Destroying the Myth About Testosterone Replacement and Prostate Cancer By Abraham Morgentaler, MD, Facs Introduction By William Faloon
DoubleOwSeven
By Abraham Morgentaler, MD, Facs Introduction By William Faloon
For decades, the medical establishment erroneously conjectured that
testosterone replacementestoster one therapy increases one’s risk of
prostate cancer.
Harvard-based Abraham Morgentaler, MD, FACS, has demonstrated this
theory to be mistaken. Contrary to the notion that restoring
testosterone to youthful levels is somehow risky, Dr. Morgentaler
meticulously shows an increased risk of prostate cancer in aging men
with low testosterone. This same information about the dangers of low
testosterone was long ago uncovered by the Life Extension Foundation.
In this exclusive excerpt from his book, Testosterone for Life, Dr.
Morgentaler recounts how it takes years, even decades, to correct a
medical myth. Inthis case, the medical establishment’ s misconception
about testosterone and prostate cancer has condemned millions of aging
men to suffer degenerative diseases caused by testosterone deficiency.
Until just a few years ago, it was almost universally believed that
testosterone therapy would lead to some degree of increased risk of
prostate cancer. During that time testosterone therapy was seen to
represent the proverbial pact with the devil, by trading short-term
sexual and physical rewards for the ultimate development of a
malignant cancer. Fortunately, this belief has been shown to be
incorrect, and medical opinion has begun to shift quite dramatically,
with good evidence that testosterone therapy is quite safe for the
prostate. There is even now a growing concern that low testosterone is
a risk for prostate cancer rather than high testosterone.
How the original fear about T and prostate cancer came to be is a
fantastic story involving Nobel Prize winners, medical breakthroughs,
and a critical paradox that took two-thirds of a century to solve. In
the end, it is also a cautionary tale of how it may take years—even
decades—to correct a medical “truth” once it has been established. I
have taken great pleasure in participating myself in the evolution of
attitudes regarding T and prostate cancer, and here describe how this
all took place.
The relationship of testosterone to prostate cancer has undergone a
significant reevaluation, and all recent evidence has reinforced the
position that testosterone therapy is safe for the prostate. I’ve been
fortunate to have participated in the evolution of this idea, which is
of critical importance to anyone considering testosterone therapy.
Origins of the Concern
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.
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.
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!
The Memorial Sloan Kettering Experience
I was still giddy when I decided to look up the article detailing the
experience of testosterone administration to men with metastatic
disease from the Memorial Sloan Kettering Cancer Institute, published
in 1981 by the urologic giant of his day, Willet Whitmore, and his
colleague, Jackson Fowler. The short summary of the paper was quite
damning. Over a course of eighteen years, fifty-two men with
metastatic disease had undergone treatment with daily T injections,
usually as a last-gasp treatment for their cancer. Of these fifty-two
men, forty-five had experienced an “unfavorable response,” most within
the first month of treatment.
This seemed pretty grim. Maybe Huggins had been right after all,
despite basing his conclusions on a solitary patient. But then I
discovered something equally shocking in the fine print of this
article. Of the fifty-two men studied, all but four had already been
treated with castration or estrogen treatment to lower testosterone.
And of these four previously untreated men, one had an early,
unspecified unfavorable response, while the remaining three men
continued to receive daily T injections for 52, 55, and 310 days
without apparent negative effects. In fact, one of these men was
reported to have had a “favorable response” to T administration.
Drs. Fowler and Whitmore were impressed by the difference in outcomes
for the untreated group of four men compared with the men who had
already undergone hormonal treatment to lower testosterone. To explain
the lack of negative effects on the untreated men, the authors
postulated the following: “Normal endogenous testosterone levels may
be sufficient to cause near maximal stimulation of prostatic tumors.”
In other words, raising testosterone levels beyond the normal range
did not seem to cause any increased cancer growth, even in men with
metastatic disease!
