Testosterone supplementation after prostate cancer?

Two experts examine the pros and cons of this controversial practice

At some point in their 40s, men’s testosterone production begins to slow. By some estimates, levels of this hormone drop by about 1% a year. As men get into their 50s, 60s, and beyond, they may start to have signs and symptoms of low testosterone. These include reduced sex drive and sense of vitality, erectile dysfunction, decreased energy, lower muscle mass and bone density, and anemia. When severe, these signs and symptoms characterize a condition called hypogonadism.

Researchers estimate that hypogonadism affects two to six million men in the United States. Yet it is an underdiagnosed problem, with only about 5% of those affected receiving treatment, according to the FDA. Deciding which patients should receive testosterone supplementation has proved tricky, however. For example, little consensus exists on what constitutes low testosterone. (The Endocrine Society considers a man to have low testosterone if the blood level is less than 300 ng/dl; some physicians set higher or lower benchmarks.) In addition, some men may have low blood levels of testosterone but not experience any symptoms. And few large, randomized studies on the long-term risks or benefits of testosterone supplementation have been completed.

One of the most heated debates centers on whether testosterone fuels prostate cancer. If that’s true, say some experts, then why do men develop prostate cancer when they are older, at the same time their testosterone levels are dropping? (See Figure 1.) Others point to the fact that many men with prostate cancer, especially those with advanced or metastatic cancers, take hormone therapy that nearly stops the production of testosterone to tamp down the disease. Under the influence of hormone therapy, tumors regress. So wouldn’t the opposite be true — that giving a man testosterone will accelerate or promote tumor growth?

Abraham Morgentaler, M.D., an associate clinical professor of surgery at Harvard Medical School and the director of Men’s Health Boston, specializes in treating male sexual and reproductive difficulties.* In his book, Testosterone for Life, he touts the benefits of testosterone supplementation, including improved libido, mood, cognition, muscle mass, bone density, and red blood cell production. He also argues in the book, an excerpt of which follows, that some men who have had prostate cancer can take testosterone without upping their risk of cancer recurrence.

Many well-respected experts advocate a more conservative approach: prescribing testosterone sparingly until more evidence convincingly shows a lack of harm in the long run, and until studies demonstrate which patients are most likely to reap significant benefits. One is Ian Thompson, M.D., chairman of the Department of Urology at the University of Texas Health Sciences Center at San Antonio and a principal investigator for the Prostate Cancer Prevention Trial (PCPT).* He shares his views on testosterone supplementation with Harvard editors following the book excerpt.

An excerpt from Testosterone for Life

The oldest and most strongly held prohibition against testosterone therapy is its use in men previously diagnosed with prostate cancer. The fear has been that even in men who have been successfully treated for prostate cancer, raising testosterone levels will potentially make dormant, or sleeping, cancer cells wake up and start growing at a rapid rate. Thus, the FDA requires all testosterone products to include the warning that T [testosterone] therapy is contraindicated in men with a prior history of prostate cancer.

However, attitudes about this are changing — and changing rapidly — over just the last few years. The reasons for this are several, including the ongoing re-evaluation of the old belief that raising the concentration of testosterone is to prostate cancer like pouring gasoline on a fire or feeding a hungry tumor. In addition, there is growing recognition that T therapy can provide important benefits to a man’s quality of life, so the delicate medical balancing act between potential risk and possible benefit is shifting.

A major push for consideration of T therapy in symptomatic men with a history of prostate cancer has come from the large population of men who have been treated for prostate cancer over the last 25 years. Many of these men had small or low-grade cancers and, after treatment, were assured that they were cured and had no trace of any remaining cancer in their body. Despite having been given a clean bill of health, they were then told that they could not receive T therapy. As these prostate cancer survivors have questioned the basis for the T therapy prohibition, many physicians have been forced to reconsider whether the old arguments learned from their former teachers still make sense.

