Drug companies that manufacture testosterone replacement drugs such as AndroGel heavily market their products, promising men increased vitality, strength, sex drive and an overall better quality of life.
The reality, however, is that testosterone replacement therapy (TRT) can cause a number of health complications that, some doctors say, might not be worth the benefits.
Studies and clinical trials have linked the drugs to serious health risks including heart problems and cancer. Replacement therapy can also upset the balance of hormones in the body. The testicles may shrink, and there is a risk of infertility that is irreversible. Women, children and pets may also experience serious side effects if they come in contact with TRT products.
Evidence from published studies and expert input from an advisory committee prompted the U.S. Food and Drug Administration (FDA) to require labeling changes to reflect additional risks associated with use of these products. Still, critics — including plaintiffs in more than 25,000 lawsuits — say even more warnings about side effects are needed.
Serious side effects are rare, and the side effects reported most often in clinical trials were mostly minor. The most frequently reported adverse events in clinical trials varied based on the product, but they generally included reaction at application site, enlargement of male breasts, oily skin, and changes in hair patterns and growth. Other reported side effects included acne, prostate disorders, back pain and abnormal lab tests.
Heart Attack Risk
The results of a clinical trial published in the Journal of the American Medical Association (JAMA) in February 2017 showed treatment of older men with testosterone gel for one year was associated with a significant increase of coronary artery plaque. The waxy substance can build up, harden and reduce the flow of oxygen to the heart. If the artery becomes completely blocked, it can lead to a heart attack, also known as myocardial infarction.
“[T]estosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months.”
Researchers for a year studied the effect of the treatments on cardiovascular health in men who had low testosterone levels that couldn’t be explained by anything other than age. A total of 138 men over the age of 64 completed the study; 73 received the drugs and 65 received a placebo.
“[T]estosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months,” the study’s authors wrote. They noted that additional, larger studies were needed to assess the risk.
A 2014 study published in PLOS One found the risk of heart attack after starting TRT “substantially increased” in older men and in younger men with pre-existing diagnosed heart disease.
The study by William D. Finkle and colleagues involved the records of 55,000 men prescribed testosterone in the U.S. It found that in the first 90 days of beginning therapy, the heart attack risk for men aged 65 or older who were using the drugs doubled compared with non-users in the same age group.
The risk was not limited to older men. The study also found men younger than 65 with pre-existing heart disease had a two- to threefold increased risk of heart attack in the 90 days after starting therapy.
The study’s authors noted that their findings were consistent with an analysis of placebo-controlled randomized trials that reported TRT increased the risk of heart attack and other serious cardiovascular risks. The trials involved mostly older men who used the drugs for 12 or more weeks.
“Taken together, the evidence supports an association between testosterone therapy and risk of serious, adverse cardiovascular-related events–including non-fatal myocardial infarction–in men,” Finkle and colleagues wrote.
In addition, a study published in JAMA in November 2013 found a 30 percent increased risk of heart attacks and other cardiovascular issues in veterans who took the hormone replacement drugs versus those who did not, according to the FDA.
Study Halted due to ‘Significantly Higher’ Rate of Cardiovascular Events
Researchers stopped a small trial in 2010 because the rate of adverse cardiovascular events was significantly higher in the group taking testosterone than in the group not using the drugs.
The New England Journal of Medicine published the results of the study, which involved frail, older men who used TRT. A total of 23 men in the group using the drugs suffered cardiovascular-related adverse events compared with five men in the placebo group.
“The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group,” the study’s authors wrote.
Calls for Black-Box Warning
The risk of cardiovascular problems led consumer advocacy groups to call for a black-box warning on all testosterone drug packaging. Dr. Sidney Wolfe of Public Citizen said in a 2014 Drugwatch Podcast that the organization petitioned the FDA to require manufacturers to add warnings to the packages of several hormone replacement products already on the market.
Previous studies “showed that there was a 50 percent increase in cardiovascular risk … 14 studies that weren’t funded by the drug industry [showed] over a doubling of risks,” Wolfe told Drugwatch.
“[Previous studies] showed that there was a 50 percent increase in cardiovascular risk . . . 14 studies that weren’t funded by the drug industry [showed] over a doubling of risks.”
Finkle echoed Wolfe’s sentiments in a 2014 interview with NPR.
“We have a 2010 study that was canceled because of unexpected cardiovascular risk,” Finkle told NPR. “I think that was sufficient to justify a warning. Why withhold that from the patient?”
To date, the FDA has not required a black-box warning for cardiovascular risks, but in 2015, the agency required manufactures of TRT drugs to add information to the products’ labels about a possible increased risk of heart attacks.
Blood Clot Warning
In June 2014, the FDA required TRT manufacturers to include a warning on drug labels about the risk of blood clots in veins. The labels now say there have been postmarketing reports that using these products led to serious blood clots.
Testosterone increases production of thromboxane, a lipid that promotes blood vessel constriction. This can slow blood flow making clots more likely to form. Deep vein thrombosis occurs when these clots form in a major vein, usually in the legs. If these clots break free, they can travel to the lungs and cause a pulmonary embolism, or they can travel to the brain and cause a stroke.
