The defining element

THE first surge of testosterone happens in the uterus, a few weeks into development, causing an embryo with the XY combination of chromosomes to develop male sex organs.

A second and poorly understood surge happens during infancy. About its only noticeable effect is when a baby boy’s spontaneous erection shocks his parents.

Then comes puberty, the third and final testosterone surge. Voices deepen. Chins and chests sprout hair. Muscles develop and limbs grow long.

By the late 20s, testosterone surges are history.

And so, many men fear, are the glory days of manhood. During their youth, testosterone helped build muscles, strength and bone. It coursed through their brains, sent signals to their genitals, awakened their sexual desires. It sharpened their visual memory so they could keep track of a puck or a ball and bring cheers from the crowds. It gave them the energy to work all night, the confidence to stare down a competitor -- maybe even the foolhardiness to jump out of an airplane or scale a peak.

Researchers are learning more about this hormone that first makes an embryo a boy, and then turns boys into men -- increasingly with an eye on the hormone’s role in the aging body. They’re finding that testosterone replacement therapy can boost muscle mass, decrease fat deposits, improve sex drive, enhance energy level and increase bone density. It may also lift depression in some men.

They are also finding that the improvements can come at a cost.

As men age, slowly but relentlessly testosterone levels start to fall, beginning at about the age of 30 and at a rate of 1% to 2% a year. The brain becomes less predictable in regulating testosterone, and production within the testes drops off. Worse, the testosterone still produced is less able to enter the cells of muscles, bones and organs to do its work.

It is no coincidence that bad things begin to happen to a man’s body, at the same relentless pace. Lean muscle mass is replaced by potbellies. Bones weaken. Memory fades. Fatigue and depression can set in.

Sex drive, which once disrupted high school classes and ruled fraternities, calms down. Sexual performance wanes. “Even Viagra cannot overcome very low testosterone,” says Dr. John Morley, chairman of the division of geriatrics at St. Louis University School of Medicine.

Meanwhile, the threat of major illness increases with each passing decade: heart disease, cancer, diabetes, dementia and arthritis.

It would be wonderful if a fountain of youth hormone could help men regain the sexual stamina, physique, strength and mental agility of the surge years while reducing -- or at least not increasing -- the risk of disease.

There are some known side effects. Taking testosterone can cause acne, enlargement of male breasts and temporary infertility. It can worsen sleep apnea, a serious disorder that causes a person to stop breathing during sleep -- sometimes hundreds of times a night.

There are also many unknowns. For instance, it isn’t yet clear whether testosterone raises the risk of heart disease, reduces it or acts neutrally. Although some studies show that testosterone therapy lowers cholesterol, it appears to lower not only the bad cholesterol, or LDL, that clogs arteries, but also the good cholesterol, or HDL, that protects against heart disease.

Testosterone therapy also increases the production of red blood cells, thickening the blood -- good for men with anemia, but potentially increasing the risk of heart attack and stroke, especially among current and former smokers who already have increased red blood cells.

Weighing risks, benefits

By far the most troublesome unknown is whether testosterone replacement therapy increases the risk of prostate cancer.

“That’s the 800-pound gorilla sitting on the living room couch,” says Dr. S. Mitchell Harman, president of the Kronos Longevity Research Institute in Phoenix, a private research center focusing on the biological underpinnings of aging. “We can’t really tell men what the risk-benefit ratio is.”

The big problem with testosterone studies so far is that they involve small numbers of patients and usually run six months or less -- leaving unanswered the risks of long-term use.

Even without solid evidence, many men are betting on the benefits of testosterone replacement anyway. In 2004, American pharmacists dispensed 1.86 million prescriptions for testosterone supplements, according to pharmaceutical consulting firm IMS Health, the vast majority of them for men. In 2000, they dispensed 590,000 prescriptions.

In earlier years, most treated men went to their physicians for injections. Today, nearly three-fourths of prescriptions are for Androgel, a topical treatment first approved in 2000. Rubbed daily onto any fatty area of the body, the gel has greatly reduced the inconvenience of treatment.

