterone- and placebo-treated men at the end of the observation period. RESULTS: Of the 100 randomized men, 82 completed the RCT and 64 the subsequent observational study. Median [IQR] observation time after completion of the RCT was 82 weeks [74; 90] in men previously receiving testosterone (cases) and 81 weeks [67;91] in men previously receiving placebo (controls), P=.51. At the end of the RCT, while losing similar amounts of weight, cases had, compared to controls, lost more fat mass, MAD -2.9 kg (-5.7, -0.2), P=.04, but had lost less lean mass MAD 3.4 kg (1.3, 5.5), P=.002. At the end of the observation period, the former between-group differences in fat mass, MAD -0.8 kg (-3.6, 2.0), P=1.0, in lean mass, MAD -1.3 kg (-3.0, 0.5), P=.39, and in appendicular lean mass, MAD -0.1 kg/m2 (-0.3, 0.1), P=.45, were no longer apparent. During observation, cases lost more lean mass, MAD -3.7 kg (-5.5, -1.9), P=.0005, and appendicular lean mass, MAD -0.5 kg/m2 (-0.8, -0.3), P<.0001 compared to controls. CONCLUSIONS: The favourable effects of testosterone on body composition in men subjected to a concomitant weight loss programme were not maintained at 82 weeks after testosterone treatment cessation.
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ItemEffects of androgen deprivation therapy on telomere length(WILEY, 2017-10)OBJECTIVE: Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. DESIGN: We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). METHODS: We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. RESULTS: Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], P=.235). CONCLUSIONS: Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings.
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ItemQuality of life decrements in men with prostate cancer undergoing androgen deprivation therapy(WILEY, 2017-03)OBJECTIVE: While androgen deprivation therapy (ADT) has been associated with decreased quality of life (QoL), controlled prospective studies are lacking. We aimed to assess QoL during ADT using two validated questionnaires and determine contributing factors. DESIGN: Prospective controlled study. PATIENTS: Sixty-three men with nonmetastatic prostate cancer newly commencing ADT (n = 34) and age- and radiotherapy-matched prostate cancer controls (n = 29). MEASUREMENTS: QoL was measured by Short-Form 12 version 2 survey (SF-12) and Aging Males' Symptoms (AMS) score at 0, 6 and 12 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. RESULTS: Compared to controls over 12 months, men receiving ADT had decreased SF-12 physical component score [MAD -3·61 (-6·94, -0·29), P = 0·013] reflecting worsening QoL but no change in the mental component (P = 0·74). Total AMS score increased [MAD 9·35 (5·65, 13·07), P < 0·001], reflecting worse QoL. Both SF-12 and AMS changes were greater than reported minimum clinically important differences. AMS sub-domains showed increased somatic [MAD 3·96 (1·94, 5·99), P < 0·001] and sexual [MAD 3·80 (2·16, 5·44), P < 0·001] components but not psychological (P = 0·19). Decrements were related to an increase in hot flushes (P = 0·016) but not haemoglobin decrease (P = 0·46). CONCLUSIONS: Within 12 months, ADT is associated with clinically significant decreased QoL, particularly physical and sexual aspects, independent of the confounding effects of a cancer diagnosis or radiotherapy. As QoL is a crucial aspect of prostate cancer treatment, addressing hot flushes, sexual dysfunction and exercise may potentially improve outcomes for men undergoing ADT.
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ItemAdjuvant endocrine therapy in women with oestrogen-receptor-positive breast cancer: how should the skeletal and vascular side effects be assessed and managed?(WILEY, 2016-11)Adjuvant endocrine therapy provides oncological benefits in women with early oestrogen-receptor-positive breast cancer, but has adverse effects consequent to induced oestradiol deficiency. Bone loss is accelerated, predisposing to increased fracture risk. Metabolic effects include changes in lipid metabolism and body composition although effects on cardiovascular risk are still unclear. Women commencing endocrine therapy should be proactively counselled about and monitored for these and other therapy-related complications including arthralgia and vasomotor symptoms. We provide strategies for prevention and management of these adverse effects, based, where available, on randomized controlled trial evidence specific to breast cancer survivors receiving endocrine treatment.