This important concept was lost in the headline of the study, which
clearly indicated that giving testosterone to men with prostate cancer
was associated with rapid onset of negative consequences in most men.
One had to read the article closely to learn that the headline applied
only to men who had been previously castrated. Although this article
has been cited for many years as evidence that T administration causes
rapid and near-universal growth of prostate cancer (PCa), the authors
in fact clearly made the point that the worrisome effects of T
administration did not appear to occur in their small group of men
without prior hormonal treatment.
Testosterone Flare
It had been an amazing day in the library, which had long since turned
to night. My head was spinning, but I wanted to tackle the last
hurdle, the problem of testosterone flare. In the early 1980s,
medications were developed to replace the need for surgical removal of
the testicles for men with advanced prostate cancer. These medications
are called LHRH agonists, and they continue to be used to this day.
LHRH injections cause T concentrations to increase by 50 percent or
more for seven to ten days, after which testosterone levels fall
rapidly to castrate levels. This transient rise in testosterone is
called testosterone flare.
Not long after LHRH agonists began to be used, there were reports of
complications occurring after men began these treatments, and these
complications were attributed to testosterone flare causing rapid
growth of prostate cancer. These complications included the inability
to urinate, worsening of bone pain, or, in the most tragic cases,
paralysis due to collapse of a vertebra in which the cancer had eaten
away the bone. As a result, for the last twenty years, it has been
routine to add medications to block testosterone flare when starting a
patient on treatment with LHRH agonists.
That night in the basement of Countway Library, I pulled all the
original studies I could find of LHRH agonists, as well as reports of
bad outcomes due to the flare. As I read, two things became apparent.
First, many of the bad outcomes attributed to testosterone flare
occurred a month or more after initiation of treatment. This meant
that these complications occurred not when testosterone levels were
high, but when testosterone levels had already dropped for some time
to castrate levels.
Second, out of the substantial literature on LHRH agonists and
prostate cancer, I could find only two articles that actually measured
and reported PSA levels during the time of the testosterone flare. And
here was the kicker: both articles showed absolutely no change in mean
PSA values during the time of the testosterone flare! Curiously,
neither article so much as mentioned this result.
PSA is an excellent indicator of prostate cancer growth. The fact that
PSA did not rise in these men during the testosterone flare strongly
suggested that the cancers did not grow during this time. Perhaps the
complications attributed to testosterone flare were nothing more than
the cancer progression that would have happened without any treatment
at all.
It had been quite a day and night in the Countway Library. I left with
my head spinning and a feeling that I had stumbled onto something very
important. It was like the children’s story The Emperor’s New
Clothes—we see what we want to see. And for two-thirds of a century,
it had been assumed that raising testosterone increased prostate
cancer growth. But maybe the emperor was naked.
Even in men with metastatic disease, there was no evidence I could
find that raising testosterone made prostate cancer grow more than it
would have anyway. Shockingly, the very publications cited so
regularly to demonstrate a dangerous relationship between testosterone
and prostate cancer contained evidence that this was not true.
The Paradox Resolved
Still, I was worried, because there was a bothersome unresolved
paradox to explain. For decades, the storyline was that lowering
testosterone levels caused prostate cancer to shrink away and raising
testosterone levels caused it grow. The second part of this story was
now seriously in doubt, yet the first part was obviously correct. In
my own practice, I had seen the beneficial effects of lowering
testosterone levels many times over in men with advanced prostate
cancer. This part of Dr. Huggins’s work was indisputable. But if
lowering testosterone levels caused these cancers to shrink, how was
it possible that raising testosterone levels did not cause the cancers
to grow? This was a paradox that needed to be solved if physicians
were to accept the possibility that testosterone therapy may not
increase the risk of prostate cancer.
