Frailty, Serum Androgens, and the CAG Repeat Polymorphism: Results from the Massachusetts Male Aging Study

Context: The CAG repeat polymorphism in the androgen receptor, denoted (CAG)n, is thought to (inversely) index androgen sensitivity. We hypothesized that (CAG) n would exhibit a modifying influence on the association between circulating total and calculated free testosterone (TT and FT) and physical frailty in aging men. Objective: The objective of the study was to establish the influence of (CAG) n on the relation between circulating TT, FT, LH, SHBG, and frailty. Design: This was a prospective cohort study of health and endocrine functioning in randomly selected men, with a baseline (T1: 1987-89) and two follow-up (T2: 1995-1997; T3: 2002-2004) visits. Setting: This was an observational study of men residing in greater Boston, MA. Participants: A total of 624 subjects aged 50-86 yr were retained. Main Outcome Measures: The frailty phenotype was measured at T3. Components included weight loss, exhaustion, low physical activity, weakness, and slowness. Subjects exhibiting two of these five components were considered to be in an intermediate state, and those exhibiting three or more were considered frail. Results: (CAG) n was positively associated with TT and FT. Multivariable regression analyses revealed no influence of CAG on longitudinal within-subject changes in hormone levels or cross-sectional (T3) associations between hormone concentrations and the prevalence of intermediate frailty or frailty. Models incorporating subjects' history of hormone decline produced similar negative results. Conclusions: This population-based study does not support the hypothesis that interindividual differences in (CAG) n can account for a lack of association between circulating androgens and the frailty phenotype. Longitudinal analyses are needed to confirm these conclusions. (J Clin Endocrinol Metab 95: 2746-2754, 2010)