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Short-acting testosterone injections are associated with greater risk of cardiovascular events, hospitalizations, and death compared with gels or patches, according to a large retrospective cohort study published online in .

The study adds new information to the ongoing controversy and concerns about the safety and proper usage of testosterone therapy. These concerns prompted the FDA to require label changes to testosterone products in March to clarify their approved uses and include a new safety warning.

However, the study did not include long-acting testosterone formulations commonly used in Europe and recently approved in the U.S., according to one commentator.

In addition, the study drew harsh criticism from the lead author of a recently published large-scale review that concluded there is no convincing evidence of increased cardiovascular risk with testosterone therapy.

Data From Half-Million Men Examined

, an epidemiologist at the University of North Carolina Chapel Hill, and colleagues analyzed data from three cohorts: a U.S. cohort of commercially insured men, a random sample from the Medicare population, and a U.K. cohort drawn from , a compilation of general practitioner medical records throughout Great Britain.

Together the three groups included more than 544,000 men who were new users of testosterone therapy. Of these, 37.4% received injections, 6.9% used patches, and 55.8% used gels. These men were followed for up to 1 year for outcomes including myocardial infarction (MI), unstable angina, stroke, and a composite of all three. All-cause hospitalization, mortality, and venous thromboembolism (VTE) were also examined.

Hazard ratios and 95% CIs were estimated with multivariable Cox proportional hazards regression models. Gels were used as the reference group since gels were the most common dosage form. This study did not compare testosterone users with non-users.

Compared with men using gels, those receiving injections had a greater risk for the composite of cardiovascular outcomes (MI, unstable angina, and stroke) (HR 1.26, 95% CI 1.18-1.35), hospitalization (HR 1.16, 95% CI 1.13-1.19), and death (HR 1.34, 95% CI 1.15-1.56) but not VTE (HR 0.92, 95% CI 0.76-1.11).

When testosterone patches were compared with gels, the investigator did not find any increased risk for cardiovascular events (HR 1.10, 95% CI 0.94-1.29), hospitalization (HR 1.04, 95% CI 1.00-1.08), death (HR 1.02, 95% CI 0.77-1.33), or VTE (HR 1.08, 95% CI 0.79-1.47).

"Different dosage forms lead to different serum testosterone levels over time -- injections result in spikes and super-normal levels -- possibly accounting for the observed risk of cardiovascular disease," Layton and colleagues wrote.

"With continuing concern about the safety and effectiveness of testosterone treatment in men with primary and age-related hypogonadism and the trend of treatment in men with normal testosterone levels or without recent baseline testing, it is important to understand the potential hazards of testosterone treatment," the investigators concluded.

Experts Point to Study's Limitations

The study is well-designed and done by a reputable group, said , an endocrinologist and professor of medicine at the University of Washington Medical Center, in an email to 乌鸦传媒. But it only included short-acting forms of injectable testosterone (testosterone cypionate, enanthate, and propionate) and not the longer-acting testosterone undecanoate which is the most common form used in Europe and which was recently approved in the U.S.

The short-acting forms of injectable testosterone are associated with higher spikes in testosterone levels, said Anawalt, who was not involved with the study.

"I don't think we should change our practice based on this study," Anawalt said. However, he added that for those using short-acting testosterone injections, the study suggests it may be prudent to use lower doses at more frequent intervals.

In addition, Anawalt said that this and previous studies have raised enough questions about the safety of testosterone therapy that physicians should be cautious about using it in men for whom there is no clear medical need.

, of the Beth Israel Deaconess Medical Center, criticized the study harshly.

"The study fails for the most basic of reasons," Morgantaler told 乌鸦传媒 Today via email. "The authors treated all men receiving a testosterone prescription as if this were a homogeneous group and the selection of treatment options (injections, gels, patches) were random. However, multiple factors play a role in the choice of testosterone treatment options, including clinical presentation, testosterone concentrations, and economics (injections are considerably less expensive than patches and gels), none of which are addressed by the authors."

"Moreover, treatment choices also reflect physician experience and expertise, as patches are rarely used by experienced clinicians because of poor efficacy and a high rate of local skin irritation. Since the groups are not the same, one cannot conclude that differences in outcomes are due to the treatment. A more likely conclusion from these data is that inexperienced healthcare providers (identified by use of testosterone patches) tend to treat healthier men at reduced risk of cardiovascular events," Morgantaler said.

Morgantaler and colleagues recently published a review in that concluded there was no link between testosterone therapy and cardiovascular risk. However, Morgantaler and his colleagues have been criticized for their connections with companies that make testosterone products.

In the Mayo Clinic Proceedings paper, Morgentaler had disclosed relationships with AbbVie, Auxilium, Clarus Therapeutics, Endo Pharmaceuticals, TesoRx, Antares, Lipocine, Eli Lilly, Bayer, Pfizer, and MHB Labs.

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