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Published On July 23, 2012

CLINICAL RESEARCH

Gaining Strength

Out of favor for decades, testosterone replacement therapy is back--and so is the debate about a possible link to prostate cancer.

ONE OF THE MOST TALKED-ABOUT BOOKS OF 1945 WAS THE MALE HORMONE, which extolled the wonders of testosterone. In it, popular science writer Paul de Kruif told of how treatment with testosterone—the primary male sex hormone, which had been identified just a decade earlier—could rejuvenate middle-aged and older men who complained of lost libido, flagging energy and sagging spirits. A review of the book inTime called it “a mixture of laboratory slang, movie-travelogue lyricism and man-to-man locker-room candor.”

The Male Hormone arrived as a debate raged in medicine: Was there a male version of menopause? And could testosterone therapy allow aging men to rediscover sexual potency and virility? Many doctors eagerly explored the hormone’s potential for these and other uses, ranging from relieving heart ailments to “curing” homosexuality. Other physicians were dubious. In the early 1940s, research by University of Chicago physician Charles Huggins (who would win the Nobel Prize for his work) found that depriving men of testosterone by castration (through surgical removal of the testicles or with estrogen, which blocked testosterone’s effects) slowed the progression of aggressive prostate cancer, and that spawned a corollary theory: Testosterone must fuel growth of the disease.

Within a decade, scientific interest in testosterone began to dwindle. Many men disliked testosterone treatments, which required frequent needle injections and often didn’t relieve their primary complaint, erectile dysfunction. Meanwhile, by the mid-1950s, medicine began to view the woes of aging males in a new light, says medical historian Elizabeth Watkins in the forthcomingAging Men: Medicine and Masculinities (Routledge, 2012). Hormones were no longer seen as the problem; loss of libido, low energy and other symptoms “resulted from a psychoneurotic condition, brought on by the social stresses and economic pressures of modern life,” Watkins writes. Tranquilizers soon became the treatment of choice, and discussion of testosterone replacement therapy “virtually disappeared from the medical literature” for the next 40 years, according to Watkins.

Fast-forward to the present: Testosterone replacement therapy is back and booming. The number of annual prescriptions for TRT in the United States doubled during the past five years, with sales of injections, gels, skin patches and even pellets implanted in the buttocks topping $1.64 billion in 2011, according to IMS Health, a health-care-industry market research firm. Part of this surge is attributable to advertising, including television commercials and print ads that ask, “Is it low T?” But there also has been a wave of research suggesting that middle-aged and older men with low testosterone levels—more than 8 million Americans overall, including one in four men older than age 70—can experience a striking pattern of symptoms that may result from the deficiency. Some physicians insist that restoring hormones to youthful levels can allow a man to regain his former sense of masculinity—and possibly prolong his life.

“For 60 or 70 years, we’ve thought about testosterone as being purely about sex,” says Abraham Morgentaler, director of Men’s Health Boston, a clinic for men with low testosterone and other health issues, and associate clinical professor at Harvard Medical School. But Morgentaler believes conventional wisdom is about to change. He and others point to a growing body of research indicating that men with “low T” suffer more than fatigue and disappointment in the bedroom. Studies also have found an increased risk for heart disease, type 2 diabetes, depression, falls and hip fractures, anemia and Alzheimer’s disease. Morgentaler thinks it’s becoming impossible to ignore the notion that low testosterone is a threat to overall health.

Yet many other physicians question the growing popularity of TRT, pointing out that ebbing libido, erectile dysfunction, low energy and other symptoms can be brought on by many conditions unrelated to male hormones. More ominously, they argue, the risks linked to testosterone, especially the threat of triggering prostate cancer cells to grow and spread, outweigh the potential benefits for most men. Skeptics also tend to draw parallels between TRT and hormone replacement for women—a therapy that the medical establishment embraced for years before a landmark study raised questions about heart disease and cancer risks.

