In 1966, investigators at the University of Chicago won a Nobel Prize for their research on the relationship between male sex hormones, known as androgens, and prostate cancer. Forty years later, researchers are still working out the intricacies of that relationship.
A recent study co-authored by the Center's Dr. Peter Nelson reports that testosterone-replacement therapy (TRT) for men with low testosterone levels has minimal effect on the prostate gland over a period of six months. Previous studies indicated that this therapy might be harmful.
"It's pretty well known that androgens are very important for the initiation as well as the progression of prostate cancer. Without any testosterone, prostate cancer essentially never develops," said Nelson, an investigator in the Human Biology Division. "Eliminating testosterone is the most active form of treatment in very advanced disease. There's been a lot of interest in studying testosterone in the context of prostate cancer."
The new study, which was led by Dr. Leonard Marks of the Urological Sciences Research Foundation and the University of California, Los Angeles, was published in the Nov. 15 issue of the Journal of the American Medical Association. Researchers studied 44 men with low serum testosterone levels between the ages of 44 and 78 years. What they anticipated and found was that TRT increased serum testosterone levels to the mid-normal range. More unexpectedly, TRT only slightly increased androgen levels in prostate tissue, and urinary symptoms, which can be affected by growth of prostate tissue, were found to be similar between the placebo and testosterone- treated groups.
Prostate may buffer
"The interesting thing was that the tissue levels of testosterone and DHT, a more potent form of androgen, did not change significantly. So although the serum levels changed substantially, the tissue levels really didn't," Nelson said, adding that they didn't measure any genes that changed significantly in response to testosterone. Researchers compared the pretreatment biopsy with the post-treatment biopsy and looked at genes testosterone is known to regulate. "I would have expected to see testosterone or DHT levels change within the prostate and probably see changes in genes known to be regulated by androgens. Importantly, markers of cell proliferation didn't change."
What surprised the researchers was the implication that the prostate may be able to buffer a range of testosterone in the serum to maintain its normal function. It was previously thought that testosterone freely diffuses in and out of cells, but this study indicates that there may be an active transport mechanism in the prostate or a way for the gland to sequester hormone therapy rather than simply rely on serum level.
"There is a disconnect between serum levels and what's happening in the prostate, so you can't assume one from the other. Many of our treatments and the way we follow patients are based on the serum levels; that's what's easy to test," said Dr. Elahe Mostaghel, a research associate in the Nelson Lab and co-author on the study. "But if you're really trying to figure out what's going on, you should look at the tissue."
As men age, their testosterone levels gradually decline. "It's not as abrupt a situation as women with menopause, but there has been a similar term, "andropause" or androgen deficiency in the aging male (ADAM) or male menopause, that is linked to a constellation of symptoms in older men that are all very vague," Nelson said. Symptoms include frailty, loss of muscle mass, depression, anemia and sexual dysfunction, but none are attributable only to low testosterone levels.
Testosterone use up
While there may in fact be a male equivalent of menopause, the trick is pinning it down to treat it. For years, physicians have occasionally prescribed testosterone in older men to try to treat these symptoms, but testosterone has never been approved for use in androgen deficiency in aging males. "It is approved for use in specific endocrine disorders where you may have low levels of testosterone or after testes cancer. But in our medical system, once a drug is approved for use, you can use it for other things," Nelson said. "Use over the last decade has increased to the point where it's probably a billion-dollar drug now. It's safe to say that the majority of that use is not for men with testes cancer or true endocrine dysfunction, but rather in the situation of testosterone decline in older men. So the questions have been: Does testosterone supplementation work and is it safe?"
Most published studies have been done over the course of six months to a year, but the majority of testosterone-replacement patients are on the treatment for years or decades. To date, there have been no long-term, large-scale studies to determine the efficacy of the treatment, but the National Institute of Aging has put out a request for such a study, and a large proposal is being reviewed.
"The major potential risks of supplementing men with testosterone would be prostate cancer or benign growth of the prostate, another disease that associates with age. And that prompted the head of the National Cancer Institute at the time to say that he was very concerned that the widespread use of testosterone supplementation could really increase the frequency of prostate-cancer diagnosis," Nelson said.
Because the new study only followed the participants for six months, the researchers are careful not to over-interpret the findings. "You need a large study for many years to determine the true risk for prostate cancer," Nelson said. "There may be some indications for short-term use, but most indications are going to be much longer-term. This was really a preamble study to what we may need to see and do in the larger study."