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The New England Journal of Medicine
After publication of my article on prostate biopsies in men with low testosterone, I published a number of additional articles looking at the relationship between testosterone and the prostate. In one provocative study, a colleague and I looked at whether testosterone therapy posed special dangers for men who were already at high risk for developing prostate cancer.
In this study, we compared the results of testosterone therapy given for twelve months in two groups of men with low testosterone. The first group consisted of twenty men considered to be at high risk for prostate cancer based on biopsy results showing an allegedly precancerous condition called prostatic intraepithelial neoplasia (PIN). The second group consisted of fifty-five men with normal biopsy results. At the end of one year of treatment, both groups had a similar, modest increase in PSA. One man in the study, who was in the high-risk group, developed cancer.
So, overall testosterone therapy resulted in a one-year cancer rate of 1.3 percent (one of seventy-five men). More importantly, the one-year cancer rate among the high-risk men with PIN was 5 percent. This compared to the known cancer rate of 25 percent over three years in this population. While the two figures are not directly comparable, these results certainly did not seem to suggest that testosterone therapy had increased the cancer rate in this high-risk group. And the overall cancer rate was not very high at all.
Here was another piece of evidence that the old assumptions about testosterone and prostate cancer were incorrect, specifically the notion that testosterone therapy was like pouring gasoline on a fire. First, we had found that men with low testosterone did not seem to be protected against developing cancer. Now, at the other extreme, we found that men at high risk for prostate cancer did not seem to suffer any dramatic “explosion” of cancer when treated for a year with testosterone therapy. And when I looked back at my extensive experience of treating men with testosterone therapy, many for ten years or longer, precious few cases of cancer had developed.
Prostate tumor confined to prostate gland.
It was heresy, but I couldn’t help thinking that the old stories linking testosterone levels to risk of prostate cancer might well be wrong. After all, if one looks at the natural progression of prostate cancer, it never occurs in men in their twenties when testosterone levels are at their lifetime peak, even though autopsy studies have shown that a significant percentage of these young men already harbor microscopic prostate cancers. Instead, prostate cancer becomes increasingly common as men age, when testosterone levels have declined.
I was coming to the conclusion that the average physician might be unduly fearful of the risk of prostate cancer with testosterone therapy. From my lectures to physicians around the country, it became clear to me that many physicians withheld testosterone therapy from their patients because they feared stimulating a sleeping cancer. I thought it might be time to write a review article that put the risks of testosterone in perspective, particularly the risk of prostate cancer. Fortunately for me, the New England Journal of Medicine was receptive to my proposal to consider such a publication.
The New England Journal of Medicine is arguably the most prestigious medical journal in the world, and its reputation stems in part from publishing only the best-researched articles. Together with Dr. Ernani Rhoden, a urology professor from Brazil who came to Boston to do a year-long research fellowship with me, we spent a year reviewing all the available scientific and medical literature on the risks of testosterone treatment to be able to provide a manuscript that lived up to such standards. Once we had written up the manuscript, our paper was subjected to multiple waves of reviews by physicians from various specialties—urology, oncology, endocrinology—to make sure that we had not left out any key studies or misrepresented any of the data.
The first thing we looked at was the rate of prostate cancer in men undergoing treatment with testosterone. Although many of the studies were small, the cumulative cancer rate in these trials was only slightly higher than 1 percent. This cancer rate was actually less than the cancer detection rate in men undergoing screening for prostate cancer. However, there was no large, long-term study looking at cancer rates in men receiving testosterone therapy and comparing them to men who did not receive testosterone therapy; thus, by themselves, these studies could not provide a definitive conclusion regarding risk.
There also were some large, sophisticated studies that indirectly addressed the risk of testosterone and prostate cancer. Unlike the studies I just mentioned, in which men given T treatment were monitored for the development of prostate cancer, these large studies simply looked to see if there was a connection between a man’s own natural level of testosterone and his risk of developing prostate cancer. In these observational studies, blood samples were taken and frozen at the beginning of the study, and then the large study group was followed for long periods of time. At the end of the study period, often ten to twenty years later, a group of men would have developed prostate cancer. The blood samples obtained from these men at the beginning of the study would then be tested for testosterone and other hormones and compared to a similar group of men who were matched for age and other characteristics but who did not develop prostate cancer. What did they find?
In 2004, when my article in the New England Journal of Medicine was published, there were fifteen of these longitudinal studies examining the relationship of hormones and prostate cancer. Since 2004, there have been approximately a half-dozen more. Not one has shown any direct relationship between the level of total testosterone in a man’s blood and the subsequent likelihood that he will develop prostate cancer. Specifically, average total testosterone levels were not higher in the cancer group compared to men without cancer, and men with the highest T values were at no greater risk for later developing prostate cancer than men with the lowest T values.