Another side effect of TRT is polycythemia, a condition characterized by increased levels of red blood cells. When bone marrow produces too many red blood cells, it causes the blood to thicken and increases the risk of blood clots.
Study Finds Blood Clots Developed as soon as 3 weeks After Starting Therapy
A study first published on Aug. 7, 2013 in Clinical and Applied Thrombosis/Hemostasis found that blood clots developed as quickly as three weeks after men began using testosterone therapy drugs.
The study identified seven men who had used the drugs before or at the time they were admitted to the hospital for serious blood clots. The men experienced blood clots at 3 weeks, 1 month, 2 months, 3 months, 12 months or 27 months after starting TRT.
“Our research found that 1.2 percent of men who landed in the hospital with dangerous and potentially lethal blood clots in the deep veins of the legs or in the lungs developed these clots within three months of starting testosterone therapy,” study author Dr. Charles Glueck of the Jewish Hospital Cholesterol and Metabolism Center told the Cincinnati Business Courier.
According to Glueck, an inherited clotting disorder can increase the risk of blood clots. He said people should be tested for risk factors before beginning TRT.
Potential Stroke Risk
In March 2015, the FDA required manufacturers to update their products’ labels to warn of a possible increased risk of stroke in patients taking testosterone. According to the FDA, some studies have shown an increased risk in stroke associated with TRT, but study results have been mixed.
“Some postmarketing studies have shown an increased risk of [heart attack] and stroke associated with use of testosterone replacement therapy,” the FDA-approved Testim label reads.
“Some postmarketing studies have shown an increased risk of [heart attack] and stroke associated with use of testosterone replacement therapy.”
A 2010 study in the New England Journal of Medicine found the drugs could increase the risk of several cardiovascular events including stroke in older men with limited mobility and a high prevalence of chronic disease. But Shehzad Basari and other authors warned that the small size of the study — just 209 men 65 and older — warranted further research into the risks.
A July 2015 investigation appearing in JAMA Internal Medicine compared different delivery systems for TRT drugs. It found injections were associated with increased short-term risk of stroke and other complications. The risk was lower with gels and patches.
More recent research has questioned the extent of stroke risk with TRT use.
A September 2017 study in the journal Maturitas reviewed previous research on the relationship between these medicines and stroke risk. It found few studies had looked specifically at the stroke risk of men treated with testosterone, and studies that had evaluated the possible association were plagued by serious limitations. Researcher Simone Loo and the other authors concluded “the association between TRT and the risk of stroke in men remains unclear.”
The FDA said it was requiring manufacturers to conduct a clinical trial to determine whether an increased risk of stroke exists among testosterone users. The agency instructed health care professionals to warn patients of the potential risk, and it cautioned patients taking TRT drugs to seek medical attention immediately if they experience symptoms of stroke, including slurred speech and weakness in one part or one side of the body.
Possible Increased Risk of Prostate Cancer
TRT drugs are also linked to a possible increase in prostate cancer risk. One of the reasons for this is a spike in testosterone levels.
Research associating TRT drugs with prostate cancer risks go back to the turn of the century.
One study led by Dr. Terrence Shaneyfelt found a twofold increase in the risk of prostate cancer among men whose testosterone levels were in the highest quartile. The study’s authors were from Beth Israel Deaconess Medical Center and Harvard.
A 2005 study in the Journal of Urology reviewed the medical records of six urology practices. They looked at cases in which men underwent therapy for sexual dysfunction or “rejuvenation” and identified 20 men who were diagnosed with prostate cancer after starting TRT.
In 55 percent of the cases, doctors detected the cancer within two years of the men first using the drugs. The rest of the men were diagnosed between 28 months and eight years after starting therapy.
“Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment.”
“Prostate cancer may become clinically apparent within months to a few years after the initiation of testosterone treatment,” the authors concluded. “Physicians prescribing testosterone supplementation and patients receiving it should be cognizant of this risk, and serum PSA testing and digital rectal examination should be performed frequently during treatment.”
But nearly two decades after the first of these studies concluded, researchers say still more study is needed.
In 2017, the National Institutes of Health concluded far-ranging research into TRT called the Testosterone Trials (TTrials). The project coordinated seven placebo-controlled, double-blind trials — the gold standard of medical studies. The findings regarding the exact association between the therapy and prostate cancer were inconclusive.
“Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk,” the researchers wrote.
In the meantime, the FDA requires the products’ labels to advise doctors to monitor men taking the therapy to make sure that prostate cancer does not develop. Men who have a history of prostate problems should not use the products.
A 2014 study led by Professor Maarten Bosland of the University of Illinois at Chicago’s College of Medicine found that rats that were exposed to a recognized carcinogen did not develop cancer but that 10 to 18 percent of ones that were exposed to testosterone did.
In addition, 50 to 71 percent of the rats exposed to both the carcinogen and the hormone developed prostate cancer. Even low doses of the hormone replacement drug were enough to create tumors, according to the study.
