The treatment effect on mobility measures was small and appeared to be related to baseline gait speed and the self-reported mobility limitation. Comparison of change in 6-minute walking distance and PF10 scores between testosterone and placebo-treated men among those who had mobility limitation vs those who did not have mobility limitation at baseline. In men enrolled in the PFT, serum total testosterone levels increased from an average of 8.0 nmol/L (230.5 ng/dL) at baseline to an average of 17.9 nmol/L (516.4 ng/dL) at month 12 in the testosterone group men, but remained unchanged in placebo-treated men (mean 8.1 nmol/L (233.4 ng/ml) at baseline vs 8.0 nmol/L (230.3 ng/ml) at month 12). As testosterone’s anabolic effects on skeletal muscle are related to testosterone dose and concentrations (1–2), we also assessed whether the changes in 6MWD and physical function component (PF10) of the Medical Outcomes Study Short Form 36 (MOS SF36) were related to changes in total and free testosterone, dihydrotestosterone (DHT), or estradiol levels. We determined if testosterone’s effects on mobility differed according to baseline walking speed, mobility-limitation, hormone levels, or other participant-level factors. These observations underscore the importance of the methods described here that will allow monitoring of testosterone levels during therapy and adjustment of the testosterone dose by an unblinded physician and also insure masking of other study personnel and the participants. Additional trials will need to be performed to establish meaningful improvements in physical function and other health-related outcomes. We have recently observed, however, that older subjects with self-reported and objective limitations in mobility demonstrate significantly lower muscle strength than those without . To date, studies of testosterone replacement in older men have either excluded objective measures of physical function or suffered methodological shortcomings. In comparison to previous studies of testosterone administration in older subjects who were higher functioning and community dwelling, the inclusion of individuals with mobility limitations presents a significant recruitment challenge. This study will provide a framework from which future clinical trials of anabolic function promoting therapies can be developed. The PF-10 scores improved significantly more in men treated with testosterone than in men treated with placebo among men whose baseline 6MWS was ≥1.2 m/sec (treatment effect 4.9, 95% CI (2.2, 7.7) PFigure 3). Adherence to assigned treatment in men enrolled in the PFT, assessed by weighing the returned bottles and comparing it to the expected weight based on the prescribed dose, was high in both the testosterone and placebo groups (means 97% and 92%), respectively, with fewer than 5% of men with compliance135%). The primary analysis was performed using random effects models for longitudinal data, which included visit time as a categorical variable and a single main effect for treatment, and included balancing factors and baseline value of the 6-minute walking distance as fixed effect covariates. Our expectation was that men who walked more slowly and perceived mobility problems would be more likely to benefit from testosterone treatment than men who were functioning at a higher level. This is because the lack of testosterone can result in the thinning of cartilage, the protective tissue that covers the ends of bones in a joint. Testosterone plays a crucial role in maintaining joint health and mobility. One area that can be significantly impacted is joint health and mobility. The authors thank Dr. Wildon Farwell and colleagues at the VA Boston Healthcare System for their efforts to establish the VA investigational site for this study. Collectively, these steps reflect a committed effort to ensuring the health and safety of study participants. There is significant controversy with respect to the safety of testosterone administration in older individuals. We acknowledge that age-related limitations in mobility are complex and multifactorial. In preliminary studies, these measures were safe, well-tolerated and demonstrated excellent reliability in older individuals . The 1RM measure will be administered in accordance with a standardized testing protocol designed to minimize the confounding influence of learning and familiarization effects, provide adequate warm-up, prevent injury and minimize fatigue in order to optimize performance. Thus, we plan to optimize recruitment efficiency by implementing the described multi-faceted and -phased community-based recruitment strategies including on-site community—based screening, fostering a relationship with the local VA hospital, and direct mailings to local residents in the study demographic based on census tract data. Interactions between the treatment groups and these covariates may also be incorporated into the model where clinically justified. Based on these estimates and allowing for a 20% drop out rate in a 6 month time period, we propose to enroll 126 men in each treatment group for a total of 252 participants. Testosterone gel is an FDA-approved product that has undergone phase I, II, and III studies for the treatment of hypogonadal men 42, 43. We have selected muscle strength of the lower extremities as our primary outcome measure for sample size determination because of its marked decline with advancing age and its critical importance for physical function and mobility (climbing stairs, getting up from a chair, maintaining balance and avoiding falls). Thus, strategies to augment muscle mass may confer improvements upon physical function and mobility by improving muscle strength and power. Secondary outcomes will include measures of physical function (walking, stair climbing and a lifting and lowering task), habitual physical activity and self-reported disability. Because both self-reported as well as performance-based measures of physical function have some assets and some inherent limitations, the TTrials included both categories of outcomes to enable a more comprehensive assessment of physical function and mobility than had been conducted before. Although lean body mass and muscle strength were not measured in this trial, testosterone administration has been shown consistently in numerous trials to increase skeletal muscle mass and maximal voluntary strength (1–11, 15–16). Further studies of longer duration are needed to determine the clinical meaningfulness of testosterone’s effects, using patient-important outcomes that are more closely aligned with testosterone-induced gains in muscle mass and strength, such as stair climbing speed and chair stand.