Among the dozens of additional calculations in each of these studies, an occasional minor correlation did show up, such as a connection with the minor androgen DHEA in one, a ratio of testosterone to SHBG in another, or a calculated free T in a third. But in all cases so far, attempts to confirm these minor connections have failed.
At the end of immersing ourselves into this literature for a full year, Rhoden and I were stunned by the fact that there was not a single study in human patients to suggest that raising testosterone increased the risk of prostate cancer. Although I was fairly convinced at this point that testosterone therapy was not a risk for prostate cancer, I had to admit that the evidence was not absolutely conclusive. And there was still a widespread belief that testosterone therapy was risky. And so our relatively sanitized conclusion appeared as follows:
“Thus, there appears to be no compelling evidence at present to suggest that men with higher testosterone levels are at greater risk of prostate cancer or that treating men who have hypogonadism with exogenous androgens increases this risk.”
Our article appeared in the New England Journal of Medicine in 2004. Whatever the truth may turn out to be regarding testosterone and prostate cancer, it was clear that raising testosterone did not appear to be like “food for a hungry tumor.” Physicians who had been interested in offering testosterone therapy to their patients but were worried about the cancer risk now had a reference article that gave them some degree of comfort.
Later that same year, the Institute of Medicine, a branch of the National Academy of Sciences, published its recommendations regarding testosterone research in aging men, with an eye toward ensuring the safety of men participating in testosterone studies. Recognizing the disparity between the concern that testosterone stimulates prostate cancer and the lack of any strong supporting evidence, the report concluded: “In summary, the influence of testosterone on prostate carcinogenesis and other prostate outcomes remains poorly defined . . .” The unwillingness of the report’s authors to identify testosterone as a definite risk for prostate cancer was a major departure from the standard story line that had colored earlier discussions of testosterone therapy and served as a nice bookend to our article on testosterone risks in the New England Journal of Medicine.
Discoveries in the Basement of the Countway Medical Library
As much as my year-long review of the scientific literature had given me confidence that testosterone therapy did not increase the risk of developing prostate cancer, there were still a few issues that disturbed me.
The first was the original observation by Huggins himself that administration of testosterone to men caused “enhanced growth” of prostate cancer in men with metastatic disease. A second was a well-known 1981 article from the Memorial Sloan Kettering Cancer Institute in New York, authored by the most prominent prostate cancer expert of his era, Dr. Willet Whitmore, that reported near-universal poor outcomes when men with metastatic prostate cancer received testosterone injections. And the third was the phenomenon known as testosterone flare. Testosterone flare refers to the temporary increase in testosterone caused by the use of medications called LHRH agonists in men with advanced prostate cancer. Testosterone flare has been associated with a variety of complications attributed to the sudden growth of prostate cancer.
All three of these issues applied only to men with known metastatic disease, and because no one was suggesting that testosterone therapy be offered to men with advanced prostate cancer, the existence of this literature wasn’t terribly troubling. What was of concern to those of us prescribing testosterone therapy was the possibility that we might be putting our otherwise healthy patients at risk for prostate cancer, but so far all the data looked reassuring on this point. Metastatic disease was something quite different, and it would not have been shocking to learn that it responded differently to high levels of testosterone than localized disease within the prostate.
But I was still bothered. I had read all the relevant articles years ago during my training, but not with a critical eye toward the relationship of testosterone and prostate cancer. One day, I found myself with an unexpectedly free afternoon and decided to investigate. Everything changed for me the day I descended into the basement of the Countway Library, Harvard Medical School’s incredible archive of medical literature. It was the most exciting day of my professional career, a day that changed my views on testosterone, prostate cancer, and, even more, on medicine itself.
The Original Huggins Article
The basement of Countway Library is where the old volumes of medical journals are kept. Some of these, from august journals such as The Lancet, go back to the 1800s. It is an amazing collection, open to any member of the Harvard community.
I found the original article by Huggins from 1941. It was in the very first published volume of what is now a highly respected journal called Cancer Research. I read how Dr. Huggins and his coinvestigator, Clarence Hodges, used the new blood test called acid phosphatase to show that lowering testosterone by castration or estrogen treatment caused prostate cancer to regress, and how T injections had caused “enhanced growth” of prostate cancer in these men. And then I noticed something that made my heart race.
Huggins and Hodges had written that three men had received T injections. But results were given for only two men. And one of these men had already been castrated. This meant that there were results for only a single man who had received T injections without prior hormonal manipulation. Dr. Huggins had based his “enhanced growth” conclusion on a single patient, using a test—acid phosphatase—that has since been abandoned because it provides such erratic results!
I sat there in the basement of the library, reading the same lines over and over to make sure I hadn’t misread it. Later, I asked several colleagues to read it as well. Dr. Huggins’s assertion that higher testosterone caused greater growth of prostate cancer, repeated for so long and accepted as gospel, was based on almost nothing at all!
