Mistaken Judgment:  Prostate Cancer Hormone Treatment (II)

How it all started
The basis for the fear that testosterone therapy increases the risk of prostate cancer originated with the work of Charles B. Huggins, a urologist at the University of Chicago. Huggins was initially interested in the medical condition called benign enlargement of the prostate, called benign prostatic hyperplasia (BPH), which causes frequent and urgent urination and also can occasionally cause complete obstruction of the urine passageway. Benjamin Franklin was reported to have suffered from BPH and was credited with inventing a tube he inserted through the urine channel to relieve the obstruction.

Origins of the Concern
Curiously, dogs are the only species we know of other than humans that naturally develop prostate problems on a regular basis. At the turn of the twentieth century, there were reports that castration was successful in treating some men with severe obstruction from BPH, and Huggins began experimenting on the effects of castration on BPH in dogs. Not only did the dogs’ prostates shrink after castration, but Huggins made an additional far-reaching observation.

Huggins noticed that the microscopic appearance of prostates of some of these dogs contained areas that were indistinguishable from human prostate cancers. Even more importantly, after castration, dogs with these cancerous-appearing areas also demonstrated shrinkage of their prostates. Indeed, when their prostates were removed, the dogs had no further evidence of the cancerous-appearing areas.

Huggins and his coworkers then applied his dog results to humans. By this time, it was known that the key effect of castration was to reduce testosterone levels in the bloodstream. He took a group of men who had prostate cancer that had already spread to their bones and lowered their testosterone levels, either by removing the testicles or by administering estrogen. A blood test called acid phosphatase was high in men with metastatic prostate cancer, and Huggins and his coworkers showed that acid phosphatase dropped substantially within days of lowering testosterone. Of even greater consequence for the future of testosterone therapy, Huggins also reported that administration of testosterone injections to men with prostate cancer caused acid phosphatase to rise. Huggins and his coworkers concluded that reducing testosterone levels caused prostate cancer to shrink and raising testosterone levels caused “enhanced growth” of prostate cancer.

This demonstration of the androgen dependence of prostate cancer was incredibly important, because until that time in the early 1940s prostate cancer was untreatable. From that point forward, lowering testosterone by castration or by estrogen became the standard treatment for advanced disease and remains a mainstay of treatment to this day. Because estrogen treatment caused heart attacks and blood clots in some men, and because most men did not care for the idea of having their testicles removed, a new type of medication—LHRH agonists—was introduced in the 1980s. Injections of this medication are now the usual way testosterone is lowered in men with prostate cancer.

Huggins was eventually awarded the Nobel Prize in 1966 for his work showing that prostate cancer grew or shrank depending on testosterone levels. Until recently, this prevailing wisdom regarding prostate cancer and testosterone had not been seriously questioned.

My Involvement in the Story
By the time I performed my urology training in the mid 1980s as a resident at the Harvard Program in Urology, based at the Brigham and Women’s Hospital in Boston, one of the unassailable assumptions held by all the urologists I trained under was that prostate cancer shrunk with low testosterone and grew with high testosterone.

In my training, we learned that men who had been castrated early in life never developed prostate cancer. In the laboratory, prostate tumors could be placed under the skin on the back of mice, and the tumors would grow to a large size. Pieces of these tumors could then be transferred under the skin of another male animal and would again grow to a large size. If the males were castrated or given estrogen (which lowers testosterone), the tumor would shrink rapidly or not even take root.

The tumor would not grow at all, however, if it was transferred under the skin of a female. On the other hand, if the female were given testosterone, the tumor would grow just as well as if it had been placed in a male. All these studies indicated that testosterone was a critical element in allowing prostate cancer growth. There seemed to be good reason to believe that it would be dangerous to give testosterone supplementation to a man with prostate cancer. I believed that, and so did everyone around me.

My fellow residents and I thus learned to repeat the comments of our teachers to our patients in the clinics. Whenever issues of testosterone would come up, we would say the relationship of testosterone to prostate cancer was like “pouring gasoline on a fire” or providing “food for a hungry tumor.” These phrases are still in use throughout the medical world. In those days, we all spoke about testosterone and prostate cancer as if there were a simple, direct relationship, but the truth is not quite so simple.

