Medicine (Austin & Northern Health) - Theses
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ItemEffect of testosterone therapy combined with a very low caloric diet in obese men: a randomised controlled trial( 2017)Context: Whilst testosterone treatment is indicated for men with classical hypogonadism, there is no consensus as to whether treatment should be given to men with functional hypogonadism due to paucity of high-quality randomised controlled trials (RCT) of long duration. Obesity is commonly associated with low testosterone with approximately one third of adult men in developed countries classified as obese and one third of these men have low testosterone levels. Weight loss through diet and exercise can lead to modest increases in testosterone levels and improve quality of life but whether the addition of testosterone treatment has additional benefits on body composition and constitutional symptoms is unknown. Objective and methods: In this 56-week RCT of 100 obese men with low total testosterone levels subjected to a rigorous weight loss program, we investigated the effect of intramuscular testosterone undecanoate treatment on fat mass, lean mass, body weight, metabolic parameters, constitutional symptoms, adipokines, gut-derived hormonal mediators of appetite, bone mineral density and bone remodelling markers. A pre-specified blinded follow-up study was conducted for a duration of at least one year following the end of the RCT to determine whether any changes in the RCT were maintained following treatment withdrawal. Results: Testosterone treatment led to reductions in total fat mass (mean adjusted difference, MAD, -2.9kg, [ 95% CI -5.7, -0.20], P=0.04) and visceral fat (-2,678mm2 [-5,180, -176], P=0.04) over and above that achieved with dieting. Diet-induced loss of muscle mass was mitigated (MAD 3.4kg [1.3, 5.5], P=0.002) following testosterone treatment. Testosterone treatment improved Aging Males Symptoms (AMS) score (MAD -0.34, [-0.65, -0.02], P=0.04) and international index of erectile function version 5 (IIEF-5) scores (MAD -0.32 [-0.59, -0.05], P=0.025). Testosterone treatment led to a reduction in circulating leptin levels, MAD -3.6ng/ml [-5.3, -1.9], P<0.001. The changes in gut-derived hormonal mediators of appetite following weight loss in men receiving placebo was not modified by the addition of testosterone treatment. There was a reduction in c-telopeptide, MAD -66ng/L [-113, -19], P=0.018 and in procollagen type 1 N propeptide, MAD -5.6ug/L [-10.1, -1.1], P=0.03, but no change in bone mineral density between testosterone and placebo-treated men. The changes in fat mass and lean mass following testosterone treatment in the RCT were not preserved in the follow-up observation period. Twelve months after RCT completion, total testosterone levels were no different in previously testosterone and placebo-treated (P=0.71) men. Conclusions: In this rigorously conducted RCT comprehensively examining testosterone treatment in obese men, the use of testosterone treatment in obese men promoted favourable changes in body composition and improved constitutional symptoms over and above those achieved with diet alone. As the benefits of testosterone treatment are not maintained following treatment withdrawal, further studies are required to establish the long-term risk/benefit profile in this large group of men who may be considered for testosterone treatment.
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ItemThe impact of low testosterone and the effect of testosterone therapy in men with advanced liver disease( 2017)Background: Cirrhosis is increasing in prevalence, and disproportionately affects men. Sarcopenia is one of commonest clinical sequelae of cirrhosis, with a reported prevalence of up to 70%. Sarcopenia has been associated with increased mortality across multiple studies, independently of the established prognostic tool the Model for End-stage Liver Disease (MELD). This association appears to be attributable to an increase in infection-related deaths. Serum testosterone is reduced in up to 90% of men with cirrhosis, and has also been independently associated with increased mortality in a single-centre cohort of men waitlisted for liver transplantation. Serum testosterone and muscle mass are closely related in non-liver populations, but the relationship between low testosterone and sarcopenia has not been investigated in cirrhosis. Testosterone therapy increases muscle mass in non-cirrhotic men with hypogonadism, but the impact of testosterone therapy on body composition in cirrhotic men is not known. Aims: This work aims to explore the interaction between low testosterone and sarcopenia and their relative impact on outcome in men with cirrhosis, and prospectively validate the prognostic value of low testosterone. The potential therapeutic application of testosterone as a means of ameliorating sarcopenia in cirrhotic men is assessed in addition to its impact on other outcomes. Methods: A retrospective analysis of 145 patients from a single centre liver transplant database was conducted to correlate muscle mass (as measured by height-adjusted muscle area at the transverse CT scan slice of the 4th lumbar vertebrae) with testosterone levels, and to investigate their respective impact on outcomes including mortality. A prospective cohort study followed 268 consecutive men with cirrhosis reviewed in the hepatology ambulatory care setting for a 12 month period after quantifying baseline circulating testosterone to evaluate the association between testosterone levels and infection, mortality and transplantation. A 12 month, randomised, placebo-controlled trial of testosterone undecanoate in 101 men with cirrhosis with low baseline testosterone levels (total testosterone <12nmol/L or free testosterone <230pmol/L) evaluated the effect of testosterone