After publication of my article on prostate biopsies in men with low testosterone, I published a number of additional articles looking at the relationship between testosterone and the prostate. In one provocative study, a colleague and I looked at whether testosterone therapy posed special dangers for men who were already at high risk for developing prostate cancer.
In this study, we compared the results of testosterone therapy given for twelve months in two groups of men with low testosterone. The first group consisted of twenty men considered to be at high risk for prostate cancer based on biopsy results showing an allegedly precancerous condition called prostatic intraepithelial neoplasia (PIN). The second group consisted of fifty-five men with normal biopsy results. At the end of one year of treatment, both groups had a similar, modest increase in PSA. One man in the study, who was in the high-risk group, developed cancer.
So, overall testosterone therapy resulted in a one-year cancer rate of 1.3 percent (one of seventy-five men). More importantly, the one-year cancer rate among the high-risk men with PIN was 5 percent. This compared to the known cancer rate of 25 percent over three years in this population. While the two figures are not directly comparable, these results certainly did not seem to suggest that testosterone therapy had increased the cancer rate in this high-risk group. And the overall cancer rate was not very high at all.
Here was another piece of evidence that the old assumptions about testosterone and prostate cancer were incorrect, specifically the notion that testosterone therapy was like pouring gasoline on a fire. First, we had found that men with low testosterone did not seem to be protected against developing cancer. Now, at the other extreme, we found that men at high risk for prostate cancer did not seem to suffer any dramatic “explosion” of cancer when treated for a year with testosterone therapy. And when I looked back at my extensive experience of treating men with testosterone therapy, many for ten years or longer, precious few cases of cancer had developed.
Prostate tumor confined to prostate gland.
It was heresy, but I couldn’t help thinking that the old stories linking testosterone levels to risk of prostate cancer might well be wrong. After all, if one looks at the natural progression of prostate cancer, it never occurs in men in their twenties when testosterone levels are at their lifetime peak, even though autopsy studies have shown that a significant percentage of these young men already harbor microscopic prostate cancers. Instead, prostate cancer becomes increasingly common as men age, when testosterone levels have declined.
I was coming to the conclusion that the average physician might be unduly fearful of the risk of prostate cancer with testosterone therapy. From my lectures to physicians around the country, it became clear to me that many physicians withheld testosterone therapy from their patients because they feared stimulating a sleeping cancer. I thought it might be time to write a review article that put the risks of testosterone in perspective, particularly the risk of prostate cancer. Fortunately for me, the New England Journal of Medicine was receptive to my proposal to consider such a publication.
The New England Journal of Medicine is arguably the most prestigious medical journal in the world, and its reputation stems in part from publishing only the best-researched articles. Together with Dr. Ernani Rhoden, a urology professor from Brazil who came to Boston to do a year-long research fellowship with me, we spent a year reviewing all the available scientific and medical literature on the risks of testosterone treatment to be able to provide a manuscript that lived up to such standards. Once we had written up the manuscript, our paper was subjected to multiple waves of reviews by physicians from various specialties—urology, oncology, endocrinology—to make sure that we had not left out any key studies or misrepresented any of the data.
The first thing we looked at was the rate of prostate cancer in men undergoing treatment with testosterone. Although many of the studies were small, the cumulative cancer rate in these trials was only slightly higher than 1 percent. This cancer rate was actually less than the cancer detection rate in men undergoing screening for prostate cancer. However, there was no large, long-term study looking at cancer rates in men receiving testosterone therapy and comparing them to men who did not receive testosterone therapy; thus, by themselves, these studies could not provide a definitive conclusion regarding risk.
There also were some large, sophisticated studies that indirectly addressed the risk of testosterone and prostate cancer. Unlike the studies I just mentioned, in which men given T treatment were monitored for the development of prostate cancer, these large studies simply looked to see if there was a connection between a man’s own natural level of testosterone and his risk of developing prostate cancer. In these observational studies, blood samples were taken and frozen at the beginning of the study, and then the large study group was followed for long periods of time. At the end of the study period, often ten to twenty years later, a group of men would have developed prostate cancer. The blood samples obtained from these men at the beginning of the study would then be tested for testosterone and other hormones and compared to a similar group of men who were matched for age and other characteristics but who did not develop prostate cancer. What did they find?
In 2004, when my article in the New England Journal of Medicine was published, there were fifteen of these longitudinal studies examining the relationship of hormones and prostate cancer. Since 2004, there have been approximately a half-dozen more. Not one has shown any direct relationship between the level of total testosterone in a man’s blood and the subsequent likelihood that he will develop prostate cancer. Specifically, average total testosterone levels were not higher in the cancer group compared to men without cancer, and men with the highest T values were at no greater risk for later developing prostate cancer than men with the lowest T values.