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ItemHigh circulating oestrone and low testosterone correlate with adverse clinical outcomes in men with advanced liver disease(WILEY-BLACKWELL, 2016-11)BACKGROUND & AIMS: Circulating testosterone is usually reduced in men with cirrhosis, but there has not been a comprehensive analysis of androgen status or circulating oestrogens. Little is known about associations between circulating sex steroids with aspects of health in this population. METHODS: We report data from men with cirrhosis and low serum testosterone (<12 nmol/L or calculated free testosterone <230 pmol/L). Comprehensive circulating sex steroid profiles were measured by liquid chromatography-mass spectrometry and compared with age-matched controls. Relationships between sex hormone levels, severity of liver disease, biochemistry and clinical outcomes were assessed. RESULTS: Serum oestrone and oestradiol were significantly elevated in men with cirrhosis compared with controls (median, 869.1 pmol/L vs. 133.8 pmol/L and 166.7 pmol/L vs. 84.6 pmol/L respectively). Serum oestrone correlated with MELD score (correlation +0.306, P < 0.001) and inversely correlated with serum sodium (correlation -0.208, P = 0.004) and haemoglobin (correlation -0.177, P = 0.012). No such correlations were observed for oestradiol. Serum testosterone levels inversely correlated with MELD score (correlation -0.294, P < 0.001) and positively with handgrip strength (correlation +0.242, P < 0.001), physical activity (correlation +0.276, P = 0.012), haemoglobin (correlation +0.282, P < 0.001) and serum sodium (+0.344, P < 0.001). Dihydrotestosterone inversely correlated with MELD score (correlation -0.225, P = 0.002) and shared similar significant relationships to testosterone. CONCLUSION: Low serum androgens and elevated serum oestrone (but not oestradiol) are associated with higher MELD and individual adverse health outcomes in cirrhotic cohort of men selected for low testosterone. Serum oestrone may be a novel marker of ill health in this population. Whether low androgens are markers or mediators of ill health requires further investigation.
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ItemLow testosterone as a better predictor of mortality than sarcopenia in men with advanced liver disease(WILEY, 2016-03)BACKGROUND AND AIM: Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact. METHODS: We conducted a retrospective longitudinal cohort study of 145 men referred for liver transplant evaluation between 2005 and 2012. Baseline demographics included hormone profile and model of end-stage liver disease (MELD) score. Baseline computerized tomography was reformatted to calculate skeletal muscle area at L4 using validated, Tomovision software-based methodology. The primary outcome was time to death or liver transplantation. RESULTS: Median testosterone was low at 6.2 nmol/L (ref. 10-27.6 nmol/L) as was muscle mass at 48.0 cm(2)/m(2) (ref. > 52.4 cm(2)/m(2)). Muscle mass correlated with both serum testosterone (tau = 0.132, P = 0.019) and MELD score (tau = -0.155, P = 0.007). In separate multivariable models, both sarcopenia (hazard ratio [HR] 1.05, P = 0.04) and low testosterone (HR 1.08, P = 0.01) were significantly associated with mortality independent of MELD score. When the variables MELD score, muscle area, and testosterone were entered into a single model, low testosterone but not sarcopenia remained significantly predictive of mortality (HR 1.07, P = 0.02, and HR 1.04, P = 0.09, respectively). CONCLUSION: Low testosterone and sarcopenia are both associated with increased mortality in men with advanced liver disease and may identify patients at high risk of mortality that would be missed by the MELD score alone. Low testosterone appears to be a better predictor of mortality than sarcopenia and is a simpler test to improve the prognostic value of the MELD score. Interventional trials are required to determine whether low testosterone and sarcopenia are markers or mediators of mortality in this population.
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ItemReview article: sarcopenia in cirrhosis - aetiology, implications and potential therapeutic interventions(WILEY, 2016-04)BACKGROUND: Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting. AIMS: To summarise existing knowledge regarding the aetiology of sarcopenia in cirrhosis, diagnostic modalities and the clinical significance of this condition. In addition to discuss recent research findings that may allow the development of more effective treatments. METHODS: We conducted a Medline and PubMed search using the search terms 'sarcopenia', 'muscle', 'body composition', 'cirrhosis', 'liver' and 'malnutrition' from inception to October 2015. RESULTS: Cirrhotic patients with sarcopenia have reduced survival, experience increased rates of infection and have worse outcomes following liver transplantation. The aetiology of this condition is more complex than simple protein and calorie malnutrition. Cirrhosis also results in depleted glycogen stores and metabolic alterations that cause excessive protein catabolism, increased activation of the ubiquitin-proteasome pathway and inappropriate muscle autophagy. Satellite cell differentiation and proliferation is also reduced due to a combination of elevated myostatin levels, reduced IGF-1 and hypogonadism. Although there is some evidence supporting the use of late evening snacks, branched chain amino acid supplementation and high protein/high calorie diets, well designed clinical trials addressing the effects of treatment on body composition in cirrhosis are lacking. CONCLUSION: Sarcopenia in cirrhosis has a complex pathogenesis and simple dietary interventions are insufficient. Improved understanding of the multiple mechanisms involved should allow the development of more effective therapies, which target the specific underlying metabolic derangements.
