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.