New guidance urges caution on testosterone

Internists considering testosterone therapy are ideally positioned to consider a broader differential diagnosis that will actually help the patient.

Testosterone therapy was once thought of as a potential quick fix for a wide range of symptoms associated with aging in men, but a new ACP guideline issued in January urges caution. Hormone therapy should not be used to treat age-related declines in cognition or vitality in the absence of sexual dysfunction, experts concluded, and testosterone levels should only be tested in older men when they report low libido.

“There is some evidence that using testosterone may improve sexual function, but the degree of benefit is small to moderate,” said guideline coauthor Devan Kansagara, MD, FACP, associate professor of medicine and medical informatics and clinical epidemiology at Oregon Health & Science University in Portland. “We don't have any evidence that testosterone improves other symptoms commonly associated with hypogonadism, such as low energy or memory impairment.”

Symptoms related to tiredness should prompt a review of medications for potential side effects as well as screening for depression Image by Dean Mitchell
Symptoms related to tiredness should prompt a review of medications for potential side effects, as well as screening for depression. Image by Dean Mitchell

In addition, there is uncertainty around the long-term safety of taking testosterone, he said. As a result, the guideline recommends re-evaluating symptoms within 12 months of starting therapy and stopping treatment if there is no improvement in sexual function.

ACP's guideline, which aligns closely with 2018 recommendations from The Endocrine Society and the American Urological Association, clarifies clinical trial data on testosterone that has been emerging, said John K. Amory, MD, MPH, FACP, a professor of medicine at the University of Washington School of Medicine in Seattle, whose research focuses on male reproductive health. It can also be an entryway into a broader conversation about health and aging.

“Probably eight out of 10 of my patients who come in thinking they have low testosterone actually have something else,” said Dr. Amory. “Internists are ideally positioned to consider the broader differential diagnosis, do a workup, and make a diagnosis that will actually help the patient.”

When to test and treat

Testosterone levels typically begin to decline when men are in their mid-30s and continue at an average rate of 1.6% per year, according to ACP's guideline. Treatment should only be considered in men with levels below 300 ng/dL, although there is no absolute threshold, and symptoms related to sexual function, the guideline said.

Many patients have been influenced by advertising around testosterone therapy in recent years and may have outsized expectations of it as a fountain of youth, capable of restoring them to previous levels of vitality, said Dr. Amory and others.

“It's very common for men to come in specifically asking about testosterone,” Dr. Amory said. “The guideline really clarifies that this is an intervention appropriate for a small percentage of men with sexual dysfunction, but not a panacea for generalized symptoms like fatigue that men often come in asking about.”

For internists, ACP's guideline provides a framework for discussing patients' concerns around a wide range of issues related to aging and whether they are likely to be related to testosterone levels or other factors, said general internist Susan Diem, MD, MPH, staff physician with the Minneapolis VA Health Care System in Minnesota and lead author of the evidence report for the ACP guideline.

“Until recently, it has been unclear what physicians should do when patients come in complaining of low energy and other nonsexual symptoms and are very focused on getting treated with testosterone,” she said. “The ACP guideline can help shift the conversation to what testosterone treatment can actually do and what other causes may underlie those symptoms.”

Physicians and patients can then discuss other approaches to alleviating symptoms related to physical function, vitality, cognition, or depression, she said.

For example, many men come in asking for testosterone treatment for chronic fatigue but turn out to have sleep apnea, said Dr. Amory. He recommends screening for sleep apnea in patients who report tiredness or low mood and have risk factors, such as obesity and snoring.

Symptoms related to tiredness should also prompt internists to review patients' medications for potential side effects and screen for depression, said Khaled Elghonemy, MD, MSc, FACP, a general internist specializing in men's health at The Polyclinic in Seattle. Medications that have been linked with erectile dysfunction (ED) include selective serotonin reuptake inhibitors for depression and beta-blockers used to treat hypertension.

Even when patients' symptoms focus on sexual function, testing for low testosterone levels is not always the best first step, said urologist Kathleen Hwang, MD, director of male reproductive health at the University of Pittsburgh School of Medicine. Before ordering tests, physicians should ask follow-up questions about the patient's symptoms and possible triggers, she said. Patients often assume that testosterone can help with ED, for example, which usually has other underlying causes.

“We get very detailed about asking exactly what type of symptoms they have and for how long,” she said. “If their symptoms relate to sexual dysfunction, we have a very thorough conversation about their sex drive and quality of their erection before deciding whether to test testosterone levels.”

Testing testosterone levels may not be necessary for a patient who has difficulty maintaining an erection but has a completely robust sex drive and no other symptoms, she said. In such cases, she often starts with prescribing a drug specifically approved for ED.

More commonly, patients describe a combination of lower sex drive and occasional or frequent problems with achieving or maintaining an erection, she said. For these patients, she checks baseline testosterone levels unless there are other likely triggers, such as medication side effects.

“If a patient asks about getting a testosterone test, I probe more deeply about why, whether it's due to low energy or if there's something else going on,” said Dr. Elghonemy. “I often uncover sexual issues that the patient wasn't comfortable bringing up.”