Such comparisons frustrate those who say it is long past time to stop demonizing testosterone. “There is a huge belief that testosterone is bad,” says St. Louis University endocrinologist John Morley. “But the data supporting that belief are virtually nonexistent.” Still, even among TRT proponents, there’s division. Some, including Morgentaler, are willing to prescribe testosterone treatments to some men who have active prostate cancer, something that would have been anathema just a few years ago and that many physicians worry could imperil broader acceptance of TRT. So will testosterone therapy fall out of fashion yet again, or is it destined this time to become a mainstay of medical care?

AS THE PRIMARY MALE SEX HORMONE, testosterone gives rise to the physical and emotional characteristics that define masculinity. During fetal development, testosterone stimulates formation of male genitalia. When a boy reaches puberty, rapidly rising hormone levels spark growth of muscles, bones, and facial and body hair—even the larynx and vocal cords get bigger, causing the voice to deepen. Internal and external male reproductive organs also mature, and by age 14 most males can produce sperm.

The average man’s testosterone level peaks in young adulthood, but after age 40 it begins a slow and steady decline—in contrast with menopause, which occurs in women somewhat later (age 51, on average) and results in a relatively rapid and near-total drop in production of estradiol, the primary form of estrogen, or female sex hormone.

For many years, medical use of testosterone was largely limited to treatment of certain genetic disorders. However, these days it’s understood that men whose testosterone levels have declined with age may experience similar signs and symptoms, according to diagnostic guidelines established by the Endocrine Society in 2010. Red flags could include low libido, erectile dysfunction, low sperm count, loss of body hair and hot flashes. The Society, however, also suggests checking testosterone if an adult male is experiencing other problems, such as poor concentration, “feeling sad or blue,” insomnia, “decreased energy, motivation, initiative and self-confidence,” and “diminished physical or work performance,” among other symptoms.

Studies suggest that these symptoms are more likely to occur if a man’s testosterone dips below 300 ng/dl (nanograms per deciliter). It’s clear, however, that many men whose testosterone falls below normal levels never notice. A 2007 survey of nearly 1,500 Boston-area males between the ages of 30 and 79 found that 24% had low testosterone. Yet just 5.6% of the men complained of symptoms commonly linked to testosterone deficiency (though the prevalence was higher—18.4%—among men 70 and older).

Critics of testosterone replacement therapy charge that erectile dysfunction, fatigue, depression and other symptoms are common and often have nothing to do with plummeting hormones. “A lot of those symptoms are just associated with aging,” says University of Texas urologist Ian Thompson. “Most of our body functions slow down as we get older.”

Nonetheless, a man with classic symptoms of low or borderline testosterone deserves a trial of TRT, says Alvaro Morales, a urologist at Queens University in Ontario, who has studied testosterone therapy for four decades. Some men will experience a potent placebo response during the first few months, Morales says, “but at nine months, if they’re still feeling better, that’s no placebo effect.”

MORALES AND OTHER PHYSICIANS DESCRIBE HOW PATIENTS who were once listless and despairing regained energy and joie de vivre once testosterone levels were boosted. Beyond anecdotes, though, the scientific literature on testosterone and aging males might be best described as incomplete, if intriguing. For example, a 2007 review found inconsistent evidence that TRT relieves erectile dysfunction. Some small studies have found that TRT improves mood and cognition, though other research has shown no benefit. TRT users usually shed flab and build lean tissue; studies of whether that translates to greater strength and improved daily functioning have been mixed. Studies also suggest that TRT strengthens bone density, though no one can say whether that means fewer fractures.

Population studies do suggest a clear association between low testosterone and metabolic syndrome‚ “a cluster of symptoms that increases the risk of type 2 diabetes and heart disease‚” says L.A. Biomedical Research Institute endocrinologist Ronald SwerdloffA 2006 review in The Journal of the American Medical Association found that men with testosterone levels higher than 400 ng/dl were 42% less likely than men with lower levels to develop type 2 diabetes. A Swedish study of men 69 and older showed that those with the highest testosterone were 30% less likely to suffer heart attacks. Meanwhile, several studies suggest a link between low testosterone and premature death;one, involving nearly 800 San Diego-area men, found that males with the lowest androgen levels had a 40% increased risk of dying from all causes during a 20-year period.