Among the dozens of additional calculations in each of these studies, an occasional minor correlation did show up, such as a connection with the minor androgen DHEA in one, a ratio of testosterone to SHBG in another, or a calculated free T in a third. But in all cases so far, attempts to confirm these minor connections have failed.
At the end of immersing ourselves into this literature for a full year, Rhoden and I were stunned by the fact that there was not a single study in human patients to suggest that raising testosterone increased the risk of prostate cancer. Although I was fairly convinced at this point that testosterone therapy was not a risk for prostate cancer, I had to admit that the evidence was not absolutely conclusive. And there was still a widespread belief that testosterone therapy was risky. And so our relatively sanitized conclusion appeared as follows:
“Thus, there appears to be no compelling evidence at present to suggest that men with higher testosterone levels are at greater risk of prostate cancer or that treating men who have hypogonadism with exogenous androgens increases this risk.”
Our article appeared in the New England Journal of Medicine in 2004. Whatever the truth may turn out to be regarding testosterone and prostate cancer, it was clear that raising testosterone did not appear to be like “food for a hungry tumor.” Physicians who had been interested in offering testosterone therapy to their patients but were worried about the cancer risk now had a reference article that gave them some degree of comfort.
Later that same year, the Institute of Medicine, a branch of the National Academy of Sciences, published its recommendations regarding testosterone research in aging men, with an eye toward ensuring the safety of men participating in testosterone studies. Recognizing the disparity between the concern that testosterone stimulates prostate cancer and the lack of any strong supporting evidence, the report concluded: “In summary, the influence of testosterone on prostate carcinogenesis and other prostate outcomes remains poorly defined . . .” The unwillingness of the report’s authors to identify testosterone as a definite risk for prostate cancer was a major departure from the standard story line that had colored earlier discussions of testosterone therapy and served as a nice bookend to our article on testosterone risks in the New England Journal of Medicine.
Discoveries in the Basement of the Countway Medical Library
As much as my year-long review of the scientific literature had given me confidence that testosterone therapy did not increase the risk of developing prostate cancer, there were still a few issues that disturbed me.
The first was the original observation by Huggins himself that administration of testosterone to men caused “enhanced growth” of prostate cancer in men with metastatic disease. A second was a well-known 1981 article from the Memorial Sloan Kettering Cancer Institute in New York, authored by the most prominent prostate cancer expert of his era, Dr. Willet Whitmore, that reported near-universal poor outcomes when men with metastatic prostate cancer received testosterone injections. And the third was the phenomenon known as testosterone flare. Testosterone flare refers to the temporary increase in testosterone caused by the use of medications called LHRH agonists in men with advanced prostate cancer. Testosterone flare has been associated with a variety of complications attributed to the sudden growth of prostate cancer.
All three of these issues applied only to men with known metastatic disease, and because no one was suggesting that testosterone therapy be offered to men with advanced prostate cancer, the existence of this literature wasn’t terribly troubling. What was of concern to those of us prescribing testosterone therapy was the possibility that we might be putting our otherwise healthy patients at risk for prostate cancer, but so far all the data looked reassuring on this point. Metastatic disease was something quite different, and it would not have been shocking to learn that it responded differently to high levels of testosterone than localized disease within the prostate.
But I was still bothered. I had read all the relevant articles years ago during my training, but not with a critical eye toward the relationship of testosterone and prostate cancer. One day, I found myself with an unexpectedly free afternoon and decided to investigate. Everything changed for me the day I descended into the basement of the Countway Library, Harvard Medical School’s incredible archive of medical literature. It was the most exciting day of my professional career, a day that changed my views on testosterone, prostate cancer, and, even more, on medicine itself.
The Original Huggins Article
The basement of Countway Library is where the old volumes of medical journals are kept. Some of these, from august journals such as The Lancet, go back to the 1800s. It is an amazing collection, open to any member of the Harvard community.
I found the original article by Huggins from 1941. It was in the very first published volume of what is now a highly respected journal called Cancer Research. I read how Dr. Huggins and his coinvestigator, Clarence Hodges, used the new blood test called acid phosphatase to show that lowering testosterone by castration or estrogen treatment caused prostate cancer to regress, and how T injections had caused “enhanced growth” of prostate cancer in these men. And then I noticed something that made my heart race.
Huggins and Hodges had written that three men had received T injections. But results were given for only two men. And one of these men had already been castrated. This meant that there were results for only a single man who had received T injections without prior hormonal manipulation. Dr. Huggins had based his “enhanced growth” conclusion on a single patient, using a test—acid phosphatase—that has since been abandoned because it provides such erratic results!
I sat there in the basement of the library, reading the same lines over and over to make sure I hadn’t misread it. Later, I asked several colleagues to read it as well. Dr. Huggins’s assertion that higher testosterone caused greater growth of prostate cancer, repeated for so long and accepted as gospel, was based on almost nothing at all!