on body composition (as measured by dual energy x-ray absorptiometry) and other outcomes including mortality, infection, bone density and haematology and biochemistry. Results: In a pre-transplant cohort of cirrhotic men, low testosterone correlates modestly with sarcopenia (tau=0.132, p=0.019) and appeared to be a better predictor of mortality than sarcopenia in a multivariable analysis incorporating the MELD score (HR 1.07, p=0.02 for low testosterone vs HR 1.04, p=0.09 for sarcopenia). In a general hepatology setting, there is an increased risk of mortality or transplantation (OR 2.36, p=0.018) when total testosterone fell below the threshold of 8.3nmol/L, independent of the MELD score. Similarly, the low testosterone group conferred an independent increase in the risk of major infection (HR 3.61, p<0.001). Administration of intramuscular testosterone undecanoate to this population resulted in a significant increase in both appendicular lean mass (mean adjusted difference (MAD) 1.69kg, p=0.021), and total lean mass (MAD 4.74kg, p=0.008) as compared to placebo. In addition, testosteronetreated patients had a reduction in fat mass (MAD -4.34kg, p<0.001) and HbA1c (MAD -0.35%, p=0.024) as well as increased bone mass (MAD 0.08kg, p=0.009) and haemoglobin (MAD 10.2g/L, p=0.041). There was no increase in adverse events in testosterone-treated subjects. Conclusion Low testosterone in men with cirrhosis is associated with increased risk for mortality or transplantation as well as major infection. It may be a better prognostic marker than sarcopenia, which may relate to its non-muscle effects. Testosterone therapy in men with cirrhosis selected for low baseline testosterone levels increases muscle mass as well as increases bone mass and haematocrit, and reduces fat mass and HbA1ct. Testosterone is the first therapy with randomised controlled data to support its use in the treatment of sarcopenia in cirrhosis. Larger-scale studies are required to assess for an effect on clinically meaningful endpoints such as infection risk, hospitalisation and mortality.
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ItemMuscle effects of androgen deprivation therapy in men with prostate cancer( 2016)BACKGROUND: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer but has many adverse effects consequent to severe testosterone deficiency including decreases in muscle and bone and increases in fat mass. Despite the decline in muscle mass, previous studies of muscle function have not demonstrated consistent deficits, likely due to imprecise methodology, which was insensitive to detect functional changes associated with ADT. We hypothesised that firstly, ADT causes clinically relevant deficits in the lower-limb muscles and has differential effects on individual muscles; secondly, ADT decreases muscle mass, increases frailty, insulin resistance and impairs quality of life (QoL); thirdly, ADT leads to changes in testosterone-regulated genes in skeletal muscle. METHODS: My colleagues and I conducted a 12-month prospective, observational case-control study of 63 men with non-metastatic prostate cancer at a tertiary hospital. Men newly commencing androgen deprivation therapy (ADT) (n=34) were compared to age-and radiotherapy-matched prostate cancer controls (n=29) using a linear mixed model. Motion capture and ground reaction force data were combined with computational musculoskeletal modeling to assess lower-limb muscle function whilst walking on level ground at self-selected speed in a Biomotion Laboratory. The following primary outcomes were determined: 1) Peak joint torques developed about the hip, knee and ankle, and corresponding individual muscle forces. 2) Individual muscle contributions to the accelerations of the body’s centre of mass. 3) Walking speed, stride length and step width. Secondary outcomes included handgrip strength, insulin resistance (updated homeostatic model assessment for insulin resistance: HOMA2-IR), Fried’s frailty criteria and QoL. Next-generation RNA sequencing was performed on skeletal muscle biopsies (n=9) to identify differentially expressed genes with ADT. RESULTS: Compared to controls over 12 months, men receiving ADT had more marked decreases in peak hip flexor torque and knee extensor torque, with mean differences of -0.11newtons/kg [-0.19, -0.03], p=0.01 (-14% of the initial mean value) and -0.11newtons/kg [-0.20, -0.02], p=0.02 (-16% of the initial mean value), respectively. Correspondingly, iliopsoas force decreased by 14% (p=0.006) and quadriceps force decreased by 11%, although this narrowly missed statistical significance (p=0.07). Soleus decreased contribution to forward acceleration of the body’s centre of mass by 17% (p<0.01) in the ADT group compared with controls. Furthermore, step width increased by 18% (p=0.042) with no change in stride length or walking speed. Insulin resistance increased which was related to increased fat mass, p=0.003, but not decreased lean mass (p=0.09) and less so to testosterone levels (p=0.088). Visceral fat was unchanged. QoL decreased in the ADT group, with predominant effects on physical and sexual subdomains. Actin alpha cardiac muscle 1 (ACTC1) gene was upregulated in skeletal muscle of men undergoing ADT. CONCLUSION: Testosterone deprivation causes selective functional deficits on lower-limb muscles, predominantly affecting iliopsoas, quadriceps and soleus, muscles involved in supporting body weight and accelerating the body forward during walking, and may also affect balance. As gain in fat mass mediates insulin resistance, implementing lifestyle measures to prevent obesity in men commencing ADT is paramount. Future exercise studies or promyogenic interventions to mitigate ADT-associated sarcopaenia and obesity should target the deficits described to maximise muscle function and QoL in men commencing ADT.
