As men age, they experience many conditions, such as mobility disability, age-associated memory impairment, and low vitality, that result in decreased ability to perform activities of daily living, increased propensity to fall, and decreased independence. They also experience anemia, osteoporosis and metabolic syndrome and decreased sexual function. One cause that could contribute to all of these conditions is a low serum testosterone concentration. As men age, their serum testosterone falls, often to levels comparable to those of younger men who have diseases of the pituitary and testes. When young men develop low testosterone due to pituitary or testicular disease, they experience similar consequences, including decreased muscle mass and strength, decreased sexual drive, impaired cognition, and low energy, as well as anemia, osteoporosis and the metabolic syndrome. When these men are treated with testosterone, all of these abnormalities improve. The concept we propose is that an unequivocally low testosterone concentration for no apparent reason other than age predisposes a man to have these geriatric conditions and that testosterone treatment will improve them. We therefore propose a closely coordinated set of four, randomized, placebo-controlled clinical trials to test the hypotheses that testosterone treatment for one year of men >65 years who have unequivocally low serum testosterone concentrations (<250 ng/dL) and both symptoms and objective evidence of mobility disability, age-associated memory impairment, low vitality, or diminished sexual function will show more favorable changes in these parameters than placebo treatment. We shall select 1200 men at 18 sites and randomize them to receive testosterone or placebo gel for one year. Primary end points for these four trials will be six minute walking distance (mobility disability), paragraph recall by the Wechsler Memory Scale Revised (age-associated memory impairment), Facit-fatigue scale (vitality) and UCLA 7-day sexual function questionnaire (sexual function). Measures across all trials will include patient global assessment of change questions, activities of daily living, falls, PHQ-9 and Positive and Negative Affect scales, as well as assessment of adverse events, including prostate diseases. Subsets of men will be assessed for cardiovascular disease by electron beam CT;volumetric bone density of the spine by quantitative CT;and anemia. The potential significance of this study is that it should determine, finally, if testosterone treatment of older men with low testosterone concentrations will improve their physical, sexual and cognitive function and vitality. This study will also provide preliminary data that will help determine if a longer-term trial of the effects of testosterone on clinical heart disease, fracture risk and prostate risk is warranted.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AG030644-05
Application #
8456120
Study Section
Special Emphasis Panel (ZAG1-ZIJ-7 (M2))
Program Officer
Romashkan, Sergei
Project Start
2009-05-15
Project End
2015-04-30
Budget Start
2013-06-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$3,619,052
Indirect Cost
$420,174
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Bhasin, Shalender; Ellenberg, Susan S; Storer, Thomas W et al. (2018) Effect of testosterone replacement on measures of mobility in older men with mobility limitation and low testosterone concentrations: secondary analyses of the Testosterone Trials. Lancet Diabetes Endocrinol 6:879-890
Wang, Christina; Stephens-Shields, Alisa J; DeRogatis, Leonard R et al. (2018) Validity and Clinically Meaningful Changes in the Psychosexual Daily Questionnaire and Derogatis Interview for Sexual Function Assessment: Results From the Testosterone Trials. J Sex Med 15:997-1009
Snyder, Peter J; Bhasin, Shalender; Cunningham, Glenn R et al. (2018) Lessons From the Testosterone Trials. Endocr Rev 39:369-386
Mohler 3rd, Emile R; Ellenberg, Susan S; Lewis, Cora E et al. (2018) The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials. J Clin Endocrinol Metab 103:681-688
Roy, Cindy N; Snyder, Peter J; Stephens-Shields, Alisa J et al. (2017) Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial. JAMA Intern Med 177:480-490
Snyder, Peter J; Kopperdahl, David L; Stephens-Shields, Alisa J et al. (2017) Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med 177:471-479
Budoff, Matthew J; Ellenberg, Susan S; Lewis, Cora E et al. (2017) Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone. JAMA 317:708-716
Resnick, Susan M; Matsumoto, Alvin M; Stephens-Shields, Alisa J et al. (2017) Testosterone Treatment and Cognitive Function in Older Men With Low Testosterone and Age-Associated Memory Impairment. JAMA 317:717-727
Rosen, Raymond C; Stephens-Shields, Alisa J; Cunningham, Glenn R et al. (2016) Comparison of interactive voice response (IVR) with paper administration of instruments to assess functional status, sexual function, and quality of life in elderly men. Qual Life Res 25:811-21
Cunningham, Glenn R; Stephens-Shields, Alisa J; Rosen, Raymond C et al. (2016) Testosterone Treatment and Sexual Function in Older Men With Low Testosterone Levels. J Clin Endocrinol Metab 101:3096-104

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