The answer turns out to be not all that complicated. All the reports
of testosterone causing rapid growth of prostate cancer occurred in
men who already had extremely low testosterone levels, due to
castration or estrogen treatment. Once we get beyond the near-castrate
range, it is hard to find any evidence that changes in T
concentrations matter at all to prostate cancer. This is essentially
what Drs. Fowler and Whitmore described in their 1981 article when
they suggested that “near maximal” growth of prostate cancer is
provided by naturally occurring T concentrations.
The experimental proof of this concept was provided by a landmark
article published in 2006 using much more sophisticated means. In this
study by Leonard Marks and colleagues, men with low testosterone
received injections of testosterone or a placebo every two weeks for a
total of six months. At the beginning and end of the study,
measurements of testosterone and DHT (the more active form of
testosterone within prostate tissue) were obtained from the blood and
also from the prostate itself. The results showed that although blood
concentrations of testosterone and DHT rose substantially in the T
injection group, as expected, the concentration of testosterone and
DHT within the prostate itself did not change at all and was similar
to the group that received placebo injections. In addition,
biochemical markers of prostate cell growth also did not change with T
injections.
This study showed in elegant fashion that raising testosterone levels
in the blood did not raise testosterone levels within the prostate. It
is as if once the prostate has been exposed to enough testosterone,
any additional testosterone is treated as excess and does not
accumulate in the prostate. In technical terms, we say the prostate
has been saturated with regard to testosterone. And it is this
saturation that resolves the paradox of testosterone and prostate
cancer.
Saturation explains the paradox in this way. At very low levels of T,
near the castrate range, prostate growth is very sensitive to changes
in T concentration. Thus, severely lowering testosterone will
definitely cause prostate cancer to shrink; adding testosterone back
will cause the cancer to regrow. However, once we get above the point
where the prostate is saturated with testosterone, adding more
testosterone will have little, if any, further impact on prostate
cancer growth. Experimental studies suggest the concentration at which
this saturation occurs is quite low.
In other words, the old analogy I learned in training was false.
Testosterone is not like food for a hungry tumor. Instead, a much
better analogy is, “Testosterone is like water for a thirsty tumor.”
Once the thirst has been satisfied, prostate tumors have no use for
additional testosterone. . And the vast majority of men with low
testosterone appear to have prostates that are not particularly
thirsty.
A New Concern: Prostate Cancer and Low testosterone
I no longer fear that giving a man testosterone therapy will make a
hidden prostate cancer grow or put him at increased risk of developing
prostate cancer down the road. My real concern now is that men with
low testosterone are at an increased risk of already having prostate
cancer.
When my colleagues and I published our results in 1996 from prostate
biopsies in men with low testosterone and PSA of 4.0 ng/mL or less,
the 14 percent cancer rate was several times higher than any published
series of men with normal PSA. In 2006, Dr. Rhoden and I published a
larger study of prostate biopsies performed in 345 men. The cancer
rate of 15 percent in this group was very similar to the first study.
But whereas the cancer rate in 1996 was much higher than anything
published to that date in men with PSA of 4.0 ng/mL or less, in 2006
the perspective had changed due to an important study called the
Prostate Cancer Prevention Trial.
In that study, the cancer rate among men with a PSA of 4.0 ng/mL or
less was also 15 percent. Because this value is identical to what we
had found in our patients with low testosterone, it was suggested that
the cancer rate in men with low testosterone is the same as the normal
population—neither higher nor lower. However, the average age of men
in our study was a decade younger than the men studied in the Prostate
Cancer Prevention Trial (fifty-nine versus sixty-nine years). Almost
half the men in the other study were seventy years or older, and age
is the greatest risk factor we know for prostate cancer. The way I
look at these numbers is that men with low testosterone have a cancer
rate as high as men with normal T who are a decade older.
More importantly, in our study of 345 men, we found that the degree of
testosterone deficiency correlated with the degree of cancer risk. Men
whose testosterone levels were in the bottom third of the group were
twice as likely to have cancer diagnosed on biopsy as men in the upper
third. This finding adds to the concern that low testosterone is a
risk factor for prostate cancer.
