Background: With a growing ageing population worldwide, frailty and its consequences have never been of more interest to healthcare systems and researchers. Whilst recognising the affected or at-risk individuals has greatly improved in the recent years, the relative lack of effective treatment strategies, largely owing to a poorly understood pathophysiology of frailty, has affected the progress in this area. Whilst a number of endocrine factors, mainly decreasing levels of anabolic hormones, are considered to be the key factors leading to frailty, the supporting evidence is largely lacking. Aim: My aim was to determine the associations of frailty with endocrine parameters in the aging European men as well as investigate the possible neuropathophysiological mechanisms linking anabolic and reproductive hormones with sarcopaenia, thought to be a central feature of frailty. Methodology: To assess the associations of baseline levels and dynamic changes (over 4.4-years) in endocrine parameters with changes in frailty status (assessed by frailty phenotype and frailty index), I analysed data from The European Male Ageing Study (EMAS), a prospective cohort study of 3369 men from 8 European centres. To investigate the associations of anabolic and reproductive hormones with electromyography-derived motor unit characteristics of quadriceps muscle I analysed data from the Motor Unit Remodelling Study, a single-centre observational cohort of 114 community-dwelling men. Results: Using prospective data from the EMAS, I have demonstrated that higher levels of IGF-1 and its binding globulin IGFBP-3, vitamin D and free testosterone were all associated with reduced risk of developing frailty during the follow-up period in middle-aged and older men. Also, lower levels of DHEA-S were associated with reduced risk of worsening frailty but only in men older than 70 years, whereas higher level of gonadotropins in younger (< 60 years old) men appeared to be a maker of frailty. With the use of electromyographic techniques I found that higher free testosterone levels were related to greater muscle contractility. The magnitude of this association was increasing with increasing frailty. Higher vitamin D level was related to larger motor unit potential, indicative of a successful compensatory reinnervation of muscle fibres after motor neuron loss. Conclusions: I have shown that higher levels of anabolic and reproductive hormones may protect elderly men from worsening frailty and physical function that occurs with age. It is possible that some of these protective actions are exerted at the level of muscle where endocrine factors appear to play a role in maintaining neuromuscular function. The causal nature of these relationships requires further investigation and specific clinical trials are needed to assess whether androgen therapy in frail and prefrail men might have a role in improving muscle function and levels of frailty.
|Date of Award||1 Aug 2020|
- The University of Manchester
|Supervisor||Frederick Wu (Supervisor) & Martin Rutter (Supervisor)|