But does low testosterone actually cause metabolic syndrome? Or do diabetes and heart disease trigger a drop in androgen levels? According to biochemist Abdulmaged M. Traish, research director at Boston University School of Medicine’s Institute of Sexual Medicine Laboratory, recent studies strongly suggest that testosterone deficiency contributes to those illnesses. For instance, mitochondria, the power source for every cell, depend on adequate testosterone to run efficiently. Having too little testosterone may slow metabolism and could lead to weight gain. (Early data from an ongoing trial indicates that men receiving testosterone injections lost nine pounds and 2.5 inches from their waistline over 30 weeks.) What’s more, notes Traish, adequate testosterone is critical for the production of nitric oxide, which helps ensure both healthy erections and healthy hearts by dilating blood vessels.

What’s missing is large, randomized, placebo-controlled trials. But in 2015, the Testosterone Trial, launched in 2009 by the National Institutes of Health, will begin to publish results. The “T Trial” includes 800 men with low androgen levels, half of whom rub testosterone gel on their torso or upper arms every day for a year while the rest apply an inert gel. The study is intended to discover whether boosting testosterone levels improves energy, physical functioning, sexual activity, anemia, and cognition and memory. Subgroups are being monitored for other changes, such as bone density and plaque in their arteries (an indication of cardiovascular risk).

AMONG RECENT SMALLER CLINICAL TRIALS EXAMINING TRT'S POSSIBLE BENEFITS was a study reported in 2010 in The New England Journal of Medicine that stirred controversy. The TOM (Testosterone in Older Men with Mobility Limitations) trial was stopped early when 23 men being treated with testosterone gel experienced cardiovascular problems, including chest pain and irregular heart rhythm; just five men given placebo gel had these effects. “That worries me a lot,” says the University of Texas’s Thompson, who notes that TRT can cause a variety of side effects, such as a worsening of existing benign prostatic hyperplasia and sleep apnea, as well as breast swelling and tenderness and other problems. But he’s particularly concerned about the risk of polycythemia, or increased red blood cell count, which can raise the likelihood of developing clots. “That could put you at risk for a whole range of cardiovascular issues,” Thompson says.

TRT’s defenders have been quick to challenge the TOM trial’s findings. Swerdloff notes that its results contrast sharply with those of other recent studies suggesting that testosterone may protect the heart—such as the 2011 study of 2,416 Swedish men over 69 that found that those with the highest testosterone levels were 30% less likely to suffer heart attacks. What’s more, as important as any link between testosterone and heart disease would be, concerns about such a connection have always paled in comparison to the controversy that looms over TRT with regard to prostate cancer.

Fear that testosterone awakens dormant prostate cells and causes them to spread began with Huggins’s seminal work in the 1940s, which found that blocking the hormone relieved pain and extended the life of men with metastatic prostate cancer. Huggins also reported that in a few cases, administering testosterone made the prostate cancer worse. In another study, begun in 1949, researchers at New York City’s Memorial Sloan-Kettering Cancer Center gave testosterone injections to a group of men with metastatic prostate cancer, motivated by reports that some patients responded well to the treatments. Instead, cancer appeared to progress and symptoms worsened in 45 of the 52 men studied.

