Does Testosterone Replacement Increase Cardiovascular Risks?
A meta-analysis with a database spanning 1981–2008 evaluated men with low or low-normal testosterone treated with testosterone for at least 90 days (23). The aim was to evaluate the adverse effects of testosterone therapy in men. Fifty-one testosterone therapy trials, ranging in duration from 3 months to 3 years, were included. There was no increase in the rates of death, myocardial infarction (MI), revascularization procedures, or cardiac arrhythmias as compared with the placebo-nonintervention groups. None of these trials, however, was powered to show a difference in these end points.
On the other hand, a number of recent studies have reported increased cardiovascular events and mortality in testosterone-treated men. In the Testosterone in Older Men with Mobility Limitations trial, 209 elderly frail men, mean age 74 years, with limitations in mobility and low total serum testosterone levels, were randomly assigned a placebo gel or testosterone gel, to be applied daily for 6 months (24). There was a high prevalence of comorbidities, including hypertension, diabetes, congestive heart failure, and renal insufficiency. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events, including 1 death in the treatment group. The study was halted because of these adverse effects. It should be noted, however, that the study was not designed to investigate cardiovascular events and no criteria for defining cardiovascular events were set out in advance. The majority of events would not be included as an “event” in any cardiovascular study due to questionable clinical significance, including peripheral edema, hypertension, and tachycardia, as well as nonspecific electrocardiogram changes. With a low number of serious events and the absence of any predetermined cardiovascular end points or specific cardiovascular investigations, this study does not demonstrate a clear increased cardiovascular disease risk. However, it raises concerns that testosterone treatment could increase cardiovascular events in men with pre-existing cardiovascular disease. Other studies in elderly populations also have not shown an increase in cardiac events after testosterone replacement (25–29). A prospective, randomized, double-blind multicenter trial of transdermal testosterone therapy for 1 year in 220 hypogonadal men with type 2 diabetes or metabolic syndrome reported that cardiovascular events were less common with testosterone therapy than with placebo (4.6% versus 10.7%), but this difference was not statistically significant (
P = .095) (18). A recent 6-month randomized, placebo-controlled trial of intramuscular testosterone therapy in 88 men with type 2 diabetes did not show a difference in rates of cardiovascular events amongst testosterone or placebo groups (30).
Five meta-analyses have evaluated the effect of testosterone therapy on cardiovascular events (23,31–34). Of these, only one reported increased cardiovascular events with testosterone therapy versus placebo (33). This study, by Xu et al (33), evaluated 27 randomized controlled trials, each at least 3 months in duration. The authors concluded that testosterone therapy increased the risk of “cardiovascular related events” by 54%. However, “events” again included clinically questionably anecdotal items, including peripheral edema and hypertension. On the contrary, a recent meta-analysis that included 75 randomized, placebo-controlled trials of testosterone treatment and evaluated the incidence of major adverse cardiovascular events did not find any association of testosterone therapy with actual cardiovascular events. (34).
It should be emphasized that none of these trials was designed to assess cardiovascular events. Randomized controlled trials designed to evaluate the effect of testosterone replacement in men on cardiovascular events or mortality have not yet been carried out. At this time, there is clearly a paucity of long-term studies to carry out a meta-analysis of the relationship of testosterone therapy with actual cardiovascular events.
Two retrospective studies have shown a benefit of testosterone treatment on cardiovascular events. An observational cohort study examined total mortality rates in 398 hypogonadal men (total testosterone <250 ng/dL) treated with testosterone therapy at 7 Veteran Affairs hospitals in the northwest United States (35). A total of 633 untreated hypogonadal men served as the comparison group. The mean age was 62 years, and the mean follow-up period was 40 months. Mortality rates in treated and untreated men were 10 and 21% (
P<.001), respectively. After multifactorial adjustment, testosterone-treated men had a 39% reduction in mortality risk (
P = .008). A retrospective cohort study in an endocrine clinic investigated the effect of TRT in 238 hypogonadal men with type 2 diabetes on all-cause mortality (36). Sixty-four men received testosterone (mean duration, 42 ± 21 months). A total of 60 patients received TRT for 12 months or more and 51 had treatment for 2 years or more. A total of 174 men were not treated. The mortality rate in the untreated group was 20%, whereas the group treated with testosterone had a mortality rate of 9.4% (
P = .002). After multivariable adjustment, the hazard ratio for decreased survival in the untreated group was 2.3 (95% confidence interval [CI], 1.3 to 3.9;
P = .004). By comparison, the mortality rate in a cohort of 343 men with type 2 diabetes and normal testosterone concentrations was 9% (36). Although this study showed a reduction in cardiovascular risk after testosterone, this study was retrospective. While of interest, retrospective studies should serve as hypothesis generating for randomized clinical trials and cannot serve as the basis for drawing firm conclusions regarding therapy.