There is now additional data from around the world associating low
testosterone and worrisome features of prostate cancer. For example,
low testosterone is associated with more aggressive tumors. In
addition, men with low testosterone appear to have a more advanced
stage of disease at the time of surgical treatment.
Whereas I originally began to perform prostate biopsies in men with
low testosterone because I was worried that treatment might cause a
hidden cancer to grow, I now perform biopsies in these men because I
am concerned they might have an increased risk of cancer. This risk is
approximately one in seven for men with PSA values less than 4 ng/mL.
Because prostate cancer tends to be curable when caught early, I feel
I’ve done these men a service by finding their cancers before they
have an abnormal PSA or DRE. With today’s ability to monitor men with
prostate cancer, not all of these men will necessarily require
treatment. But the ones who have evidence of more aggressive tumors
should definitely have an advantage by having their diagnosis made
early.
The Evidence as it Now Stands
For over sixty-five years, there has been a fear that testosterone
therapy will cause new prostate cancers to arise or hidden ones to
grow. Although no large-scale studies have yet been performed to
provide a definitive verdict on the safety of testosterone therapy, it
is quite remarkable to discover that the long-standing fear about
testosterone and prostate cancer has little scientific support. The
old concepts, taken as gospel, do not stand up to critical
examination. I believe the best summary about the risk of prostate
cancer from testosterone therapy, based on published evidence at the
time this book is written, is as follows:
Low blood levels of testosterone do not protect against prostate
cancer and, indeed, may increase the risk.
High blood levels of testosterone do not increase the risk of prostate
cancer.
Treatment with testosterone does not increase the risk of prostate
cancer, even among men who are already at high risk for it.
In men who do have metastatic prostate cancer and who have been given
treatment that drops their blood levels of testosterone to near zero,
starting treatment with testosterone (or stopping treatment that has
lowered their testosterone to near zero) might increase the risk that
residual cancer will again start to grow.
Prostate cancer with infiltration into bladder, lymph nodes, and
urethra.
One of the most important and reassuring studies regarding
testosterone and prostate cancer was an article published in the
Journal of the National Cancer Institute in 2008, in which the authors
of eighteen separate studies from around the world pooled their data
regarding the likelihood of developing prostate cancer based on
concentrations of various hormones, including testosterone. This
enormous study included more than 3,000 men with prostate cancer and
more than 6,000 men without prostate cancer, who served as controls in
the study. No relationship was found between prostate cancer and any
of the hormones studied, including total testosterone, free
testosterone, or other minor androgens. In an accompanying editorial,
Dr. Carpenter and colleagues from the University of North Carolina
School of Public Health suggest scientists finally move beyond the
long-believed but unsupported view that high testosterone is a risk
for prostate cancer.
More and more physicians are coming around to recognize that
testosterone therapy is not a true risk for prostate cancer, but it
can take many years to alter established beliefs. Don’t be surprised
if your own doctor still raises this issue with you if you are
considering testosterone therapy.. If he objects to treating you for
that reason, you should refer him to the article above, or one of the
other review articles listed in the References at the back of this
book. Even better, have him read this chapter!
Q. I’m fifty-three years old and I’ve been on testosterone therapy for
two years, with good results. However, my father was diagnosed with
prostate cancer at age seventy-five. Does this mean I need to stop
testosterone?
A. There is a familial form of prostate cancer, but only in families
in which prostate cancer occurs at age sixty-five or younger. Even in
those families where a family member develops cancer at a young age,
this does not necessarily mean that every other male in the family
will develop cancer. Men with a family history of prostate cancer
should be sure to have a yearly PSA and prostate exam. There is no
need to discontinue testosterone treatment.
Q. My physician started me on testosterone, but I never had a prostate
biopsy. I am sixty-four years old. Was this a mistake?