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ItemLate-onset hypogonadism: metabolic impact(WILEY, 2020-11)BACKGROUND: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. OBJECTIVE: To review the metabolic impact of late-onset hypogonadism. METHODS: Comprehensive literature search with emphasis on recent publications. RESULTS: Obesity is one of the strongest modifiable risk factors for late-onset hypogonadism, and coexisting diabetes leads to further hypothalamic-pituitary-testicular axis suppression. The hypothalamic-pituitary-testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic-pituitary-testicular axis suppression is mediated by dysregulation of pro-inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic-pituitary-testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic-pituitary-testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance. DISCUSSION: The relationship between diabesity and late-onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects. CONCLUSIONS: While recent research has provided new insights into mechanistic and clinical aspects of diabesity-associated late-onset hypogonadism, more evidence from well-designed large trials is needed to guide the optimal clinical approach to such men.
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ItemAssessment and management of bone health in women with oestrogen receptor-positive breast cancer receiving endocrine therapy: position statement summary(WILEY, 2019-09)INTRODUCTION: Representatives appointed by relevant Australian medical societies used a systematic approach for adaptation of guidelines (ADAPTE) to formulate clinical consensus recommendations on assessment and management of bone health in women with oestrogen receptor-positive early breast cancer receiving endocrine therapy. The current evidence suggests that women receiving adjuvant aromatase inhibitors and pre-menopausal woman treated with tamoxifen have accelerated bone loss and that women receiving adjuvant aromatase inhibitors have increased fracture risk. Both bisphosphonates and denosumab prevent bone loss; additionally, denosumab has proven anti-fracture benefit in post-menopausal women receiving aromatase inhibitors for hormone receptor-positive breast cancer. MAIN RECOMMENDATIONS: Women considering endocrine therapy need fracture risk assessment, including clinical risk factors, biochemistry and bone mineral density measurement, with monitoring based on risk factors. Weight-bearing exercise and vitamin D and calcium sufficiency are recommended routinely. Anti-resorptive treatment is indicated in women with prevalent or incident clinical or morphometric fragility fractures, and should be considered in women with a T score (or Z score in women aged < 50 years) of < - 2.0 at any site, or if annual bone loss is ≥ 5%, considering baseline bone mineral density and other fracture risk factors. Duration of anti-resorptive treatment can be individualised based on absolute fracture risk. Relative to their skeletal benefits, risks of adverse events with anti-resorptive treatments are low. CHANGES IN MANAGEMENT AS RESULT OF THE POSITION STATEMENT: Skeletal health should be considered in the decision-making process regarding choice and duration of endocrine therapy. Before and during endocrine therapy, skeletal health should be assessed regularly, optimised by non-pharmacological intervention and, where indicated, anti-resorptive treatment, in an individualised, multidisciplinary approach.
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ItemTestosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment(WILEY, 2020-02)Epidemiological studies consistently demonstrate that lowered serum testosterone is not only common in men with established Type 2 diabetes, but also predicts future diabetic risks and increased mortality. Preclinical studies report plausible mechanisms by which low testosterone could mediate dysglycaemia. Exogenous testosterone treatment consistently reduces fat mass, increases muscle mass and improves insulin resistance in some studies, but the majority of currently available randomized controlled trials (RCTs) do not report a consistent glycaemic benefit. In men with diabetes, testosterone treatment effects on androgen deficiency-like clinical features are inconsistent, and effects on sexual dysfunction may be attenuated compared with men without diabetes. The long-term risks of testosterone treatment in older men without medical disease of the hypothalamic-pituitary-testicular axis are not known. Current RCTs are not definitive, owing to their small size, short duration and enrolment of men with mostly relatively good baseline glycaemic control not specifically selected for the presence of androgen deficiency symptoms. Although large, well-designed clinical trials are needed, given the benefit-risk ratio of testosterone treatment is not well understood, routine serum testosterone testing or testosterone treatment of asymptomatic men with Type 2 diabetes is currently not recommended. Carefully selected, symptomatic men with low testosterone who are informed of the lack of high-level evidence regarding the long-term benefits and risks of this approach may be offered a trial of testosterone treatment in combination with lifestyle measures, weight loss and optimization of comorbidities.
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