Clinical Context

Testosterone therapy has been associated with improvements in libido and energy among men, but many clinicians have been hesitant to prescribe testosterone because of concern about the possibility of adverse cardiovascular events. Testosterone therapy has been associated with an increased risk for cardiovascular events in observational research.

To address this concern, Cheetham and colleagues performed a retrospective cohort study of men at least 40 years old with evidence of androgen deficiency. Their results are published in the current issue of JAMA Internal Medicine.^[1] Study data were drawn from a large US managed-care health system.

A total of 8808 men treated with testosterone for androgen deficiency were compared with 35,527 men with hypoandrogenism who were not treated. The adjusted hazard ratio (HR) of a composite cardiovascular event endpoint was 0.67 (95% confidence interval [CI], 0.62-0.73) in comparing the testosterone treatment group vs the no-treatment group. Testosterone therapy remained associated with a lower risk for events in analyses limited to cerebrovascular or cardiac results alone. In addition, subgroup analyses based on age older or younger than 65 years or a previous history of cardiovascular disease failed to alter the main study conclusion.

These data are reassuring regarding the safety of testosterone, but the efficacy of testosterone treatment remains an issue as well. Two studies published in the current issue of JAMA Internal Medicine (the first study by Snyder and colleagues, the second by Roy and colleagues) address the effects of exogenous testosterone on anemia and bone mineral density (BMD). Their results are summarized in "Study Highlights."

Study Synopsis and Perspective

Testosterone therapy increases BMD and strength and corrects anemia of known and unknown cause in older men with low levels of the hormone, show the 2 latest publications from the Testosterone Trials (so-called T Trials)^[2], published in JAMA Internal Medicine February 21.

Also published in the same issue of JAMA Internal Medicine is a study that reports a lower risk for cardiovascular outcomes in men with low testosterone levels treated with testosterone-replacement therapy after 3.5 years of follow-up, compared with those who never received testosterone treatment. This study is not part of the T-Trial series.

Also in JAMA, results of 2 additional T-Trials studies are published. One study finds no effect of testosterone treatment on memory or other cognitive functions in men with memory impairment and low testosterone levels.^[3] The second study shows that after men with hypogonadism were given 1 year of testosterone therapy, there was a significant increase in noncalcified coronary artery plaque^[4] compared with placebo.^[5] The author of this latter study warns: "Plaque progression is bad; there's no mechanism by which this could be helpful" and suggests caution in treating older men who have already had a cardiovascular event or have significant atherosclerosis. An accompanying editorial calls the findings "unprecedented" and "ominous."

Overall, experts say that these findings in their totality show some added benefits of testosterone therapy -- in bone density and anemia -- in men with low testosterone levels. However, they repeatedly stress that the hormone should not be prescribed as an "elixir of youth" for those with normal or borderline-normal testosterone levels.

T Trials Designed to Address Risks and Benefits Associated With Testosterone

The T Trials are a series of 7 linked studies performed to address recommendations made by the US Institute of Medicine in 2003 to critically evaluate the usefulness -- including potential benefits and harms – associated with testosterone supplementation for several clinical indications.

Susan S. Ellenberg, PhD, professor of biostatistics from Perelman School of Medicine, University of Pennsylvania, Philadelphia, is an author on all 4 newly published T Trials. "This therapy has been used by millions of men without much rigorous study," she told Medscape Medical News. "There have been many benefits claimed but also many risks that people have been worried about. The intent of these trials was to see whether there were any benefits that would warrant doing larger studies on risks."

Last year, Medscape Medical News reported on the publication of the first three T Trials in the New England Journal of Medicine.^[2] In brief, these studies found that testosterone treatment in older men may help improve sexual function, mood, depressive symptoms, and possibly walking distance, but not vitality.

Testosterone Ups Density and Strength of Trabecular Spinal Bone

The new bone-density T trial, published with lead author Peter J. Snyder, MD,^[6] Perelman School of Medicine, University of Pennsylvania, randomly assigned men older than 65 years with low testosterone levels (averaged <275 ng/dL) to receive testosterone or placebo gel for 1 year. Testosterone therapy aimed to raise levels of the hormone to the normal range for young men. Spine and hip volumetric BMD (vBMD) was determined after 1 year, with spine vBMD being the primary outcome.

Testosterone therapy was associated with significantly greater increases in mean spine trabecular vBMD from baseline than placebo, at 7.5% compared with 0.8%, respectively, equating to a treatment effect of 6.8% (P <.001).

These BMD findings were reflected in the mean estimated strength of spine trabecular bone, which showed a change from baseline of 10.8% with testosterone treatment vs 2.4% with placebo, giving a treatment effect of 8.5% (P <.001). The estimated strength increases were greater in trabecular than in peripheral bone and greater in the spine than in the hip.