A. Because there is no evidence that testosterone treatment increases
the risk of prostate cancer, it is fine to begin therapy as long as
your PSA and DRE are normal. My own practice is to recommend prostate
biopsy in men with low testosterone because our published data
indicate there is an increased risk that cancer is already present in
men with low testosterone, but this is by no means a standard
recommendation yet among physicians.
Q. Why do you perform prostate biopsies on men with low testosterone
if you don’t feel that testosterone treatment will make a hidden
cancer grow?
A. Because so many men with prostate cancer will not die from it, even
without treatment, there is a fair amount of controversy over how
aggressive to be in making the diagnosis. My perspective is that it is
worth knowing the diagnosis, whether or not one chooses to be treated
immediately. And because low testosterone seems to represent a small
but definite increased risk, I feel that biopsy in men over fifty with
low testosterone is worthwhile.
Q. A man in my bowling league was started on testosterone treatment
and then developed prostate cancer one year later. Doesn’t that show
that testosterone is risky for prostate cancer?
A. If the wife of this man had switched to a new type of laundry
detergent before the cancer was diagnosed, would we assume the cancer
was caused by the detergent? Of course not. But we are predisposed to
believe that testosterone therapy causes prostate cancer, so it is
easy to hear a story like this and assume that testosterone therapy
caused the cancer. Prostate cancer and testosterone therapy are both
common in the United States, and both tend to occur in the same age
range, so there will always be stories of men developing cancer some
time after beginning testosterone therapy. If testosterone really made
prostate cancers grow, then we should see high rates of cancer among
men who start testosterone therapy. But we don’t. It’s false logic.
Q. Isn’t it true that all men would eventually get prostate cancer if
they lived long enough? If so, why does it even matter if testosterone
were to increase the risk of something that is inevitable anyway?
A. Men do get prostate cancer at an increasingly high rate as they
age. And it is true that most men diagnosed with prostate cancer would
never have a moment’s trouble from it, even if it were left untreated,
because most of these cancers grow so slowly that other medical
conditions eventually become more troublesome. Yet for those with more
aggressive forms of prostate cancer, the danger is very real. The
challenge is to identify men at risk, because even high-grade prostate
cancer is curable when caught early.
Q. It took more than thirty years for scientists to learn that
hormones were dangerous for women and caused breast cancer. Isn’t it
possible we’ll eventually find out the same is true for testosterone
and prostate cancer?
Abraham Morgentaler, MD
A. The fear that hormone therapy is dangerous in women is currently
being reevaluated, and it appears to not be as dangerous as was
originally proclaimed. More to the point, it is critical to understand
that men are not women and that testosterone is not estrogen. Anyone,
particularly a scientist, must always allow for the possibility that
new information will one day change current views. But after so much
research over so many decades, there is little reason to believe that
testosterone therapy poses a major risk for prostate cancer. As a
medical student once said to me, “If testosterone is really so
dangerous for prostate cancer, why is it so hard to show it?”
Abraham Morgentaler, MD, is an associate clinical professor of urology
at Harvard Medical School, and is the founder of Men’s Health Boston,
a center focusing on sexual and reproductive health for men. He is the
author of a number of popular books including The Male Body and The
Viagra Myth.
Excerpted with permission from Testosterone for Life: Recharge Your
Sex Drive, Muscle Mass, Energy and Overall Health by Abraham
Morgentaler, MD, FACS. Published by McGraw-Hill.
If you have any questions on the scientific content of this article,
please call a Life Extension Health Advisor at 1-800-226-2370.
e...@math.uchicago.edu
> Q. It took more than thirty years for scientists to learn that
> hormones were dangerous for women and caused breast cancer. Isn’t it
> possible we’ll eventually find out the same is true for testosterone
> and prostate cancer?