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A number of physicians have told me that they have treated occasional patients with testosterone despite the fact that they’d been treated for prostate cancer in the past. The first people to publish their experience with doing this were Drs. Joel Kaufman and James Graydon, whose article appeared in the Journal of Urology in 2004.

In this article, Drs. Kaufman and Graydon described their experience in treating seven men with T therapy some time after these men had undergone radical prostatectomy as treatment for prostate cancer, with the longest follow-up being 12 years. None of the men had developed a recurrence of his cancer. Soon afterward, there was another paper by a group from Case Western Reserve University School of Medicine describing a similar experience in 10 men with an average follow-up of approximately 19 months. Then another group from Baylor College of Medicine reported the same results in 21 men.

In all these reports, not a single man out of the 38 treated with testosterone developed a cancer recurrence. It is important to emphasize that all these reports included only men who were considered good candidates because they were at low risk of recurrence anyway. And in some cases, the duration of time the men received T therapy was relatively short. But it was reassuring that none of the 38 men who had suffered from prostate cancer in the past and who were treated for years with testosterone had developed a recurrence of prostate cancer.

This reassuring experience was bolstered by the published experience of Dr. Michael Sarosdy, who reported the results of T therapy in a group of 31 men who had received prostate cancer treatment in the form of radioactive seeds, called brachytherapy. This less-invasive form of treatment does not remove the prostate, so theoretically there is the possibility that a spot of residual cancer might still be present. With an average of five years of follow-up in these men, none of the 31 men had evidence of cancer recurrence.

The total number of men treated in these reports is still very small — much too small for anyone to be able to stand up and declare definitively, “Testosterone therapy is safe in men who have been treated for prostate cancer.” But these reports have at least given us some perspective on the degree of risk of T therapy in men treated for prostate cancer. At a minimum, it is now possible to say that there is evidence from a number of small studies that T therapy in men who have been successfully treated for prostate cancer does not appear to be associated with a substantial risk of cancer recurrence over the first several years of treatment.

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I’d like to make a few final points to give some perspective on this story. First, it has become obvious that raising testosterone levels in a man with a history of prostate cancer is not like pouring gasoline on a fire. In fact, with the important exception of men who have undergone hormonal treatment to bring down their T levels to castrate levels, the limited evidence suggests that raising T levels does very little to the growth of prostate cancer.

Of course, one day new studies may suggest that there is a risk. However, no such study is likely to appear for at least five to 10 years because it takes at least that long to judge whether a treatment has stimulated the growth of a cancer. Until then, we have to make decisions based on the available evidence, supported by logic and experience. For the moment, I am comfortable explaining to my patients that the use of T therapy in men with a history of prostate cancer entails an “unknown degree of risk” but that my assessment is that this degree of risk is small.

Second, it is important to recognize that even if you have low levels of testosterone as well as the symptoms of chronic fatigue, decreased libido, and erectile dysfunction, there is no certainty that raising T levels will alleviate your symptoms. There may be other reasons you are feeling this way. Moreover, there is no known benefit to T therapy if T levels are not truly low. Thus, the decision about whether to try T therapy requires balancing possible benefits with possible risks. This decision will be different for every man.

Third, T therapy is not itself a treatment for prostate cancer. Even though [one patient’s] PSA dropped with T therapy, fluctuations in PSA values are common and no conclusions should be drawn from any one case.

Finally, it is important for any man with a history of prostate cancer to maintain his perspective on what is important to him. For some, it is enough to be alive and feeling reasonably well despite prostate cancer treatment. Adding a treatment that may stir up anxiety about their cancer may not be worth any benefit they may experience with regard to sex, mood, energy, or vitality. For others, the important thing is to live well. For them, an improved quality of life may be important enough to take on an unknown degree of risk, including a treatment that still lacks approval from the broader medical community.

Dr. Thompson’s perspective on testosterone replacement

What concerns do you have about prescribing testosterone to men who have been successfully treated for prostate cancer?

