Medicine (Austin & Northern Health) - Research Publications
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ItemThe effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.(Bioscientifica, 2024-03-01)We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.
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ItemTestosterone Treatment, Weight Loss, and Health-related Quality of Life and Psychosocial Function in Men: A 2-year Randomized Controlled Trial(ENDOCRINE SOC, 2024-02-09)OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year, randomised controlled, testosterone therapy trial for prevention, or reversal of newly diagnosed, type 2 diabetes, enrolling men > 50 years at high risk for type 2 diabetes from six Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomised into T4DM, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and two years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and less depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSIONS: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.
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ItemNo Preview AvailableApproach to the Patient: The Evaluation and Management of Men ≥50 Years With Low Serum Testosterone Concentration(ENDOCRINE SOC, 2023-08-18)Although testosterone replacement in men with classic hypogonadism due to an identified pathology of the hypothalamic-pituitary-testicular axis is uncontroversial, the role of testosterone treatment for men with age-related declines in circulating testosterone is unclear. This is due to the lack of large, long-term testosterone therapy trials assessing definitive clinical endpoints. However, men ≥50 years of age, particularly those who have a body mass index >25 kg/m2 and multiple comorbidities, commonly present with clinical features of androgen deficiency and low serum testosterone concentrations. Clinicians are faced with the question whether to initiate testosterone therapy, a difficult dilemma that entails a benefit-risk analysis with limited evidence from clinical trials. Using a case scenario, we present a practical approach to the clinical assessment and management of such men.
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ItemNo Preview AvailableMediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial(OXFORD UNIV PRESS, 2023-07-10)OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed. RESULTS: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.
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ItemNo Preview AvailableTestosterone is lower in men with non-alcoholic fatty liver disease and alcohol-related cirrhosis and is associated with adverse clinical outcomes(TAYLOR & FRANCIS LTD, 2023-11-02)BACKGROUND/AIMS: Low serum testosterone is common in cirrhotic men, but the impact of disease aetiology remains uncertain. This study compares serum total testosterone (TT) levels by disease aetiology and assesses its prognostic value. METHODS: Single-centre retrospective study of cirrhotic men who had TT levels measured between 2002 and 2020. A cut-off of 12 nmol/L was used to define low TT and 230 pmol/L for calculated free testosterone (cFT). Linear and logistic regression used to adjust for variables known to affect testosterone levels and assess for an association between levels and outcomes. RESULTS: Of 766 cirrhotic men, 33.3% had alcohol-related liver disease (ALD) and 11.9% had non-alcoholic fatty liver disease (NAFLD). The median age was 56 years (interquartile range (IQR) 50-61), and the model for end-stage liver disease (MELD) score 14 (IQR 9-20). TT levels were low in 53.3% of patients, (median 11.0 nmol/L; IQR 3.7-19.8) and cFT low in 79.6% (median 122 pmol/L; IQR 48.6-212). Median TT was lower in men with ALD (7.6 nmol/L; IQR 2.1-16.2) and NAFLD (9.8 nmol/L; IQR 2.75-15.6) compared to other aetiologies (11.0 nmol/L; IQR 3.73-19.8) (p < 0.001 for all), which remained true after adjustment for age and MELD score. TT was inversely associated with 12-month mortality or transplant (381 events, p = 0.02) and liver decompensation (345 events, p = 0.004). CONCLUSIONS: Low serum testosterone is common in cirrhotic men and is associated with adverse clinical outcomes. TT levels are significantly lower in ALD and NAFLD compared to other disease aetiologies. Further large-scale studies are required to assess the potential benefits of testosterone therapy.
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ItemPrevalence of polycythaemia with different formulations of testosterone therapy in transmasculine individuals(WILEY, 2021-06)BACKGROUND: Masculinising hormone therapy with testosterone is used to align an individual's physical characteristics with his or her gender identity. Testosterone therapy is typically administered via intramuscular or transdermal routes, and polycythaemia is the most common adverse event. AIMS: To compare the risk of polycythaemia with different formulations of testosterone therapy in transmasculine individuals. METHODS: A retrospective cross-sectional analysis was undertaken of transmasculine individuals at a primary and secondary care clinic in Melbourne, Australia. A total of 180 individuals who were on testosterone therapy for >6 months was included. Groups included those receiving: (i) intramuscular testosterone undecanoate (n = 125); (ii) intramuscular testosterone enantate (n = 31); or (iii) transdermal testosterone (n = 24). Outcome was prevalence of polycythaemia (defined as haematocrit > 0.5). RESULTS: Mean age was 28.4 (8.8) years, with a median duration of testosterone therapy of 37.7 (24.2) months; 27% were smokers. There was no difference between groups in serum total testosterone concentration measured. While there was no difference between groups in haematocrit, there was a higher proportion of patients with polycythaemia in those who were on intramuscular testosterone enantate (23.3%) than on transdermal testosterone (0%), P = 0.040. There was no statistically significant difference in polycythaemia between intramuscular testosterone undecanoate (15%) and transdermal testosterone, P = 0.066 nor between intramuscular testosterone enantate and undecanoate, P = 0.275. CONCLUSIONS: One in four individuals treated with intramuscular testosterone enantate and one in six treated with testosterone undecanoate had polycythaemia. No individual treated with transdermal testosterone had polycythaemia. This highlights the importance of regular monitoring of haematocrit in transmasculine individuals treated with testosterone, and findings may inform treatment choices.