Actually, this is total nonsense. All one has to do is read the
article "Disruption of androgen receptor signaling by synthetic
progestins may increase risk of developing breast cancer" at
http://www.fasebj.org/cgi/content/abstract/21/10/2285 as well as my
own article "Can a single model explain both breast cancer and
prostate cancer?" at http://www.tbiomed.com/content/4/1/28 in order to
understand that it is only the synthetic progestin MPA, and not
progesterone itself, that causes the increase in breast cancer by
increasing anti-apoptotic proteins such as Bcl-2 by blocking the
intracellular androgen receptor. All evidence points to the fact that
progesterone actually decreases Bcl-2 and thus should greatly reduce
the incidence of breast cancer.
The rest of the article is interesting, but in my opinion, Dr.
Morgentaler understates the risk of giving T to men who already have
prostate cancer. The earlier the stage of the cancer, the more
beneficial T should be, but because of the heterogeneous nature of
the population, there is always the risk that some of the cancer
cells will thrive in the presence of T, especially if Arimidex is not
added to prevent estradiol formation. This risk becomes greater on
average the more advance the cancer is.
Ed Friedman
zero...@midsouth.rr.com
weighing in on it. Didn't take you long. :-)
Have you ever developed a theoretical [for discussion purposes only,
people!] Tx protocol based on your model? I'm curious how traditional
Tx may vary, and actually be counter-productive if you are right.
Bill/Memphis
jur...@tampabay.rr.com
> On Dec 12, 12:08 am, DoubleOwSeven <doubleowse...@yahoo.com> wrote:
>
> > Q. It took more than thirty years for scientists to learn that
> > hormones were dangerous for women and caused breast cancer. Isn’t it
> > possible we’ll eventually find out the same is true for testosterone
> > and prostate cancer?
>
> Actually, this is total nonsense. All one has to do is read the
> article "Disruption of androgen receptor signaling by synthetic
> own article "Can a single model explain both breast cancer and
> understand that it is only the synthetic progestin MPA, and not
> progesterone itself, that causes the increase in breast cancer by
> increasing anti-apoptotic proteins such as Bcl-2 by blocking the
> intracellular androgen receptor. All evidence points to the fact that
> progesterone actually decreases Bcl-2 and thus should greatly reduce
> the incidence of breast cancer.
>
> The rest of the article is interesting, but in my opinion, Dr.
> Morgentaler understates the risk of giving T to men who already have
> prostate cancer. The earlier the stage of the cancer, the more
> beneficial T should be, but because of the heterogeneous nature of
> the population, there is always the risk that some of the cancer
> cells will thrive in the presence of T, especially if Arimidex is not
> added to prevent estradiol formation. This risk becomes greater on
> average the more advance the cancer is.
>
> Ed Friedman
Ed,
The question that you responed to above was from some other source
than Dr. Morgentaler. He responds to the question himself below his
name in the article; "A. The fear that hormone therapy is dangerous in
women is currently being re-evaluated, and it appears to not be as
dangerous as was originally proclaimed."
RonS
Ed Friedman
>
> The question that you responed to above was from some other source
> than Dr. Morgentaler. He responds to the question himself below his
> name in the article; "A. The fear that hormone therapy is dangerous in
> women is currently being re-evaluated, and it appears to not be as
> dangerous as was originally proclaimed."
>
> RonS
Ron,
You are correct, and I want to make it clear that I respect Dr.
Morgentaler's position and understand that his area of expertise is not
breast cancer. I just wanted to point out the myth that is being
perpetrated that synthetic hormone-like chemicals behave the same way as
real hormones in spite of the evidence that points out that this is not so.
Ed Friedman
Ed Friedman
Bill,
Yes, I have posted theoretical protocols on this newsgroup in the past,
but my views are continually evolving as my understanding of prostate
cancer (PCa) grows.
Basically, the traditional approach of relying on ADT as the standard
treatment for advanced PCa dooms thousands of men to senseless deaths.