Once the patient engages in that discussion, it's important to determine the precise nature of the sexual issue and do a risk assessment before jumping to testosterone testing, he added. For example, look for risk factors associated with coronary artery disease, such as smoking, diabetes, or hypertension, because these can be precursors of sexual dysfunction.

Low testosterone levels in younger men should always be investigated further because they can be a sign of certain rare diseases, such as hereditary hemochromatosis, said Dr. Amory. If caught early, appropriate treatment can be initiated to protect patients from progressing to conditions like cirrhosis or heart failure.

However, most symptoms related to low vitality or fatigue are due to obesity, depression, sleep problems, and lack of physical activity, the experts said.

Explaining treatment and risks

Before testing for low testosterone levels, physicians should explain the treatment process, said Dr. Elghonemy. Patients often don't understand that treatment usually requires injections and frequent bloodwork.

ACP's guideline recommends favoring intramuscular over transdermal administration due to the much higher cost of the latter, $2,135 versus $156 annually. Most insurers do not cover the more expensive option, as it has not been proven more effective than injections.

However, according to an accompanying editorial, the need for an injection every one to four weeks is a potential barrier to adherence. Other forms of administration, including transdermal patch, topical gel, or buccal tablet, are far easier and more convenient to use for most patients, the editorial said.

“Some patients can self-administer injections, but others have to travel to a clinic or pharmacy for treatment,” said Dr. Elghonemy. “Injections can be very inconvenient, especially for men who travel frequently, and many say they would switch to transdermal if the cost went down.”

Patches and gels are easier to apply but still require vigilance on the part of the patient because they must be applied and/or changed daily, said Dr. Hwang. A longer-lasting option is the testosterone pellet, which is implanted under the skin near the hip and slowly dissolves over about six months.

“There are certainly men for whom the intramuscular formulation is not going to be tolerated or feasible,” said Dr. Kansagara. “However, we found that, on average, given the large cost differential, it's reasonable to offer the intramuscular injections as a first option.”

Patients should be aware that treatment requires close monitoring of their prostate health, said Dr. Hwang.

“I explain to patients that being on therapy will require regular bloodwork, and regular prostate exams and PSA [prostate-specific antigen] tests, which men younger than 50 may not have been required to have yet,” she said. “They should know up front that this is a door that opens for everybody who's considering testosterone treatment.”

It's also important to manage patients' expectations about the effect of treatment and make them aware of the potential risks, said Dr. Diem. For some men, the small potential benefits may not justify the potential long-term risks.

Although current evidence on risk is not definitive, some studies have found an association between testosterone therapy and increased risks for cardiovascular disease and prostate cancer. For example, one small trial of men with mobility limitations and high prevalence of chronic disease published in the July 8, 2010, New England Journal of Medicine found an association between testosterone gel and adverse cardiovascular events. Another small 2019 prospective study presented at the National Cancer Research Institute Cancer Conference in 2019 found that men with higher levels of free testosterone and insulin-like growth factor-1 in their blood are more likely to be diagnosed with prostate cancer.

A large, five-year clinical trial, known as TRAVERSE, is currently underway to test whether therapy in symptomatic men with low testosterone levels increases incidences of major cardiovascular events and high-grade prostate cancer. However, results will not be available for several years.

In the meantime, physicians should be cautious about prescribing testosterone therapy to patients at increased risk for these conditions, said Dr. Hwang. “We don't have clear objective evidence suggesting that prostate cancer is a direct correlation with testosterone treatment, but we can check whether patients have a history of elevated PSA at baseline,” she said. “Those are very high-risk patients that you have to be very thoughtful about whether to even consider testosterone.”

Similarly, there is no clear guidance on whether it's safe to treat men who have been successfully treated for prostate cancer, said Dr. Elghonemy. “Patients who have undergone prostate cancer treatment often have complaints of sexual dysfunction, which is common after treatment,” he said. “Part of the reason might be low testosterone, but the guidelines haven't really addressed whether it would be too risky to consider in these patients.”

In a small percentage of men, testosterone therapy has been shown to cause an increase in hematocrit and hemoglobin concentration, leading to erythrocytosis or polycythemia, as was found in a 2017 review published in Sexual Medicine Reviews. Therapy may also increase the likelihood of having a prostate biopsy because patients are monitoring their PSA levels more closely.

Since the longer-term risks and benefits are not yet clear, the ACP guideline recommends discontinuing therapy within a year in the absence of any improvement in sexual function.

“The small potential benefit of therapy has to be viewed through the lens of the patient and their individual priorities around sexual function,” said Dr. Amory. “We find that less than half of patients continue therapy for longer than six months because the benefits they experience are not what they had hoped for.”

Overall, he said, the hype around testosterone therapy could be considered a boon because it's led to more men scheduling visits and taking a bigger role in managing their health.

“A lot of men are not super health engagers and are hoping that testosterone therapy will be a quick fix for a wide range of issues,” he said. “Typically, they turn out to have normal levels, but the visit opens the door to a broader discussion of how they can take better care of themselves.”