No one doubts that there are men who benefit from testosterone therapy. They include men who were born with a limited ability to produce the hormone or who have had surgery or an illness that disrupted their ability to naturally produce it.

Others who doctors feel could clearly benefit are elderly men with low levels of testosterone and who have symptoms, such as bone loss, that might be eased with the hormone.

But what number constitutes “low”? Researchers in the field disagree on the cut-off for treatment of aging men, though common numbers range from blood levels of 250 to 350 nanograms per deciliter.

What makes testosterone therapy controversial is the concern that additional men may be gambling on it as a lifestyle-enhancing drug: a way to pharmaceutically recapture the vigor of youth, whether in the bedroom, competitive boardroom or gym.

The Internet has a raft of sites touting the use of testosterone, backed by testimonials from anonymous patients: “It saved my marriage.” “I feel like I’m in my teens again.”

This worries some doctors and scholars. “Fantasies are trumping science,” says John Hoberman, a professor at the University of Texas at Austin and author of “Testosterone Dreams: Rejuvenation, Aphrodisia, Doping.”

“This is a phenomenon that extends far beyond the doctor’s office. There may be a million men who are off the books, getting advice wherever they find it. That includes the anti-aging therapy clinics dealing with 50-year-old anxiety-stricken narcissists,” he says.

In a sense, men today are a lot like women in the 1960s through the ‘90s who took the hormones estrogen and progestin as possible protection against heart disease before a gold-standard clinical trial was done.

When that trial, the Women’s Health Initiative, finally happened in the 1990s, some major expectations about hormone replacement therapy’s benefits were proved wrong. In fact, the women’s therapy slightly increased the risk of heart attack, stroke and, in some cases, breast cancer.

Now men, some fear, are participating in a similarly uncontrolled national experiment. One of those men is 62-year-old Peter Williams, who lives in Southern California.

At the age of 49, Williams came down with the mumps, an infection that can interfere with testosterone production. When the swelling in his cheeks went down, he had his hormone level checked. “They said I had the testosterone level of a 90-year-old man,” he says.

For several years, Williams received injections of testosterone from his doctor every other week. As advised, twice a year he faithfully had two cancer screening tests: a prostate specific antigen (PSA) blood test and a digital rectal exam.

Testosterone, he says, brought his old libido back -- and that delighted him. “I wasn’t a stud or anything,” he says. “But I was normal. Able to perform. That’s very important for a man.”

Then, about five years ago, he was diagnosed with prostate cancer and was treated with radiation for several months. He’s fine now -- except that he has no sex life. Impotence is a common side effect of prostate cancer treatment.

“I love my wife. But it doesn’t go beyond hugs and kisses,” he says. “I have absolutely no drive, but yet it doesn’t bother me. It’s a funny kind of way to be.”

Williams has no family history of prostate cancer, and no explanation on why he got it in his late 50s. He only knows he took testosterone for a few years and, he suspects, “I got nailed.” Or did he? “Maybe I would have gotten [prostate cancer] anyway,” he says.

Despite all, he would advise other men considering testosterone therapy to “do it. But get your regular checkups.”

Williams’ experience underscores the importance of diligent monitoring of the prostate for any man who takes supplementary testosterone, says Dr. Franklin Gaylis, a La Mesa urologist and professor at UC San Diego.

In August, Gaylis reported on 20 prostate cancer cases among men who had taken testosterone. He observed that their cancers often were aggressive, and that they were discovered earlier by digital rectal exams than by PSA tests.

Suspicion versus proof

Individual stories such as Williams’ are compelling, but they offer no proof that testosterone actually raises cancer risks.

There are theoretical grounds for concern. As men age, their prostates are increasingly likely to carry slow-growing cancerous cells, most of which never develop into disease. About half of men at age 50, and virtually all men at age 90, have these cells, but most live oblivious of them and die of something else.

The worry is that testosterone may nudge those tiny cells into becoming life-threatening cancers. So far, there’s no evidence that taking testosterone fuels those cells.

“Testosterone does not create cancer,” says Dr. Adrian Dobs, a Johns Hopkins Medicine researcher in male gonadal function. “The safety concerns have never been proven.”

