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The Lowdown on Testosterone Replacement Therapy

Promoters of prescription testosterone products promise that the hormone is nothing less than a fountain of youth for men of a certain age. And sales of pills, gels, and patches have soared, nearly quadrupling in the United States between 2000 and 2011.

Many claims from drug companies and “anti-aging” clinics are directed at men who hope to regain their youthful vigor and improve their strength, sexual prowess, athletic performance, and appearance.

Natural levels of the male sex hormone normally decline with age. As they ebb, sex drive often slips into low gear, youthful energy fades, bones get thin and brittle, and physical ability sags, among other changes.

Some doctors began to surmise that testosterone replacement therapy could reverse certain age-related changes men experience, or at least hold them off for a while.

But many men prescribed testosterone replacement therapy don’t have an abnormally low blood level of testosterone-related symptoms or haven’t even had the hormone measured.

Until recently, there has been little scientific evidence to support male hormone replacement, except for men whose bodies don’t produce enough testosterone, a medical condition called hypogonadism, or androgen deficiency. It differs from the natural process of decreasing testosterone that comes with normal aging, sometimes referred to as late-onset hypogonadism.

The Testosterone Trials

To test whether testosterone replacement offered older men any benefits, the National Institutes of Health sponsored a series of seven rigorously controlled, randomized trials, known as the Testosterone Trials, or TTrials, the largest of their kind.

Findings from four clinical trials were published online in February 2017 by the Journal of the American Medical Association and JAMA Internal Medicine. Findings from the first three trials appeared in February 2016 in The New England Journal of Medicine.

Putting ‘T’ to the test

The TTrials recruited 790 men ages 65 and older who had low testosterone levels and exhibited symptoms that could be related to low testosterone. Blood testosterone levels of 275 ng/dL (nanograms per deciliter) or below were considered low. Their low levels were attributed to aging and not to another recognized cause, such as hypogonadism.

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Some men were randomly assigned to receive hormone replacement in the form of a 1 percent prescription gel applied to the skin daily. Others received a placebo, or inactive gel. Scientists tested whether testosterone replacement therapy offered any benefit over the course of one year. Here’s what they found:

• Sexual function. Testosterone replacement therapy modestly boosted sex drive and improved erections in men with low testosterone enrolled in the sexual function arm of the TTrials.

But improvements tended to decline over a year, leading experts to suggest that testosterone replacement therapy isn’t as effective as drugs such as tadalafil (Cialis) and sildenafil (Viagra) for treating erectile dysfunction—although they won’t help sex drive.

• Physical function. Researchers studied whether testosterone replacement therapy improved men’s walking speed over six minutes. Disappointingly, there was no difference between the testosterone group and the placebo group on either measure.

• Vitality. In the trial that gauged how men rated their energy and vitality, testosterone replacement therapy fell flat. Scores for both the testosterone and placebo groups remained the same.

• Bone density. Among the more encouraging findings is evidence that testosterone replacement therapy can help protect against bone loss. After a year on testosterone, volunteers who had normal bone density (none had osteoporosis) had a significant increase in bone mineral density and bone strength compared with men on a placebo.

Because the trial lasted only one year, researchers can’t say with certainty that the increased bone density will ultimately lower fracture risk or if the same effect would be seen in men with osteoporosis. For now, men with low bone density and at high risk of fracture should look to proven osteoporosis medication, which has been studied for long-term use and is known to help prevent fractures.

• Anemia. For years, doctors have been puzzled by a form of anemia (an abnormally low number of red blood cells) that appears in some men as they age. To test whether low testosterone levels might be the culprit, researchers studied the effect of testosterone replacement therapy on a group of 126 men with known and unknown causes of anemia.

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After 12 months, testosterone treatment significantly increased their hemoglobin levels by stimulating the production of red blood cells: 58 percent of the men with unexplained anemia were no longer anemic, compared with only 22 percent of the men in the placebo group. Testosterone replacement therapy also helped men who had anemia from known causes, such as iron deficiency.

• Brain health. Hopes ran high that testosterone replacement therapy might help counter some age-related changes affecting memory and cognition. No such luck. The Cognition Trial included 493 men with low testosterone and age-associated memory impairment. Testosterone replacement therapy offered no benefits for memory or other aspects of brain function.

• Heart health. Past studies have raised red flags that testosterone might increase the risk for heart attacks, strokes, and blood clots. The new findings add to those concerns.

Using scans to measure plaque in the arteries of 170 men with heart disease risk factors, researchers found that men on testosterone replacement therapy had more plaque buildup and greater narrowing of their arteries than men in the placebo group. The findings are worrisome because plaque buildup can raise the risk of a heart attack or a stroke.

Risks remain a worry

The TTrials have gone a long way in separating the hype from the real benefits testosterone replacement therapy may offer. But one important question remains unanswered: Is long-term testosterone replacement therapy use safe?

Because the TTrials were only one year long, they don’t shed light much on the therapy’s risks. Some long-term studies have associated testosterone replacement therapy with prostate cancer, whereas others report no evidence that testosterone replacement therapy in men with low testosterone levels increases prostate cancer risk.

And concern remains about the effects of testosterone replacement therapy on cardiovascular health over time. In 2015, the U.S. Food and Drug Administration began requiring testosterone products to carry a warning about their associated risk for heart attack and stroke.

Other risks associated with testosterone replacement therapy include erythrocytosis (an abnormal increase of red blood cells) and benign prostatic hyperplasia (an enlarged prostate), or BPH.

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Testosterone replacement therapy side effects include acne, breast enlargement, unwanted hair growth, and infertility. Men who have prostate or breast cancer, sleep apnea, BPH, or heart failure shouldn’t use testosterone replacement therapy because it can worsen those conditions.

Most experts agree that doctors should consider testosterone replacement therapy only for men with proven low levels of testosterone who have symptoms that might improve with treatment, such as anemia, bone loss, or loss of sexual desire or function.

The only sure way to know whether your testosterone is low is to be diagnosed by a doctor, who will perform a physical exam, take your medical history, test your blood on at least two separate days, and rule out other conditions.

The bottom line

If you’re considering testosterone replacement therapy, you might do well to start with a few healthy lifestyle changes that can offer even more benefits than hormone replacement.

Being overweight or obese is closely associated with low testosterone. Losing weight can raise hormone levels. Regular exercise—even a brisk 30-minute walk a few times a week—can improve vitality, strengthen muscles and bones, lower heart disease, and possibly even improve your sex life. That’s far more than testosterone replacement therapy can promise.

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