A Fateful Interaction
Once I finished training, I began my specialization in the treatment of “guy stuff,” primarily male infertility and sexual problems. I also began diagnosing and treating a large number of men with low testosterone. This was not a common practice at the time; in fact, I had very little experience with testosterone therapy during my training. This was because there was little research showing that testosterone treatment helped the symptoms seen in men with low testosterone. Indeed, one of the most bothersome symptoms—erectile dysfunction—was believed at the time not to improve with testosterone treatment (later research has shown this belief to be incorrect). Doctors also were reluctant to prescribe testosterone because of the fear of promoting a prostate cancer that might be lurking silently inside the man’s prostate gland.

At the end of my second year of practice, I ran into one of my former teachers at the national meeting of the American Urological Association. He asked me if it were true that I was treating men with testosterone. I replied that I was and explained that I had been pleasantly surprised to find so many good responders despite my earlier training.

“I wouldn’t do that anymore, if I were you,” he said. “I just had a patient diagnosed with prostate cancer within a year after beginning testosterone treatment. If you’re going to continue treating men with testosterone, and I recommend you don’t, you should at least do a prostate biopsy first to make sure they don’t have cancer.”

Naturally, this was a disconcerting conversation, especially coming from a former teacher of mine whom I respected greatly. So I followed his suggestion and began performing prostate biopsies before initiating testosterone therapy. At least with a biopsy, I could rule out the presence of cancer.

At the time, the only reasons to do a prostate biopsy were for an abnormal-feeling prostate, as determined by digital rectal exam (DRE), or for an abnormally high result for the prostate-specific antigen (PSA) blood test, which can indicate an increased risk of prostate cancer. Surprisingly, despite a normal DRE and PSA, one of the very first men I biopsied had cancer. This was very strange, because it was assumed at the time, as I’ve explained earlier, that a man with low testosterone should have been protected against prostate cancer. It didn’t take long to find several more cancers in men with low testosterone despite normal DRE and PSA results. Indeed, of the first thirty-three men I biopsied, six had cancer. This was a very high cancer rate, especially for a group of men without known risk factors. After presenting these results at the national urology meeting, one of the academic chiefs, a well-respected man, declared in his trademark booming voice, “This is garbage! Everyone knows that high testosterone causes prostate cancer, not low testosterone. You guys just got unlucky. I bet if you biopsy the next 100 men, you won’t find another cancer.”

It was a dramatic moment—I was a young unknown being castigated on a national stage by a major figure in the field. And he was right—given what we knew about testosterone and prostate cancer, the results made no sense. All I could do was to respond, “These are the results we obtained. We present them here because they do fly in the face of conventional wisdom, which is why we believe they may be of interest to this audience.”

When the size of the group we had biopsied was fifty men and the cancer rate was unchanged, my colleagues and I submitted a manuscript to the Journal of the American Medical Association, one of the top medical journals in the world. The associate editor soon called me up to say, “Our editorial board finds your data very interesting, because it runs counter to what we would expect. But our concern is that your numbers are small, and perhaps you may have just had an unlucky run with your biopsies. If you gather additional men and your cancer rate holds up, we will seriously consider publishing your manuscript.” Before long I submitted data on seventy-seven men, eleven of whom had cancer, and the paper was published.

At the time, in 1996, the 14 percent cancer rate we reported was several times greater than any previously reported cancer rate in men with normal PSA (4.0 ng/mL or less). Several studies had reported biopsy results in men with normal PSA with cancer rates of 0 percent or 2 percent, with the highest value reported being 4.5 percent. The much higher cancer rate in our population certainly seemed to suggest there was something different about prostate cancer risk in men with low testosterone.

Frankly, most experts just didn’t know what to make of our results. A high cancer rate among men with low testosterone didn’t fit into the existing way of thinking regarding testosterone and prostate cancer. And because we hadn’t biopsied a control group of men (men with normal T and no other risk factors), it was impossible to say whether men with normal T would have had a different cancer rate than our patients with low testosterone.

In retrospect, though, that paper was the first direct evidence in a major medical journal that standard assumptions about testosterone and prostate cancer might not be correct. At a minimum, it was obvious that low testosterone could not be considered protective against the development of prostate cancer, as had been assumed for so long. And it made me wonder whether other assumptions about testosterone and prostate cancer were also incorrect.

Dr. Raphael Nyarkotey Obu: PhD is a research Professor of Prostate cancer and Holistic Medicine at Da Vinci College of Holistic Medicine, Larnaca city, Cyprus and the National President of the Alternative Medical Association of Ghana(AMAG). He is also the President of Men’s Health Foundation Ghana