The Testosterone Trials: Seven coordinated trials of testosterone treatment in elderly men

Abstract

Background The prevalence of low testosterone levels in men increases with age, as does the prevalence of decreased mobility, sexual function, self-perceived vitality, cognitive abilities, bone mineral density, and glucose tolerance, and of increased anemia and coronary artery disease. Similar changes occur in men who have low serum testosterone concentrations due to known pituitary or testicular disease, and testosterone treatment improves the abnormalities. Prior studies of the effect of testosterone treatment in elderly men, however, have produced equivocal results. Purpose To describe a coordinated set of clinical trials designed to avoid the pitfalls of prior studies and determine definitively if testosterone treatment of elderly men with low testosterone is efficacious in improving symptoms and objective measures of age-associated conditions. Methods We present the scientific and clinical rationale for the decisions made in the design of this trial. Results We designed The Testosterone Trials as a coordinated set of seven trials to determine if testosterone treatment of elderly men with low serum testosterone concentrations and also symptoms and objective evidence of impaired mobility and/or diminished libido and/or reduced vitality would be efficacious in improving mobility (Physical Function Trial), sexual function (Sexual Function Trial), fatigue (Vitality Trial), cognitive function (Cognitive Function Trial), hemoglobin (Anemia Trial), bone density (Bone Trial), and coronary artery plaque volume (Cardiovascular Trial). The scientific advantages of this coordination were common eligibility criteria, treatment and monitoring and the ability to pool safety data. The logistical advantages were a single steering committee, data coordinating center and data safety monitoring board (DSMB), the same clinical trial sites, and the possibility of men participating in multiple trials. The major consideration in subject selection was setting the eligibility criterion for serum testosterone low enough to ensure that the men were unequivocally testosterone deficient, but not so low as to preclude sufficient enrollment or eventual generalizability of the results. The major considerations in choosing primary end points for each trial were identifying those of the highest clinical importance and identifying the minimum clinically important differences between treatment arms for sample size estimation. Potential Limitations Setting the serum testosterone concentration sufficiently low to ensure that most men would be unequivocally testosterone deficient, as well as many other entry criteria, resulted in screening approximately 30 men in person to randomize one subject. Conclusions The Testosterone Trials were designed to determine definitively if testosterone treatment of elderly men with low testosterone would have any clinical benefit. Designing The Testosterone Trials as a coordinated set of seven trials afforded many important scientific and logistical advantages but required an intensive recruitment and s...

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

“…These negative reports have had a chilling effect on the medical community with regard to the treatment of men with TD, and the concern regarding CV risks has fueled a wide variety of complaints and opinions on the merits of T therapy in general. It is anticipated that further clarity will be achieved with reporting of results from the Testosterone Trials, 213 the largest prospective T trial to date, in which approximately 800 men were followed for 12 months. This trial may provide suggestive results regarding CV risk markers, but is underpowered for a comparison of CV outcomes in T-treated vs placebo-treated men.…”

Estrogen and bone health in men and women

“…Many of the trials included men who did not have unequivocally low circulating T. In 2004, the Institute of Medicine recommended that clinical trials of T treatment in older symptomatic men with unequivocally low testosterone be carried out [32]. Thus, the T Trials were funded by the National Institutes of Health(NIH) and will assess the efficacy of T treatment in symptomatic men with low T (<275 ng/dl) on physical and sexual function, vitality, LS volumetric BMD, anemia, coronary plaque and age-associated memory impairment [33]. Results from these trials are expected in 2015.…”

Androgens Inhibit the Osteogenic Response to Mechanical Loading in Adult Male Mice

“…The effects of T on the male skeleton, either directly via the androgen receptor (AR) or indirectly as the substrate for aromatization into estrogens acting via estrogen receptor (ER)-␣, continues to be debated (13). Substudies from the trial by Finkelstein et al (14) as well as the National Institutes of Health-sponsored Testosterone Bone Trial (15) will hopefully shed light on this issue in the near future. Given the well-known anabolic actions of T on muscle, however (14,16), and its importance for male skeletal conservation (13), androgens could in principle be of great interest to simultaneously ameliorate both skeletal and extraskeletal determinants of fracture like muscle mass, falls, and frailty (17).…”