"We were pleased to see a clear improvement in bone density and strength, as measured in this trial," remarked Dr Ellenberg, who is senior author on this study.

However, the ultimate test of whether testosterone is beneficial in increasing bone density and strength will be in whether the therapy reduces fractures in those older than 65 years, she noted.

"The fact that testosterone in this study increased bone density and strength may [mean that it] reduces fractures, but data on fractures were insufficient to draw any conclusions," Dr Ellenberg added.

Eric S. Orwoll, MD,^[7] director of the Bone and Mineral Clinic and the Bone Density Lab at Oregon Health and Science University, Portland, penned an accompanying editorial to both T-Trial studies in JAMA Internal Medicine.

With regard to the bone effects, he noted, "These results provide very strong evidence that testosterone therapy in older men with low testosterone levels yields a positive skeletal effect. Nevertheless, important issues remain."

Average BMD in the trial participants was not low, and "whether testosterone replacement would be as effective in men with osteoporosis was not directly addressed," he observes.

Nevertheless, if a man needs testosterone therapy because of hypogonadism and looks like he may also require osteoporosis agents, then testosterone would be a good start, he noted. He also points out that testosterone treatment for more than 1 year would likely show accumulated positive effects on bone, but that has yet to be demonstrated.

One of the bone study's coauthors, Jane A. Cauley, DrPH, from the University of Pittsburgh, Pittsburgh, Pennsylvania, said the findings were exciting: "Men who are taking testosterone therapy for low testosterone have an added benefit that their bone density will increase."

However, she also pointed out the lack of fracture data with testosterone treatment. Given that approved medications for osteoporosis have all demonstrated efficacy in preventing and reducing fractures, she noted, "It would be prudent for men with osteoporosis to be treated with a medicine proven to reduce fractures, even if they have low testosterone."

However, the magnitude of effect of testosterone on BMD was similar to other drugs for osteoporosis, suggesting a true beneficial effect. "But we need a clinical trial large enough to show an effect on fractures," she emphasized.

In addition, Bradley Anawalt, MD, an endocrinologist from the University of Washington, Seattle, who was not involved in the T Trials, said that testosterone therapy could be a good initial therapy to increase bone mass and strength.

"The gain was comparable to commonly used drugs that have been approved for treatment of osteoporosis," he commented.

Testosterone for Anemia of Known and Unknown Cause

In the second T trial published in JAMA Internal Medicine, with Cindy N. Roy, PhD,^[8] from Johns Hopkins University, Baltimore, Maryland, as lead author, testosterone treatment significantly increased the hemoglobin levels in older men with low levels of testosterone, whether they had unexplained anemia or anemia from known causes.

A greater percentage of men (54%) with unexplained anemia had 1-year hemoglobin levels that increased by 1.0 g/dL or more over baseline compared with men (15%) who received placebo (adjusted odds ratio [OR], 31.5; P =.002).

In men with anemia of known cause and treated with testosterone, a greater number (52%) had 1-year hemoglobin levels that had increased by 1.0 g/dL or more during baseline, compared with men (19%) receiving placebo (adjusted OR, 8.2; P =.003).

The authors note that few studies have specifically addressed the effect of testosterone in men with anemia, and none, until now, have examined the effect of testosterone on men with unexplained anemia.

They point out that the findings do not translate into improved walking distance or reduction in fatigue, however, but the rise in hemoglobin level was significantly associated with participants' global impression of change in overall health and energy, suggesting that the increase in hemoglobin levels was clinically significant.

In his editorial, Dr Orwoll points out that, given the response seen in older men with anemia, "an assessment of gonadal status would be warranted. If hypogonadism is present, testosterone replacement should be considered."

However, he also emphasized that, given the potential for adverse effects with excessive levels of hemoglobin, "these results serve to highlight the need to monitor hemoglobin levels in [testosterone]-treated men."

Harvey Jay Cohen, MD, from Duke University Medical Center, Durham, North Carolina, who was a coauthor on the anemia study, said, "Since there are no other known treatments of unexplained anemia in the elderly, assessment of testosterone levels followed by a trial of testosterone treatment in those with low testosterone might be considered."

Commenting on the modest findings related to physical performance in the anemia study, Dr Cohen nevertheless suggested, "They might be meaningful to an older man with precariously balanced functional status. Often small changes in function can make a big difference in quality of life for those whose decline in functional level interferes with their daily activities."

Reassuring Cardiovascular Data, but Questions Remain

In the entire T-Trial population of 790, no significant differences were found in major adverse cardiovascular events, serious adverse events, or prostate cancer between those receiving testosterone and those receiving placebo.

