Risks of Testosterone Replacement Therapy

Medically Reviewed

Low testosterone in men—or “low T,” as it’s sometimes called in TV, print, and online advertisements—can be caused by certain medical conditions or medications. It can also occur naturally; in men, levels of the hormone drop by about 1 percent each year after the age of 30. As the ads point out, low T, also known as hypogonadism, can be associated with a host of troubling symptoms, including a flagging sex drive, erectile dysfunction, and diminished energy levels and strength.

But one problem the ads don’t discuss is low testosterone’s effect on bone mineral density (BMD). One worrisome finding, from the 2006 Osteoporotic Fractures in Men Study, showed that elderly men with low testosterone levels lost bone rapidly and had twice the risk of developing osteoporosis of the hip as their counterparts with normal levels of the hormone. Men who had very low levels (less than 200 ng/dL) had three times the risk.

Consequently, some doctors and professional groups, such as the Endocrine Society—a leading professional organization in the field of endocrinology—recommend testosterone replacement therapy for men with symptoms of testosterone deficiency if their levels of the hormone are low and they are at high or borderline high risk for osteoporotic fractures.

Experts agree that testosterone replacement therapy is not appropriate for men with symptoms of low testosterone but normal levels of the hormone—even if fracture risk is high—because testosterone fails to increase bone density in such cases. And now findings from several recent studies may cause doctors to be even more cautious about who should or should not be treated with testosterone replacement therapy. Taken together, the studies suggest an increased risk of stroke, heart attack, and even death among men who use it. If you’re using testosterone replacement therapy because your fracture risk is elevated, here’s what you should know.

New safety questions emerge

One of the first troubling reports came from the Testosterone in Older Men with Mobility Limitations (TOM) trial, which was published in 2010 in The New England Journal of Medicine.

To investigate the impact of testosterone on muscle strength and physical function, the investigators randomly assigned 209 men age 65 and older who had low testosterone levels and mobility problems to treatment with a testosterone gel or a placebo gel. The products were to be applied daily for six months, but the study was stopped early due to a noticeable uptick in certain side effects, including heart attack and stroke; 23 men in the testosterone group experienced a cardiovascular-related adverse event compared with only five in the placebo group. This increased risk remained constant throughout the study period and persisted for at least three months after the study ended.

A string of publications in the last few years have reported similar findings. The most recent is from a study published in 2014 in the journal PLOS ONE. Researchers examined data from the medical and pharmacy records of 55,593 men to determine their risk of heart attack after using prescription testosterone therapy. They found that the relative risk of a heart attack in the first 90 days of testosterone replacement therapy use increased twofold for those 65 and older and in men with a known history of heart disease.

These findings are from an observational study—a type of investigation that can only show an association between a treatment and a response, not a direct cause-and-effect relationship, which is an important factor to keep in mind when considering the significance of the results. But the study also involved a large number of men, which gives the findings more weight.

What’s more, the results came on the heels of a report that analyzed findings from 27 randomized trials—considered the gold standard of studies because they can show causation. The analysis, which was reported in 2013 in the journal BMC Medicine and involved nearly 3,000 mostly older men, also showed that testosterone replacement therapy increased the risk of cardiovascular events.

Interestingly, the researchers reported that the risk of a cardiovascular event was greater in trials that were not funded by the pharmaceutical industry. Also in 2013, an observational study in JAMA reported a significant link between men on testosterone replacement therapy who underwent coronary angiography (a relatively minor cardiac procedure) and adverse outcomes—up to a 25.7 percent risk of events such as heart attack and stroke in those taking testosterone compared with 19.9 percent in those taking a placebo. However, critics have raised concerns about flaws in that study’s design and interpretation.

Although the results of this study have been called into question by some doctors, the authors stand by their conclusions. And when taken together, findings from these studies raised enough red flags to cause the U.S. Food and Drug Administration to take a fresh look at the evidence on the cardiovascular safety of prescription testosterone therapy.

Another concern has recently come to light—an increased risk of potentially life-threatening blood clots in the veins, known as venous thromboembolism. This risk of venous thrombolembolism is discussed in the labeling of testosterone products as a possible consequence of polycythemia, an abnormal increase in the number of red blood cells that sometimes occurs with testosterone treatment. However, there have been more recent reports of venous thromboembolism unrelated to polycythemia, and last summer, the FDA began requiring that manufacturers add a warning about this risk to all testosterone replacement therapy product labels.

Our advice

For now, the FDA has stopped short of advising men for whom testosterone replacement therapy is appropriately prescribed to discontinue using it. Nevertheless, if you’re concerned, make an appointment with your doctor to talk about the risks and benefits of the treatment for you. Don’t stop taking the medication without speaking to the doctor first. In addition, it’s prudent to take the following steps to safeguard your health:

Be sure your testosterone level was tested more than once. Because testosterone levels can fluctuate from week to week, day to day and even from hour to hour, blood tests should be performed on at least two different mornings at the same time. Testing is recommended in the morning because testosterone levels are at their highest then, with levels dropping by as much as 30 to 40 percent by midafternoon.

Know your fracture risk. Testosterone replacement therapy is not recommended as a treatment for osteoporosis for men who aren’t at high or borderline high risk. You or your doctor can calculate your 10-year probability of having a fracture using the Fracture Risk Assessment tool, or FRAX. If your risk is lower than 10 percent, you’re at low risk; if it is between 10 percent and 20 percent, you are at medium risk; and greater than 20 percent is considered high risk.

For men at high risk, the Endocrine Society recommends treatment with testosterone replacement therapy plus an osteoporosis medication proved to reduce fracture risk, such as a bisphosphonate, or the synthetic human parathyroid hormone, teriparatide (Forteo). For men who are borderline high risk, the group recommends testosterone replacement therapy alone. If symptoms of testosterone deficiency have not been alleviated in three to six months, the Endocrine Society recommends discontinuing testosterone replacement therapy.

If you continue using testosterone replacement therapy, you should see your doctor regularly. Ongoing monitoring is important to determine whether the treatment is working and to evaluate for potential complications.