Cindy N Roy1, Peter J Snyder2, Alisa J Stephens-Shields3, Andrew S Artz4, Shalender Bhasin5, Harvey J Cohen6, John T Farrar7, Thomas M Gill8, Bret Zeldow3, David Cella9, Elizabeth Barrett-Connor10, Jane A Cauley11, Jill P Crandall12, Glenn R Cunningham13, Kristine E Ensrud14,15, Cora E Lewis16, Alvin M Matsumoto17, Mark E Molitch18, Marco Pahor19, Ronald S Swerdloff20, Denise Cifelli3, Xiaoling Hou3, Susan M Resnick21, Jeremy D Walston22, Stephen Anton19, Shehzad Basaria5, Susan J Diem14, Christina Wang20, Stanley L Schrier23, Susan S Ellenberg3. 1. Divisions of Geriatric Medicine and Gerontology and Hematology, Johns Hopkins University, Baltimore, Maryland. 2. Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 3. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 4. Section of Hematology/Oncology, University of Chicago, Chicago, Illinois. 5. Research Program in Men's Health: Aging and Metabolism, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 6. Duke University Medical Center, Center for the Study of Aging, Durham, North Carolina. 7. Center for Clinical Epidemiology & Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 8. Division of Geriatric Medicine, Yale School of Medicine, New Haven, Connecticut. 9. Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois. 10. Department of Internal Medicine and Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego School of Medicine, La Jolla. 11. Department of Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, Pennsylvania. 12. Divisions of Endocrinology and Geriatrics, Albert Einstein College of Medicine, Bronx, New York. 13. Departments of Medicine and Molecular & Cellular Biology, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine and Baylor St Luke's Medical Center, Houston, Texas. 14. Department of Medicine, Division of Epidemiology & Community Health, University of Minnesota, Minneapolis. 15. Minneapolis VA Health Care System, Minneapolis, Minnesota. 16. Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham. 17. Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs Puget Sound Health Care System, and Division of Gerontology & Geriatric Medicine, Department of Internal Medicine, University of Washington School of Medicine, Seattle. 18. Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Chicago, Illinois. 19. Department of Aging & Geriatric Research, University of Florida, Gainesville, Florida. 20. Division of Endocrinology, Harbor-University of California at Los Angeles Medical Center and Los Angeles Biomedical Research Institute; Torrance. 21. Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, Maryland. 22. Division of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, Maryland. 23. Department of Medicine, Stanford University, Stanford, California.
Abstract
Importance: In one-third of older men with anemia, no recognized cause can be found. Objective: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration. Design, Setting, and Participants: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. Interventions: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. Main Outcomes and Measures: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. Results: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. Conclusions and Relevance: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.
RCT Entities:
Importance: In one-third of older men with anemia, no recognized cause can be found. Objective: To determine if testosterone treatment of men 65 years or older with unequivocally low testosterone levels and unexplained anemia would increase their hemoglobin concentration. Design, Setting, and Participants: A double-blinded, placebo-controlled trial with treatment allocation by minimization using 788 men 65 years or older who have average testosterone levels of less than 275 ng/dL. Of 788 participants, 126 were anemic (hemoglobin ≤12.7 g/dL), 62 of whom had no known cause. The trial was conducted in 12 academic medical centers in the United States from June 2010 to June 2014. Interventions: Testosterone gel, the dose adjusted to maintain the testosterone levels normal for young men, or placebo gel for 12 months. Main Outcomes and Measures: The percent of men with unexplained anemia whose hemoglobin levels increased by 1.0 g/dL or more in response to testosterone compared with placebo. The statistical analysis was intent-to-treat by a logistic mixed effects model adjusted for balancing factors. Results: The men had a mean age of 74.8 years and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 30.7; 84.9% were white. Testosterone treatment resulted in a greater percentage of men with unexplained anemia whose month 12 hemoglobin levels had increased by 1.0 g/dL or more over baseline (54%) than did placebo (15%) (adjusted OR, 31.5; 95% CI, 3.7-277.8; P = .002) and a greater percentage of men who at month 12 were no longer anemic (58.3%) compared with placebo (22.2%) (adjusted OR, 17.0; 95% CI, 2.8-104.0; P = .002). Testosterone treatment also resulted in a greater percentage of men with anemia of known cause whose month 12 hemoglobin levels had increased by 1.0 g/dL or more (52%) than did placebo (19%) (adjusted OR, 8.2; 95% CI, 2.1-31.9; P = .003). Testosterone treatment resulted in a hemoglobin concentration of more than 17.5 g/dL in 6 men who had not been anemic at baseline. Conclusions and Relevance: Among older men with low testosterone levels, testosterone treatment significantly increased the hemoglobin levels of those with unexplained anemia as well as those with anemia from known causes. These increases may be of clinical value, as suggested by the magnitude of the changes and the correction of anemia in most men, but the overall health benefits remain to be established. Measurement of testosterone levels might be considered in men 65 years or older who have unexplained anemia and symptoms of low testosterone levels. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.
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