Obviously, testosterone supplementation has salutary effects for someone who is hypogonadal and suffering from osteoporosis, muscle loss, erectile dysfunction, and other problems. Unquestionably, otherwise healthy men given the choice of being on testosterone or being off testosterone would rather be on it. So, why not prescribe testosterone supplements to men who are hypogonadal and have been treated for prostate cancer?

Well, imagine two men with prostate cancer. The first man had a 12-core biopsy that showed cancer in just a small percentage of one core, cancer that was graded a Gleason 3 + 3. He’s had several prior biopsies, all of which have been negative, and his PSA is 2.5 ng/ml, which is within the normal range. The second man’s biopsy shows cancer in every core on the right side of his prostate, graded a Gleason 5 + 4. The cancer can be felt during a digital rectal exam but is confined to the prostate capsule. Both men have undergone treatment.

The first man’s risk of developing progressive prostate cancer is very, very low; his prostate cancer probably didn’t even need to be treated. In his case, the risk of testosterone supplementation is low. For the second man, who has very high-risk disease, you have to ask yourself, “How would testosterone replacement affect his risk of disease recurrence?” Well, several high-quality studies have shown that men with high-risk disease who have had external beam radiation or surgery and then take androgen deprivation therapy improve their disease-free survival. And that would suggest that testosterone supplementation would increase his risk of disease recurrence.

How does that happen? Testosterone could reactivate existing disease. Or, if the patient had external beam radiation, not all of the tissue becomes fibrotic. Some normal epithelium, the cell layer that lines the prostate, will persist, and that normal epithelium is at risk of becoming cancerous.

So you wouldn’t prescribe testosterone to a patient who’s had prostate cancer unless his case was like that of the first patient you described?

My point is that we can’t make broad, generalized statements. Just because we don’t know if it’s harmful, we can’t presume that it’s safe. For the man with very low risk of disease recurrence who is experiencing serious symptoms of hypogonadism, it’s probably okay. But symptoms like “I’m not as lively and strong as I was at 18” aren’t really sufficient to justify supplemental testosterone. If you apply that standard, every older man would be clinically hypogonadal.

Also, let’s take a look at testosterone levels. Some people say that the threshold for low testosterone is below 250 ng/dl, but other people use different numbers. Where did those numbers come from?

And what else is going on in the body? There are differences from one person to the next in how testosterone is used. And the interactions of other androgens and the androgen receptors are so variable. What other medical tests have a “normal” range as large as 250 ng/dl to 1,250 ng/dl? And then there’s the fact that the variation in test results from one lab to the next is enormous. That’s why I’m unconvinced that there is a blood test you can do to unequivocally label someone as biochemically hypogonadal.

Do you have patients who are on testosterone therapy?

I don’t have very many patients on androgen replacement. If I think someone might need it, I refer him to an endocrinologist who will manage his condition. Managing hypogonadism is a very complicated matter. In fact, an endocrinologist who specializes in hypogonadism often will obtain a blood sample every half hour for two hours, pool them, and then run a testosterone level. A one-time reading isn’t sufficient.

Yes, there will be some clear-cut cases on both sides — the man at very low risk of prostate cancer who won’t die of the disease even if it develops, and the man who has had prostate cancer and has a very high risk of recurrence. But what about the man in the middle? Again, just because we haven’t proven testosterone supplementation harmful doesn’t mean we should prescribe it.

So what’s your biggest concern?

My biggest concern is that, with very little data, we are assuming that androgen replacement is safe. We know that the studies necessary to answer this question will require thousands of patients; they haven’t even begun. We only have to look at history — hormone replacement in women — to see the error of assuming that hormone replacement is safe and effective. We’re living in the era of evidence-based medicine; that we accept current data and then potentially harm our patients just doesn’t seem reasonable today.

Originally published June 2009; last reviewed February 22, 2011.