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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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.
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ItemClinical and physiological differences in obese individuals with and without diabetes mellitus undergoing a very-low-calorie diet program.( 2012)In Australia, the rising prevalence of obesity and type 2 diabetes mellitus represents the major health challenge of the 21st Century. Weight reduction is a cornerstone of modern management of overweight and obese patients with type 2 diabetes; however, management of the obese diabetic patient remains one of the most challenging in clinical medicine. Very-low-calorie diets (VLCDs) – defined as diets limiting energy intake to 800 kcal (3.35 MJ) per day while providing at least 50 g of high-quality protein and amino acids, essential fatty acids and daily requirements of trace elements, vitamins and minerals – have been advanced as a therapeutic intervention for weight loss in overweight and obese individuals with type 2 diabetes mellitus. However, whether obese individuals with diabetes lose as much weight as non-diabetic individuals using VLCDs remains uncertain, as earlier studies had significant limitations. The aim of this thesis was to examine the question: are obese individuals with type 2 diabetes mellitus as “successful” as obese individuals without diabetes participating in a VLCD program? Success may variably be defined in terms of weight loss, decreases in anthropometric measurements such as waist circumference, improvements in body composition such as reductions in percentage body fat or visceral adipose tissue, improvements in metabolic parameters or insulin dosage, or improvements in renal and cardiac function. While previous studies have been primarily focused upon weight loss, the focus of this thesis is to explore the effects of VLCDs in this broader context of successes that may be attributable to participation in these weight loss programs. Importantly, the comparison of diabetic and non-diabetic individuals using VLCDs is an area hitherto under-investigated. Chapter 2 presents the results of a single centre, prospective, case-control study investigating change in weight and body composition in obese subjects with type 2 diabetes mellitus or normal fasting glucose concentrations undergoing a 24-week VLCD program. It was found that while following a 24-week VLCD program, obese subjects with and without diabetes achieved comparable weight loss but the decrease in adiposity per unit weight loss was attenuated in diabetic subjects. Hyperinsulinemia may have inhibited lipolysis in the diabetic group; however, other factors may also have contributed. Chapter 3 extends the findings of Chapter 2 by reporting on change in abdominal adipose tissue compartments, namely visceral and subcutaneous adipose tissue depots, and the changes in adipokines associated with change in visceral fat. In diabetic subjects, increased VAT volume at baseline, not baseline BMI, predicted greater weight loss. Reduction in VAT relative to abdominal SAT was attenuated in the diabetic compared to control group. Differences between the groups related to insulin and adiponectin concentrations may have contributed to this observation. Chapter 4 reports on a pilot study of abdominal magnetic resonance imaging, originally performed to image visceral adiposity, to measure skeletal muscle area at the 3rd lumbar vertebral level, allowing estimation of whole body skeletal muscle mass derived by dual-energy X-ray absorptiometry. The use of formulae previously developed in a cancer patient population was verified, with suggestions for improving these calculations for use in an obese population. Chapters 5, 6 and 7 present data on changes in renal and cardiac function and reproductive hormone profiles. Renal function was measured using the plasma clearance of the radioisotope 99mTc-diethylene-triamine-penta-acetic acid (DTPA) technique, with the Brochner-Mortensen correction. Change in advanced glycation end-products was also documented. Cardiac function was measured using transthoracic echocardiography, adding to the existing literature which is largely derived from studies of bariatric surgery. In summary, the efficacy of VLCDs in facilitating weight loss was shown to be preserved in obese individuals with diabetes. However, significant differences in the change in body composition including reductions in body fat and visceral adiposity were found. The findings of this study have implications for the management of obese individuals with diabetes undergoing intensive dietary therapies, with a greater clinical focus on fat reduction and attention to antidiabetic and weight loss pharmacotherapies mandatory in this difficult to treat population.