For example, a major review of studies published in the New England Journal of Medicine in January 2004 found only five cases of prostate cancer among 461 men who had been on testosterone therapy for six months to three years. That’s similar to the rate of prostate cancer among men not taking hormones.

“The belief that testosterone increases the risk of prostate cancer is so widely accepted that study after study that tries to show it and can’t keeps getting repeated over and over,” says Dr. Abraham Morgentaler, a Boston urologist and author of the 2004 review. “People don’t believe it.”

Perhaps, though, none of the studies so far have been large enough to identify some rare but real risks. After all, it took five years and nearly 17,000 women to determine the risks of long-term estrogen and progestin therapy.

The Institute of Medicine, an independent scientific advisory body, estimates that a study to assess whether testosterone therapy increases the risk of prostate cancer would take 5,000 men followed for three to five years. And no such study is even on the drawing board yet.

“It’ll be at least 10 years before we start a large study,” says Morley. “And then it’ll take three to 10 years. So we’ve put off for 20 years knowing whether testosterone has the same problems for men that estrogen has for women.”

Until they get their study, men are making decisions based on small studies and nuanced findings. Take for instance the intriguing link between testosterone and depression.

When Dr. Harrison Pope, director of the biological psychiatry laboratory at McLean Hospital in Boston, put out a call for research participants -- men ages 30 to 65 who were depressed despite being on medications -- the phone rang off the hook with melancholy volunteers.

He studied 56 men and expected perhaps 10% of them to have low testosterone levels.

“To my amazement, almost half of them had low or borderline low testosterone,” he says.

For eight weeks, he gave half the men with low testosterone a testosterone supplement in addition to their antidepressant. The other half received their antidepressant and, instead of testosterone, a placebo.

The testosterone group, overall, reported greater mood improvements than the placebo group. But not all the men taking the hormone experienced relief to the same degree.

“The reason that there was a significant difference between the groups was not because there was a uniform effect of testosterone, but rather that testosterone worked dramatically well for three men, but didn’t do much for the other seven,” says Pope.

In other words, the hormone appears to have individualized idiosyncrasies -- and so far, there’s no way to predict who will respond to testosterone therapy and who will not.

For Pope, adding testosterone to antidepressants is an easy call.

“I was seeing people who had major depression. They had already been treated with standard treatment and failed,” he says. “It’s easy to make the case that a trial of testosterone is a reasonable thing to do. If they’re not better within six or eight weeks, you cut your losses and abandon the testosterone.”

Deciding when it’s needed

It’s a tougher medical decision when the symptoms a man complains of are more vague. Maybe he feels he can no longer compete in the office. Or he’s watching his belly grow and muscles sag. Perhaps he has no interest in sex, or sees himself turning into a stereotypical old grouch.

Eric Parkinson, 50, of Placerville, didn’t notice that he was irritable, but his wife did.

“She thought I was cranky,” he says. His doctor measured his testosterone level and found it low.

Parkinson has been using a topical gel daily for a year and counts himself among the estimated 60% to 70% of men who use testosterone and, by one measure or another, say they feel better.

His libido, never noticeably waning, remains the same. But his wife says he’s mellowed, and little things don’t annoy him any more.

“Now I can wait a minute or two and say, ‘Hey, that’s not a big deal,’ ” he says.

He’s not interested in beating back the clock: “I find aging fulfilling,” he says. “But I believe in preventive maintenance. I don’t like attacking things that have gotten too far along. It’s your mental state that’s important.”

With the surge years behind them, and a clear bottom line from science not even on the horizon, testosterone therapy remains a calculated risk for men.

“I’m an aging male myself,” says author Hoberman. “I guess people have the right to deal with the aging process the way they see fit.”

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Testing testosterone

Normal testosterone levels cover a wide range, but all tend to decline over time. Measurements that fall below these thresholds are considered abnormally low.

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Normal testosterone levels for men ages 40 to 79

(In nanograms per deciliter)

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Age Ranges

40s: 251 - 914

50s: 216 - 876

60s: 196 - 859

70s: 156 - 818

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Source: Massachusetts Male Aging Study