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ItemControl of musculoskeletal function and body composition by androgens in males( 2014)Context: Testosterone is the main male sex hormone and is important for normal male development and reproductive health. Testosterone also has actions on non-reproductive tissues including bone, fat and muscle, although the understanding of these actions is incomplete. The effects of testosterone withdrawal (in men about to commence androgen deprivation therapy (ADT) for prostate cancer) and testosterone replacement (in men about to commence testosterone replacement therapy (TRT) for classical androgen deficiency) on bone microarchitecture, bone mineral density (BMD), body composition, abdominal fat distribution, insulin resistance and metabolic profile were studied using rigorous, identical methodology. Objective and Patients: We prospectively investigated changes in bone microarchitecture in 26 men (70.6 ± 6.8 years) with non-metastatic prostate cancer during the first year of ADT and 10 men (52.0 ± 17.6 years) with classical androgen deficiency during the first year of TRT using the new technique high resolution peripheral quantitative computed tomography (HR-pQCT). BMD and body composition were studied using dual energy x-ray absorptiometry and subcutaneous and visceral abdominal fat were quantitated from abdominal computed tomography images using Slice-O-Matic software. Results: After 12 months ADT, total volumetric bone density decreased by 5.2 ± 5.4% at the distal radius and 4.2 ± 2.7% at the distal tibia (both p <0.001). This was due to a decrease in cortical volumetric BMD (by 11.3 ± 8.6% radius and 6.0 ± 4.2% tibia, all p<0.001) and trabecular density (by 3.5 ± 6.0% radius and 1.5 ± 2.3% tibia, all p<0.01), after correcting for trabecularisation of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (p<0.05). Total testosterone (TT), not estradiol (E2), was independently associated with total and corrected cortical volumetric BMD at the tibia. 12 months ADT increased visceral abdominal fat area from 160.81 ± 61.68 to 195.94 ± 69.71 cm2 (p<0.01) and subcutaneous abdominal fat area from 240.74 ± 107.54 to 271.27 ± 92.83 cm2 (p<0.01). Fat mass increased by 3.4 kg (24100 ± 9240 to 27500 ± 8702g; p<0.001) and lean body mass decreased by 1.9 kg (52500 ± 7105 to 50600 ± 7150g; p<0.001). Insulin resistance (HOMA-IR) increased after 12 months of ADT (2.50 ± 1.12 to 2.79 ± 1.31, p<0.05) but there was no change in fasting glucose or glycated haemoglobin levels. TT was inversely associated with visceral fat area independently of E2, but not vice versa. Visceral fat area, not TT or E2, was independently associated with insulin resistance. After 12 months of TRT, trabecular density increased at the radius, but there were no other significant changes in bone microarchitecture, abdominal fat distribution, body composition or insulin resistance Conclusions: Sex steroid deficiency induced by ADT for prostate cancer results in bone microarchitectural decay and accumulation of visceral and subcutaneous abdominal fat. Increased insulin resistance may arise secondary to visceral fat accumulation, rather than directly due to sex steroid deficiency. TRT in men with classical androgen deficiency results in improved trabecular bone density; other conclusions regarding the effects of TRT are limited by small numbers of study subjects.