Since then, although a number of studies have failed to show that men with high testosterone levels have an increased risk of prostate cancer, most physicians still believe that testosterone can cause prostate cancer cells—which often lie dormant for years—to grow, form tumors and spread. The Food and Drug Administration requires every TRT product to carry warnings that the drug may increase the risk of prostate cancer and should be avoided by men who know they have the disease, as well as by those suspected of having prostate cancer (usually because they have elevated levels of prostate-specific antigen, or PSA, a marker of the disease). Skeptics of TRT concede that there is little strong evidence to suggest that testosterone causes prostate cancer. “But I don’t think there’s any conclusive evidence that it doesn’t in some men,” says Johns Hopkins University urological oncologist H. Ballentine Carter.

According to one estimate, it would take a placebo-controlled study involving 6,000 men lasting at least five years to determine whether testosterone increases the risk for prostate cancer by 30%, and no one knows whether NIH will decide to fund a large safety study if the current T trial—which is designed only to measure TRT effectiveness—yields promising results. Carter’s own analysis of data from the Baltimore Longitudinal Study of Aging (a long-running examination involving more than 1,400 men and women) suggests that testosterone may actually protect against prostate cancer in younger men but raise the risk for aggressive cancer in males 65 and older.

Carter and others question whether TRT benefits outweigh the risks. He suspects that many men receiving prescriptions for androgen therapy would be better off losing weight and getting more exercise. That’s especially true, skeptics insist, in light of what the Women’s Health Initiative (WHI) revealed about hormone therapy for menopausal women. One arm of the huge government-sponsored study was stopped early when a review board determined that women given estrogen and progestin had an increased risk for breast cancer, heart attacks and strokes.

“The Women’s Health Initiative should teach us a fair degree of humility,” says Michael Morris, an oncologist who specializes in treating prostate cancer at Memorial Sloan-Kettering. “We can’t assume that by replacing a hormone that is falling, we won’t have unpredictable and perhaps untoward clinical effects down the line.”

RAISING THE WHI CONTROVERSY ANGERS SOME DEFENDERS OF TRT. Estrogen and testosterone may both be sex hormones, but that’s where the similarities end, insists Boston University’s Traish. “They have different mechanisms, they have different receptors, and they mobilize different pathways,” he says. “You can’t apply what we know about one hormone”—estrogen—“to others.”

Traish and other TRT proponents maintain that long-held assumptions about the hormone are illogical. Take, for example, the belief that a man with low testosterone is protected against prostate cancer. Morgentaler points out that prostate cancer is virtually unheard of among men in their twenties, when testosterone levels are highest. Instead, the disease becomes more prevalent after 40, when androgen levels begin to drop. “Prostate cancer is also more aggressive the older we are,” says Morgentaler.

Morgentaler became interested in testosterone therapy in the late 1980s, when he began giving blood tests to male patients complaining of sexual dysfunction, lack of energy and other symptoms, and found that many had low androgen levels. But he was also keenly aware of what he had learned in medical school—that giving testosterone to a man with prostate cancer “is like pouring gasoline on a fire.” In 1991, Morgentaler launched a study with several colleagues that came to include 77 middle-aged and older men with low testosterone. All of the men underwent digital rectal exams (DREs) and PSA tests, and had normal results. But to be certain they didn’t have prostate cancer, Morgentaler asked each to undergo a prostate biopsy.

He was shocked when the biopsies showed that 14% of the men actually had prostate cancer. That finding was three to seven times higher than would have been expected in a random sampling of men who had normal DRE and PSA test results. But the men Morgentaler tested all had low testosterone, which according to medical doctrine should have reduced their risk of prostate cancer.

When one of Morgentaler’s research fellows presented these data at the annual American Urological Association meeting in 1995, the response was angry. “This is garbage!” cried one doctor. But the results only increased Morgentaler’s doubts about the conventional wisdom—that testosterone awakens dormant prostate cancer cells and makes them spread like wildfire. Eventually he and a few other clinicians began offering TRT to men with low testosterone who had undergone treatment for prostate cancer (through surgery or radiation) and were presumably free of the disease. Several studies have since shown that men who undergo successful surgery or radiation for localized prostate cancer (that is, cancer that has not spread beyond the gland) can receive TRT without causing a recurrence of cancer.