“If these same findings hold true in humans, there is serious cause for public health concern,” Bosland said in a UIC Today article.
Sleep Apnea May Worsen
Testosterone replacement therapy may make sleep apnea worse or increase the likelihood of it developing, especially in patients with risk factors such as obesity or chronic lung disease, according to the drugs’ labels.
Some researchers have found TRT may worsen a type of sleep apnea known as obstructive sleep apnea (OSA), but others said the link between the therapy and the sleep condition was weak.
With OSA, the flow of air stops or decreases during sleep because of a blocked or narrowed airway. It can cause stroke, atrial fibrillation and cardiac ischemia, a condition where not enough blood is flowing to the heart.
“The elevated risk of OSA in men using TRT is noteworthy.”
An article published in 2007 in The Journal of Sexual Medicine said further studies are needed to determine whether there is a relationship between the hormone treatment and obstructive sleep apnea. The author reviewed literature about TRT and OSA and concluded there was “a lack of convincing evidence” that such treatment causes or aggravates the sleep condition. The author noted that most studies involved small numbers of men.
A 2012 study published in Clinical Endocrinology looked at a group of 67 obese men with severe obstructive sleep apnea. The randomized, double‐blind, placebo‐controlled trial put all the subjects on a low-calorie diet and then injected the men with either the hormone or placebo over 12 weeks.
“Testosterone therapy in obese men with severe OSA mildly worsens sleep‐disordered breathing in a time‐limited manner, irrespective of initial testosterone concentrations,” Camilla Hoyos and the other authors wrote.
A more recent study published in March 2018 in BJU International found the risk of OSA was higher in men treated with testosterone than in those who didn’t receive the therapy. The study looked at 3,422 men ages 40 to 64 years old who were prescribed TRT between 2006 and 2010 to treat low levels of the hormone. Researchers matched those men based on age and medical history with participants who were not prescribed the drugs.
According to the study results, the two-year risk of OSA was 16.5 percent in the group that received the drugs compared to 12.7 percent in the control group.
“The elevated risk of OSA in men using TRT is noteworthy,” the authors wrote.
Risks to Women
The FDA has not approved any TRT product for use in women. However, some doctors have begun supplementing testosterone in women, typically as part of a midlife hormone replacement regime to counter the symptoms of perimenopause and menopause.
Women prescribed TRT, or who accidentally come in contact with the products, should be aware of potential side effects.
- Hair growth on the face or body
- Hair loss on the scalp
- Oily skin or acne
- Hoarseness or deepening of the voice
- Fluid retention
- Diminished breast size
- Increased clitoris size
Researchers do not yet know whether these drugs can affect factors like risk of breast cancer, heart disease or blood clots in women. However, products in this class carry a Pregnancy Category X, which means that they may cause fetal harm.
Women who are pregnant, who could become pregnant or who are nursing should not use testosterone and should avoid contact with an area of skin where topical gels have been applied. Unborn and nursing babies may experience inappropriate virilization, which is the development of male secondary sexual characteristics in a female or very early development of such characteristics in a boy.
Black-Box Warning for Secondary Exposure in Children
Accidental exposure in children who live or interact closely with men who are using topical testosterone drugs is a serious problem. That exposure typically occurs through contact with skin that has been treated with gels or other topical products. For this reason, the FDA requires that these products carry warnings on their labels to inform users of the dangers of accidental exposure and give users information on how to avoid it.
Two TRT gels, AndroGel and Testim, carry a black-box warning for secondary exposure in children. Because the gel is applied to the skin, children may come in contact with application sites or even leftover gel on unwashed clothes or towels.
- Children who are exposed to the gel may suffer from inappropriate virilization.
- Children should not have contact with the “unwashed or unclothed application sites.”
- Doctors and other providers should warn patients that these products should be used as directed and to strictly follow instructions for use.
Side effects reported in children who have come into contact with these drugs include enlarged genitals, premature growth of pubic hair, increased self-stimulation and aggressive behavior.
While these effects typically fade when exposure stops, genitals may remain enlarged in some cases. In addition, children exposed to these medications may experience advanced bone aging. As a result, these children may stop growing prematurely and may be shorter in height as an adult than they might have been without exposure.
Dangers to Pets
There is little research into the dangers TRT gels may pose to pets. Their labels mention simply that patients should “prevent accidental exposure of children or pets” without going into specific risks to animals.
However, in 2010, the Veterinary Information Network, a news service for veterinarians, detailed roughly 20 cases of pets suffering side effects after coming into contact with hormonal patches or gels. Most of the cases involved estrogen products prescribed to women, but veterinarians were quick to include warnings about TRT products as well.
The National Institutes of Health’s Medline Plus service says pets may rub against exposed skin where the drug is applied or play with discarded envelopes or patches. It recommends disposing of used TRT drug containers or patches in ways that keep them from dogs, cats and other pets.
Please seek the advice of a medical professional before making health care decisions.