BACKGROUND Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials — the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy–Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.)

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 PARTICIPANTSA 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 Յ12.7 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 MEASURESThe 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. RESULTSThe 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

IMPORTANCEAs men age, they experience decreased serum testosterone concentrations, decreased bone mineral density (BMD), and increased risk of fracture.OBJECTIVE To determine whether testosterone treatment of older men with low testosterone increases volumetric BMD (vBMD) and estimated bone strength.DESIGN, SETTING, AND PARTICIPANTS Placebo-controlled, double-blind trial with treatment allocation by minimization at 9 US academic medical centers of men 65 years or older with 2 testosterone concentrations averaging less than 275 ng/L participating in the Testosterone Trials from December 2011 to June 2014. The analysis was a modified intent-to-treat comparison of treatment groups by multivariable linear regression adjusted for balancing factors as required by minimization.INTERVENTIONS Testosterone gel, adjusted to maintain the testosterone level within the normal range for young men, or placebo gel for 1 year.MAIN OUTCOMES AND MEASURES Spine and hip vBMD was determined by quantitative computed tomography at baseline and 12 months. Bone strength was estimated by finite element analysis of quantitative computed tomography data. Areal BMD was assessed by dual energy x-ray absorptiometry at baseline and 12 months. RESULTS There were 211 participants (mean [SD] age, 72.3 [5.9] years; 86% white; mean [SD] body mass index, 31.2 [3.4]). Testosterone treatment was associated with significantly greater increases than placebo in mean spine trabecular vBMD (7.5%; 95% CI, 4.8% to 10.3% vs 0.8%; 95% CI, −1.9% to 3.4%; treatment effect, 6.8%; 95% CI, 4.8%-8.7%; P < .001), spine peripheral vBMD, hip trabecular and peripheral vBMD, and mean estimated strength of spine trabecular bone (10.8%; 95% CI, 7.4% to 14.3% vs 2.4%; 95% CI, −1.0% to 5.7%; treatment effect, 8.5%; 95% CI, 6.0%-10.9%; P< .001), spine peripheral bone, and hip trabecular and peripheral bone. The estimated strength increases were greater in trabecular than peripheral bone and greater in the spine than hip. Testosterone treatment increased spine areal BMD but less than vBMD.CONCLUSIONS AND RELEVANCE Testosterone treatment for 1 year of older men with low testosterone significantly increased vBMD and estimated bone strength, more in trabecular than peripheral bone and more in the spine than hip. A larger, longer trial could determine whether this treatment also reduces fracture risk.TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00799617

In older men with low libido and low T levels, improvements in sexual desire and activity in response to T treatment were related to the magnitude of increases in T and estradiol levels, but there was no clear evidence of a threshold effect.

Objective To define confounding bias in difference‐in‐difference studies and compare regression‐ and matching‐based estimators designed to correct bias due to observed confounders. Data sources We simulated data from linear models that incorporated different confounding relationships: time‐invariant covariates with a time‐varying effect on the outcome, time‐varying covariates with a constant effect on the outcome, and time‐varying covariates with a time‐varying effect on the outcome. We considered a simple setting that is common in the applied literature: treatment is introduced at a single time point and there is no unobserved treatment effect heterogeneity. Study design We compared the bias and root mean squared error of treatment effect estimates from six model specifications, including simple linear regression models and matching techniques. Data collection Simulation code is provided for replication. Principal findings Confounders in difference‐in‐differences are covariates that change differently over time in the treated and comparison group or have a time‐varying effect on the outcome. When such a confounding variable is measured, appropriately adjusting for this confounder (ie, including the confounder in a regression model that is consistent with the causal model) can provide unbiased estimates with optimal SE. However, when a time‐varying confounder is affected by treatment, recovering an unbiased causal effect using difference‐in‐differences is difficult. Conclusions Confounding in difference‐in‐differences is more complicated than in cross‐sectional settings, from which techniques and intuition to address observed confounding cannot be imported wholesale. Instead, analysts should begin by postulating a causal model that relates covariates, both time‐varying and those with time‐varying effects on the outcome, to treatment. This causal model will then guide the specification of an appropriate analytical model (eg, using regression or matching) that can produce unbiased treatment effect estimates. We emphasize the importance of thoughtful incorporation of covariates to address confounding bias in difference‐in‐difference studies.