But Morgentaler has gone a step further, to the consternation of some like-minded physicians: He has begun offering TRT to men with untreated prostate cancer, in clear defiance of recommendations by such organizations as the Endocrine Society. Last year he reported on his experience treating 13 men with localized prostate cancer who had chosen to forgo treatment in favor of active surveillance. TRT improved mood, energy and sexual satisfaction in all of the men. But during an average of two-and-a-half years, none saw his prostate cancer worsen.

“The idea that testosterone necessarily makes prostate cancer grow has to be false,” says Morgentaler, challenging a theory that has held sway for 70 years. He points out that the vast majority of men whose prostate cancer worsened after receiving TRT in the damning Huggins and Memorial Sloan-Kettering studies had undergone castration. Giving these men TRT would naturally cause their symptoms to worsen, Morgentaler acknowledges, and is a bad idea. Yet his research suggests that prostate cancer patients who have not undergone castration may be able to receive TRT.

One explanation for the difference between those two notions—that testosterone does fuel aggressive prostate cancer but may not cause all prostate cancer to get worse—could lie in the results of a study by UCLA urologist Leonard Marks and colleagues showing that very low levels of naturally occurring testosterone are sufficient to saturate the prostate—and that once it is already saturated, administering TRT can’t increase the concentration. Morgentaler proposes a “saturation model” that explains why men with less aggressive prostate cancer who have not undergone castration can receive TRT‚—because the prostate has already been exposed to enough of their own naturally produced testosterone to cause their cancer. “And if you give more,” says Morgentaler, “nothing is going to happen.” In fact, biopsies showed that half the men he studied were cancer-free after undergoing TRT, supporting Morgentaler’s belief that low testosterone may somehow actually promote prostate cancer.

It’s probably fair to say that many doctors still think it’s crazy to offer testosterone to men who have or once had prostate cancer. But a growing number of physicians feel that TRT shouldn’t be off limits for all men who have survived prostate cancer. One such practitioner is Tanya Dorff. A University of Southern California oncologist, she is co-author of the largest study to date of prostate cancer survivors who were given TRT, involving 96 men. Of those—some of whom were deemed cured after undergoing surgery or radiation, while others were in remission after undergoing androgen-deprivation therapy—58% had to stop treatments because their PSA was rising, a clue that their cancer could be worsening, though none developed symptoms. The remaining men tended to have undergone surgery to remove their prostate, though Dorff notes that there is still no good way to determine which prostate cancer survivors can safely use TRT. Yet the improved quality of life many of the men enjoyed suggests to her that the idea of treating prostate cancer patients with TRT shouldn’t be dismissed out of hand. “Some said they felt like the had had their life handed back to them,” says Dorff. “For those men, it clearly wasn’t crazy.”

 

DOSSIER

1. “Testosterone Therapy in Men With Androgen Deficiency Syndromes: An Endocrine Society Clinical Practice Guideline,” by Shalender Bhasin et al.,Journal of Clinical Endocrinology & Metabolism, June 1, 2010. From the world’s largest organization of endocrinologists, recommendations for prescribing therapeutic testosterone for the treatment of symptoms associated with low androgen levels. Essential diagnostic criteria: ‚“consistent‚” symptoms and ‚“unequivocally low‚” serum testosterone.

2. “Testosterone Treatment of Older Men—Why Are Controversies Created?” by Ronald Swerdloff and Christina Wang, Journal of Clinical Endocrinology & Metabolism, Jan. 1, 2011. An editorial that concisely summarizes the reasons testosterone therapy is still hotly debated more than 70 years after its introduction, such as the lack of a clear definition of testosterone deficiency and the fact that many men with “low T” have no symptoms.

3. Testosterone Dreams: Rejuvenation, Aphrodisia, Doping, by John Hoberman (University of California Press, 2005). Sports historian Hoberman offers a scholarly but lively social history of testosterone.

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