Two recent publications have raised concern that testosterone therapy increases cardiovascular risk (1,2). These studies were retrospective observational analyses and have been criticized, based on detailed epidemiologic and statistical analyses (37,38). One study examined mortality, MI, and stroke rates in men with low testosterone levels (<300 ng/mL) who had undergone coronary angiography (1). The published critiques have focused on many flaws in this study, among which are:
Actual reported rate of events was 10.1% for the testosterone-treated group and 21.2% in controls, showing a reduced event rate in the treated group by more than 50% (38,39). The Kaplan-Meier calculation based on statistical adjustment for more than 50 variables converted this into an event rate of 19.9% in the untreated group and 25.7% in the testosterone-therapy group at 3 years, thus reversing the results of raw data. The risk differences were 1.3% (95% CI, −7.1 to 9.7%) at 1 year, 3.1% (95% CI, −4.9 to 11.0%) at 2 years, and 5.8% (95% CI, −1.4 to 13.1%) at 3 years. While these were not statistically significant, the reported overall Kaplan-Meier survival curve based on these estimates over 3 years suggested a hazard ratio of 1.29 (95% CI, 1.04 to 1.58;
P = .02).
Statistical adjustments were done for over 50 variables, but not were done for baseline testosterone concentrations. This is an important lapse, since the patients in the testosterone-therapy group had lower baseline testosterone concentrations than the untreated group (175.5 ng/dL versus 206.5 ng/dL;
P<.001) and since testosterone concentrations are inversely related to mortality in elderly men (3).
The mean duration of therapy was only 1 year. Men receiving testosterone therapy had limited follow-up. There was no information about whether subjects in the testosterone arm of the study actually took testosterone. Moreover, 40% did not have follow-up testosterone measurements during testosterone therapy. Of the 60% who had posttreatment testosterone concentration measured, the mean concentration increased from 175.5 ng/dL to only 332.2 ng/dL, evidently due to inadequate replacement (7,40,41). The fact that complex statistical adjustments reversed the conclusions of the raw data likely point to the importance of comorbidities in predicting cardiovascular events, rather than that of testosterone therapy.
This study has undergone 2 published corrections. The first was for misreporting their results as “absolute risk” when in fact the results were based on highly statistical, derived estimates and, as noted above, were not supported by the raw data. A second correction was published 4 months after publication, when the authors admitted to a series of data errors. To date, 29 medical societies have called for retraction of this article based on the conclusion that the reported results represent “misinformation” (42).
The second study, by Finkle et al (2), examined 55,593 insurance claims with the information based on diagnosis codes, procedure codes, and prescription data. No data were available on indications for testosterone therapy prescription, race, laboratory findings, occupational, environmental, or lifestyle factors. They reported an increased rate of nonfatal MIs (from 0.35 to 0.48%; rate ratio, 1.36; 95% CI, 1.03 to 1.81) within the first 90 days of filling the testosterone prescription compared with the previous 12 months. However, since this was a retrospective study and not a prospective one, it is critical to understand that the population was preselected based on potentially requiring testosterone and thus being hypogonadal and having a relatively higher cardiovascular risk. There was no control group of untreated hypogonadal patients. Furthermore, there were no data on testosterone concentrations prior to or following testosterone treatment. Nor were any data available on the diagnosis, blood pressure, smoking, or body mass index. The “lead-in” period of 12 months prior to the prescription of testosterone does not represent an adequate control, especially in view of an increase of 36% within 90 days of testosterone use, which seems highly improbable in view of other studies with testosterone replacement.
AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON THE ASSOCIATION OF TESTOSTERONE AND CARDIOVASCULAR RISK 