The third testosterone-related study in JAMA Internal Medicine was a retrospective cohort study looking at the cardiovascular risks associated with testosterone-replacement therapy in 8808 men with androgen deficiency who were categorized as "ever-dispensed' testosterone therapy (mean age, 58.4 years). By comparison, data from 35,527 men also with androgen deficiency categorized as "never-dispensed" testosterone therapy (mean age, 59.8 years) were analyzed.

In the study, led by T. Craig Cheetham, PharmD, from Southern California Permanente Medical Group, Pasadena, testosterone therapy was not associated with an increased risk for cardiovascular outcomes.

In fact, write the authors, testosterone therapy was associated with a lower risk for cardiovascular outcomes during a median follow-up of 3.4 years, with a rate of 23.9 vs 16.9 events per 1000 person-years in the never-testosterone therapy and ever-testosterone therapy groups, respectively.

The adjusted HR for the composite cardiovascular endpoint in the ever-testosterone therapy group was 0.67 (P <.001). The same pattern was reflected when the outcome was restricted to combined stroke events (HR, 0.72; P <.001) and combined cardiac events (acute myocardial infarction, sudden cardiac death, unstable angina, revascularization procedures) (HR, 0.66; P <.001).

There has long been debate about whether giving testosterone therapy to older men is associated with any alteration in the risk for cardiovascular events. In 2015, the US Food and Drug Administration required the manufacturers of prescription testosterone products to add information about the possible increased risks for heart attack and stroke with use of these products,^[9] warning that these products should be used only for men who have low testosterone levels due to disorders of the testicles, pituitary gland, or brain that cause hypogonadism. The European Medicines Agency, however, concluded that there was little consistent evidence of any increased risk for cardiovascular events associated with use of testosterone products.

Now in his editorial, Dr Orwoll points out that most of the men included in this current study were relatively young and healthy, and older men are more likely to be at higher risk for cardiovascular events with testosterone therapy: "While the study certainly provides reassuring data concerning the effects of testosterone on cardiovascular health, convincing answers about this question...remain elusive and will require large, prospective randomized trials.

"At this point, clinicians and their patients should remain aware that the cardiovascular risks and benefits of testosterone replacement in older hypogonadal men have not been adequately resolved," he writes.

Overall Clinical Implications: Still Reserve T Therapy for Hypogonadism

Summarizing these latest findings, Dr Anawalt discussed the potential clinical use of testosterone in men with low levels of the hormone with Medscape Medical News.

"Because results of the T Trials have shown improved sexual function in many men with a low blood testosterone concentration, testosterone therapy would be a particularly good choice for such men who have low bone-mineral density and decreased sexual function," he observed.

In addition, testosterone therapy "would be a reasonable treatment for men with mild anemia that is not due to bleeding, iron or vitamin deficiency, or a disease of the bone marrow," he added.

Finally, he agreed that uncertainty remains about whether testosterone therapy affects the risk for myocardial infarction or stroke in men, and therefore "testosterone therapy should be reserved for men who have unequivocally low blood testosterone concentrations and symptoms or signs of testosterone deficiency."

Of importance, he highlighted that testosterone should not be used as an "elixir of youth" for the large number of older men worldwide who have normal or borderline low blood concentrations without clear evidence of specific effects of testosterone deficiency, such as low BMD, low sex drive, or unexplained loss of muscle mass and strength.

Dr Ellenberg discloses receiving grants from the National Institutes of Health (NIH) and AbbVie during the conduct of the study and grants from AbbVie outside of the submitted work. Dr Snyder discloses receiving grants from the National Institute on Aging (NIA) and the NIH and grants and nonfinancial support from AbbVie during the conduct of the study; and personal fees from Watson Laboratories outside of the submitted work. Dr Roy discloses receiving grants from the NIH during the conduct of the study and grants from Celgene Corporation and the NIH outside of the submitted work. Disclosures for the coauthors are listed in the original studies. Dr Cheetham and coauthors have disclosed no relevant financial relationships, as do Drs Anawalt, Cohen, Cauley, and Orwoll.

JAMA Intern Med. Published online February 21, 2017.

Clinical Implications

• A retrospective cohort study by Cheetham and colleagues finds that testosterone therapy among men with evidence of testosterone deficiency is associated with lower risks for cardiac disease and cerebrovascular disease, even among men older than 65 years and those with preexisting cardiovascular disease.
• Two new studies demonstrate that testosterone treatment can correct anemia and improve BMD among men with low testosterone levels at baseline.
• Implications for the Healthcare Team: The current studies further demonstrate potential benefits of testosterone therapy among men with testosterone deficiency. Testosterone therapy was also associated with a lower risk for cardiovascular events in one study. Nonetheless, clinicians should continue to perform shared decision making regarding testosterone therapy and apply this treatment only among men with established testosterone deficiency.

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