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ItemEffects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer(WILEY, 2023-02)OBJECTIVE: Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor-positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. METHODS: We conducted a prospective 12-month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6 months and 12 months using dual X-ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. RESULTS: In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of -5.00 cm2 (-16.9, 6.91), p = .55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. CONCLUSIONS: These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study.
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ItemBone health assessment with dual energy X-ray absorptiometry in men with high-risk prostate carcinoma commencing adjuvant androgen deprivation therapy.(VM Media SP. zo.o VM Group SK, 2022)BACKGROUND: Androgen deprivation therapy (ADT) is a key component of therapy for patients with high-risk prostate carcinoma, but it may be deleterious for bone health. We sought to determine the frequency of dual energy x-ray absorptiometry (DXA) scanning in patients commencing adjuvant ADT for treatment of high-risk prostate cancer at a large integrated regional cancer centre. MATERIAL AND METHODS: The electronic medical records (EMR) of all patients with high-risk prostate carcinoma commenced on adjuvant ADT between January 1, 2016 and December 31, 2017 at the Mid-North Coast Cancer Institute, Coffs Harbour, Australia were reviewed. Patients commenced on neoadjuvant ADT and long-term suppressive ADT for metastatic disease were excluded. The following data were obtained: socio-demographic information, prostate cancer data, ADT details and DXA results. RESULTS: 188 men (mean age ± SD, 75.4 ± 7 years) were commenced on adjuvant ADT for a total duration (mean ± SD) of 23.4 ± 7 months. Most (n = 155/188, 82%) were commenced on leuprorelin acetate. While only 26/188 (14%) had a DXA scan performed prior to ADT, another 133 (71%) had a DXA scan at a median of 20 days (interquartile range 7-98), later. Of the 159 men with DXA readings, 76 (48%) were osteopaenic and 38 (24%) were osteoporotic by DXA criteria. CONCLUSION: A high level (85%) of DXA scanning in men commencing ADT for prostate cancer can be achieved at a regional centre. The high prevalence (72%) of low bone mass in our unselected cohort underscores the importance of routine DXA scanning to guide bone health management during ADT.
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ItemNo Preview AvailableEffects of estradiol on bone in men undergoing androgen deprivation therapy: a randomized placebo-controlled trial(BIOSCIENTIFICA LTD, 2022-08)OBJECTIVE: In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T. DESIGN: This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling. METHODS: 78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers. RESULTS: For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: -0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers. CONCLUSION: Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.
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ItemNo Preview AvailableEffects of oestradiol treatment on hot flushes in men undergoing androgen deprivation therapy for prostate cancer: a randomised placebo-controlled trial(OXFORD UNIV PRESS, 2022-11-01)OBJECTIVE: Most men undergoing androgen deprivation therapy (ADT) for prostate cancer experience hot flushes. Current treatments have low or limited evidence of efficacy. It is likely that oestradiol depletion is the mediator of these hot flushes, and transdermal oestradiol might be an effective treatment. DESIGN: This is a 6-month randomised, placebo-controlled trial with the hypothesis that oestradiol would reduce hot flush frequency and intensity and improve quality of life (QoL). METHODS: Seventy-eight participants receiving ADT were randomised to 0.9 mg of 0.1% oestradiol gel per day or matched placebo. Hot flush frequency and severity were assessed by 7-day diary at baseline, month 1, month 3, and month 6. QoL was assessed by validated questionnaire. RESULTS: Oestradiol reduced daily hot flush frequency, with a mean adjusted difference (MAD) of -1.6 hot flushes per day (95% CI: -2.7 to -0.5; P = 0.04). The effect on weekly hot flush score was non-significant, with a MAD -19.6 (95% CI: -35.5 to -3.8; P = 0.11). On per protocol analysis, E2 significantly reduced daily hot flush frequency, with a MAD of -2.2 hot flushes per day (95% CI: -3.2 to -1.1; P = 0.001), and weekly hot flush score, with a MAD of -27.0 (-44.7 to -9.3; P = 0.02). Oestradiol had no significant effect on QoL. CONCLUSION: We confirmed our hypothesis of a clinical effect of assignment to oestradiol to reduce hot flush frequency in men with castrate testosterone due to ADT. Transdermal oestradiol could be considered for men with burdensome hot flushes in whom other treatments have failed as long as the risk of breast effects and fat gain are considered.