Androgen deprivation therapy for prostate cancer : novel mechanisms of testosterone action and the benefits of home-based progressive resistance training

Abstract

Testosterone is a key anabolic hormone which has a major role in the regulation of muscle mass and function, glucose and fat metabolism, mental well-being and general health. Androgen deprivation therapy (ADT) is a common treatment modality in men with prostate cancer. In reducing testosterone to castrate levels, it offers a unique model to study the physiological effects of testosterone. Testosterone is known to act on multiple pathways which regulates muscle mass, fibre hypertrophy and protein turnover. Protein is hydrolysed into amino acids which are then available for synthesis of new protein, or alternatively can be eliminated as urea by the hepatic urea cycle; a rate limiting step in the irreversible loss of protein nitrogen. Although testosterone deficiency is well-known to be associated with loss of muscle mass and other protein depots, the effect of testosterone on the hepatic urea cycle has not been studied in humans. ADT also leads to a substantial increase in fat mass, worsening glucose tolerance, impairment in muscle function, and deterioration in mental health. In fact, cardiovascular disease accounts for approximately a quarter of deaths amongst men with prostate cancer. Exercise has been used to improve ADT-induced adverse effects, but existing studies focus on reversing established changes with supervised programs which have limitations in terms of access and cost. Home-based progressive resistance training (PRT), if found effective, may provide a viable alternative to supervised training programs. The work described in this thesis aimed to determine a hepatic site of testosterone action via the urea cycle- firstly in a cohort of hypogonadal men, followed by a population of men with prostate cancer starting ADT. A home-based PRT program was 16 also evaluated in this population regarding its efficacy in preventing the adverse effects of ADT when initiated at the start of treatment. In summary, the work described in this thesis demonstrates, for the first time, a hepatic site of testosterone action via the urea cycle in humans. Additionally, it shows the benefits of a home-based PRT program in preventing ADT-induced adverse effects. These findings may contribute to the discovery of a potential, novel treatment method for sarcopenia, and a viable alternative to supervised exercise programs during prostate cancer treatment.

Date of Award	2021
Original language	English