Association of Testosterone Levels With Anemia in Older Men: A Controlled Clinical Trial

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Roy reports grants from National Institutes of Health, during the conduct of the study; grants from Celgene Corporation, grants from National Institutes of Health, grants from National Institutes of Health, outside the submitted work; Dr Snyder reports grants from National Institute on Aging, NIH, grants and non-financial support from AbbVie (formerly Solvay and Abbott Laboratories), during the conduct of the study; personal fees from Watson Laboratories, outside the submitted work; Dr Stephens-Shields reports grants from National Institute on Aging (NIA), NIH, grants from NIA, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study; Dr Bhasin reports grants from NIA, during the conduct of the study; grants and personal fees from Abbvie, grants and personal fees from Lilly, grants from Transition Therapeutics, grants and personal fees from Regeneron, outside the submitted work; in addition, Dr Bhasin has a patent Free testosterone calculator pending and has equity interest in FPT, LLC.; Dr Farrar reports grants from National Institute on Aging (NIA), NIH, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study; Dr Cella reports grants from National Institute on Aging, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study; Dr Cauley has nothing to disclose; Dr Cunningham reports personal fees from AbbVie, personal fees from Apricus, personal fees from Besins, personal fees from Clarus Therapeutics, personal fees from Endo Pharma, personal fees from Ferring, personal fees from Lilly, personal fees from Pfizer, personal fees from Repros Therapeutics, outside the submitted work; Dr Ensrud reports grants from National Institute on Aging, during the conduct of the study; Dr Lewis reports grants from NIH, grants from AbbVie, during the conduct of the study; Dr A. Matsumoto reports personal fees from AbbVie, personal fees from Endo, personal fees from Lilly, personal fees from Lipocine, personal fees from Clarus, outside the submitted work; Dr Molitch reports grants from National Institutes of Helath, grants from Abbott Laboratories, during the conduct of the study; personal fees from Abbvie (Abbott Laboratories), personal fees from Eli Lilly & Co, personal fees from Pfizer, outside the submitted work; Dr Pahor reports grants from NIH, during the conduct of the study; Dr Swerdloff reports grants from The Bone Trial of the Testosterone Trial during the conduct of the study; grants and other from Clarus, grants from Lipesene, grants and other from Antares, outside the submitted work; Dr Resnick reports grants from National Institute on Aging (NIA), NIH, grants and other from AbbVie (formerly Solvay & Abbott Lab), during the conduct of the study; Dr Basaria reports other from Eli Lilly, other from Takeda Pharmaceuticals, outside the submitted work; Dr Diem reports grants from National Institute on Aging, during the conduct of the study; Dr Wang reports grants from Besins Health International, other from Abbvie, during the conduct of the study; grants from Clarus Therapeutics, outside the submitted work; Dr Ellenberg reports grants from National Institutes of Health, grants from AbbVie Inc during the conduct of the study; grants from AbbVie Inc outside the submitted work. No other disclosures are reported.

Figures

Figure 1. Screening and Retention of Participants in the Anemia Trial

a Five Testosterone Trials participants were missing baseline hemoglobin levels and were not classified with respect to anemia. An additional 2 were randomized incorrectly and did not provide any baseline clinical data. b Participants excluded from analysis and with no follow-up data are the same.

Figure 2. Association of Testosterone vs Placebo Treatment for 12 Months With Hemoglobin Concentrations in Participants in the Anemia Trial

A and B, Results in men with unexplained anemia. C and D, Results in men with anemia of known causes. E and F, Results in nonanemic men. The graphs on the left (A, C, and E) show the results as dichotomous variables, ie, the percent of men who demonstrated an increase above baseline of 1.0 g/dL or more, and the graphs on the right (B, D, and F) show the results continuously. The values are means ± pointwise confidence intervals.

Figure 3. Relationship Between Change in Hemoglobin Levels and Patient Global Impression of Change Questions in All Anemic Men in the Testosterone Trials

Participants were asked at each 3-month visit if their overall health, walking, sexual desire, energy and memory were much better, a little better, not changed, a little worse, or a lot worse than at the beginning of the trial. For analysis, the much worse and little worse categories were combined. Boxes represent the interquartile ranges (IQR), and the whiskers represent 1.5× the IQR for the change in hemoglobin levels pooled across months. P values were calculated by a mixed effects proportional odds model with 4-level PGIC response as the outcome and change in hemoglobin levels as the primary predictor. Models adjusted for treatment arm and balancing factors age, as described in the Methods section.