For the past two years I have made the decision of treating prostate cancer patients who are documented to be hypogonadal with testosterone replacement therapy. Many of my colleagues have asked me about this decision and I would like to provide you with the evidence that this treatment of hypogonadal men who have been treated for localized prostate cancer with either radical prostatectomy or radiation therapy is safe.
In the late 1980s Dr. Abraham Morgentaler, a urologist in Boston, Massachusetts, began researching the relationship between testosterone and prostate cancer. Since the early 1940s testosterone had been believed to be a key contributor to the development of prostate cancer, and once cancer was established, testosterone was believed to be its fuel. As a result, generations of medical students around the world were taught that providing additional testosterone to a man with prostate cancer was “like pouring gasoline on a fire.” On the flip side, it was similarly believed that low levels of testosterone protected a man from ever having prostate cancer.
As one of the first physicians in the modern era to offer testosterone therapy to otherwise healthy men with sexual problems, Dr. Morgentaler was concerned that this treatment, while effective, might precipitate rapid growth of undetected, “occult” prostate cancers in his patients. In order to avoid causing more harm than good, Dr. Morgentaler took the bold step of performing prostate biopsies in these men to exclude the possibility that these men harbored an undetected prostate cancer, even though they had none of the standard indications for a biopsy, such as elevated PSA or a nodule. Although it had been assumed these men were at extremely low risk for prostate cancer because of their low testosterone levels, Dr. Morgentaler and his colleagues found exactly the opposite. One in seven of these “normal” men that underwent biopsy was found to have cancer, a rate similar to that seen in men known to be at increased risk.
Dr. Morgentaler presented his findings at the annual meeting of the American Urological Association in 1995. At the end of the presentation an influential chairman of a major urology department came to the microphone and loudly described this work as “garbage.” “Everyone knows high testosterone causes prostate cancer and low testosterone is protective,” he proclaimed in a booming voice. The research was published the following year in the prestigious Journal of the American Medical Association.
As the testosterone and prostate cancer link became less persuasive, Dr. Morgentaler began to offer testosterone to men with pre-cancerous abnormalities on prostate biopsy, and reported no increased rate of subsequent cancer. Yet at his own hospital, the Beth Israel Deaconess Medical Center, a senior endocrinologist complained to the administration that this research was “dangerous”.
However, Dr. Morgentaler prevailed and went on to publish clinical research on the safety of testosterone in men with actual prostate cancer, some treated with radiation or surgery, and even in selected men with untreated prostate cancer.
Dr. Morgentaler’s results were difficult to accept initially because a longstanding treatment for advanced prostate cancer has been androgen deprivation, a surgical or medical treatment designed to permanently reduce testosterone levels as much as possible. Numerous studies in these men had shown improvement in prostate cancer with this treatment, so it seemed logical that raising testosterone would cause prostate cancer progression.
Dr. Morgentaler’s elegant solution to this apparent paradox was the saturation model, based on studies in humans, animals, and in prostate cancer cell lines in the laboratory. It turned out that prostate tissue does indeed require testosterone for optimal growth, but that it can only use a limited amount of testosterone (or its metabolite, dihydrotestosterone) before it reaches a maximum. In biological terms, this is called saturation. Once saturation is achieved, additional testosterone has little or no capability to stimulate further growth. And saturation occurs at very low levels of testosterone, approximately 20ng\dl. This explained why testosterone treatments did not appear to harm men with existing or treated prostate cancer, namely because the cancers already had seen all the testosterone they could use.
A number of physicians have treated patients with testosterone despite the fact that they’d been treated for prostate cancer in the past. The first 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.
Men who have low-grade prostate cancer, i.e., Gleason score of <6, and low stage disease, T1 or T2, and have a nadir of their PSA following curative treatment with either surgery or radiation for 9-12 months, and have symptoms of hypogonadism and documented low testosterone levels, are candidates for hormone replacement therapy. I provide them with educational materials similar to what is in this newsletter and request that they return every month to monitor their PSA levels. Any increase in PSA levels for two successive months results in cessation of their hormone replacement therapy. Of the several dozen patients that meet this criteria and have received testosterone replacement therapy, none have had a rise in their PSA or evidence of recurrence of their prostate cancer.
Bottom Line: Today, most urologists throughout the world, myself included, are comfortable using testosterone in men without the fear of causing prostate cancer, and in the US a majority will now offer testosterone treatment to some men previously treated for prostate cancer. This revolutionary change in medical beliefs and practice resulted directly from the work of Dr. Morgentaler, who became a David against Goliath and was relentless in his pursuit of scientific truth and making it possible for some men who have prostate cancer with documented hypogoandism to receive hormone replacement therapy.