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Frailty can be broadly defined as the vulnerable health status that occurs in older adults. With the ageing population understanding frailty is becoming an increasingly important issue. While no consensus exists on the exact definition of frailty, two models have become prominent in geriatric research. These are the frailty phenotype, a model that measures frailty according to the syndromic aggregation of 5 physical criteria and the frailty index (FI), a broad index of age related health deficits. While recent years have seen a substantial increase in research into frailty, there remains a relative paucity of data from European studies and studies in men. Of the many mechanisms suggested to contribute to frailty there has been particular interest in the role of declining levels of anabolic hormones, partly because replacement of these hormones represents a potential strategy for managing this condition. The broad aim of this thesis was to explore the condition of frailty and its relationship to anabolic hormones, particularly testosterone (T) in ageing European Men. This project involved analysis of data from 2 studies: The European Male Ageing Study (EMAS), a longitudinal cohort study of 3369 men from 8 European centres and a trial of T treatment in 262 men with low testosterone and symptoms of frailty. A set of phenotypic frailty criteria were developed for use in the EMAS, using this model the prevalence of frailty was 2.6%. This increased with age from 0.1% in men aged 40-49 up to 6.7% in men aged 70-79. This model was compared against an FI, the correlation between the two models was moderate, r=0.41, and both models were related to incident falling at 2 year follow up; Ordinal OR (95% CI), 3.15 (1.75 to 5.66) for the frailty phenotype and 5.28 (3.35 to 8.32) for the FI in adjusted analyses. In the hormone analyses frailty was related to lower free T according to both models, Ordinal OR (95% CI); 1.19 (1.02 to 1.39) for the phenotype and β-coefficient (95% CI); 0.006 (0.003 to 0.009) for the FI (FI values range from 0-0.7). Free T was particularly related to the sarcopenia criteria OR (95% CI); 1.40 (1.09 to 1.80). Frailty was also related to LH, FSH and SHBG. Deficiency in multiple anabolic hormones was related to frailty, in adjusted analyses each additional deficiency was associated with an RRR (95% CI); 1.71 (1.38 to 2.13) increased risk of phenotypic frailty and a β-coefficient (95% CI); 0.016 (0.012 to 0.02) increase in FI score. The trial analyses focussed on a 6 month post treatment follow up phase. It was found that gains in lean mass and muscle strength were not maintained at 6 months post treatment. The adjusted difference between groups at 6 months post treatment for knee extensor strength was 4.0 (-3.9 to 11.9) Nm compared to 8.1 (-0.2 to 16.5) Nm at the end of treatment, similarly the difference in lean mass declined from 1.2 (0.8 to 1.7) kg at end of treatment to 0.3 (-0.1 to 0.8) kg at 6 months post treatment. In summary, the frailty phenotype was adapted and validated for use in the EMAS study. Analyses using this model and the trial follow up analyses are supportive of an influence of T on lean body mass in ageing men. The other hormone relationships seen suggest frailty may be broadly related to changes in the endocrine system in ageing men. The lack of sustained benefit from T treatment combined with the relationships with multiple endocrine markers suggests more complex management strategies may be required for this condition.

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Doctor of Philosophy / A large number of neuroendocrine studies indicate a possible relationship between the Hypothalamo-Pituitary-Gonadal (HPG) axis and major depressive illness in men. This observation is not surprising, considering the similarities between the symptom profiles of depression and hypogonadism. However, owing to the strong likelihood that a number of other demographic, clinical and treatment covariates may potentially obscure a possible relationship between HPG and depression, studies in this area have produced somewhat inconsistent results. The main objective of the present study was to investigate the relationship between depression and HPG hormone levels in a population of hospitalised men. Another objective was to examine the relationship of a number of demographic, behavioural, clinical and treatment variables with HPG hormone levels and depression. METHOD: Serum hormones of the HPG axis (Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH), Free Testosterone (free T), Total Testosterone (total T) and Sex Hormone Binding Globulin (SHBG)) were compared between fifty-two male patients with Major Depressive Disorder (mean age = 42.04; SD = 14.1) and twenty-five male patients with other psychiatric conditions (mean age = 40.72; SD = 13.8) on admission into hospital. In addition, to elucidate the possible relationship between clinical outcome of depression and gonadal function, HPG parameters were measured in patients with depression 3 to 6 months following discharge. Based on their HDRS (Hamilton Depression Rating Scale) score, patients were categorised as remitters and non-remitters. Demographic, behavioral, clinical and treatment variables were also examined as possible correlates of hormone levels. RESULTS: Comparison between patients with depression and patients with other diagnoses indicated a significantly lower free T and total T in patients with depression. There were no differences in other hormone parameters between the two diagnostic groups. Correlational analyses indicated significant negative relationships between free T and total T and severity as well as duration of depression. Age was inversely correlated to both free T and total T, whereas BMI was negatively correlated with Total T and SHBG. There was a positive relationship between Total T as well as Free T and measures of sexual dysfunction. While no difference in hormone parameters was observed as a function of psychotic features, patients with melancholic features exhibited significantly lower levels of free T and total T compared to patients with no melancholic features. In the multiple regression analyses, age, duration and severity of depression were the strongest predictors of both free and total T. In separate regression analyses somatic features, over and above other features of depression were found to account most in the variability in free T and total T. Longitudinal analysis revealed significantly higher free T and total T levels on follow-up compared to baseline in the patients who remitted. There was no significant change in any of the hormones studies in the non-remitting group. CONCLUSION: The main findings of the present study support previous results that both total and free testosterone levels are lower during depression and that concentrations of free T and total T parallel changes in severity of depressive symptomatology. Further investigations into the mechanism for this observation, and perhaps examinations of testosterone supplementation for treatment of depression are in order.