As has been shown in LNCaP (the hormone sensitive cell line used by most
researchers) transplanted into mice, intermittent ADT followed by high
levels of testosterone (T) coupled with finasteride (F) is 5 times more
effective than continual ADT. This high T/low DHT protocol is currently
being used by Dr. Robert Leibowitz on human PCa patients with incredible
success http://compassionateoncology.org/pdfs/TRTcase_reports_03_07.pdf
It amazes me that the medical establishment is ignoring the fantastic
results shown with high T/low DHT. If continual ADT was not already
grandfathered in as the "standard" course of treatment, I can't imagine
any ethics board of any hospital that would allow it to be administered.
Imagine going to an ethics board and saying something like I want to
use continual ADT and so far the animal studies show that it is only
five times worse than the high T/low DHT protocol. I imagine that they
would insist that you come up with a study that shows that continual ADT
produces better results that high T/low DHT before giving you permission
to try it on humans.
The interesting thing about using high T/low DHT is that a very small
percentage of patients seem to have an increase in PSAV when using it.
Removing the T drops the PSA levels back down, but my model would
predict an even better way of treating such patients. In theory, there
are two main ways that high T/low DHT could increase PCa population
growth. First, there could be increased amounts of intracellular
androgen receptor (iAR), such as in the LNCaP 104-R2 cell line, which
grows just fine in the presence of T plus F, but can't grow at all in
the presence of T alone. Such patients should be treated with T alone.
The second possibility is a harmful mutation on the iAR such as some
of the gene-fusions which are the hot new item in PCa research. In that
case, patients should be treated with T plus F plus Casodex, to prevent
all possible agonism of the iAR. Finally, it is theoretically possible
(although no cases have ever been observed yet) that there could be a
mutation on the membrane androgen receptor (mAR) that prevents it from
upregulating pro-apoptotic proteins, but if that were the case, not much
can be done today except to remove the T supplementation, at least until
a drug is developed that specifically blocks mAR. With such a drug
added to T (but no F), you might come close to finding a cure for PCa
(as well as for breast cancer).
In addition to all of this, I now would recommend silybin-phytosome (an
enhanced version of silibinin which is better absorbed by humans).
Silibinin is found naturally in milk thistle weed. It kills PCa in
multiple ways (independent of hormone receptors), while not affecting
normal cells nor having any serious side effects. The most aggressive
PCa cell lines have their doubling times reduced to 60% of normal when
treated with silibinin. Also, enough Vitamin D3 should be added to get
the serum level up close to the maximum safe value.
Another good combination to add to all of this is RU-486 plus
progesterone, which has been shown to greatly decrease Bcl-2 levels, as
predicted by my model. This is important because high T/ low DHT raises
both Bcl-2 and pro-apoptotic proteins, and if you can lower Bcl-2 while
on this protocol then the rate of apoptosis should increase. The
problem with this is that in the U.S., our government has restrictions
on RU-486 which makes it almost impossible for any doctor to dispense it
(this was due to the battle with the FDA since RU-486 can be used as a
chemical abortion agent).
Finally, I must agree with Dr. Leibowitz that systemic treatment, such
as what I described above, should ideally be used in place of local
treatment. This is because following elimination of the primary tumor,
surviving metastases have their doubling rate increase approximately
five-fold due to angiogenesis. For patients who have metastateses, Dr.
Leibowitz has developed an anti-angiogenic cocktail, but the last I
heard, none of his patients with early stage PCa (average PSA ~13) who
did intermittent ADT followed by high T/low DHT have ever had metastases
develop.
Ed Friedman
J
> You are correct, and I want to make it clear that I respect Dr.
> Morgentaler's position and understand that his area of expertise is not
> breast cancer. I just wanted to point out the myth that is being
> perpetrated that synthetic hormone-like chemicals behave the same way as
> real hormones in spite of the evidence that points out that this is not so.
http://en.wikipedia.org/wiki/Prostate_cancer
Hormonal therapy
Hormonal therapy in prostate cancer. Diagram shows the different organs (purple
text), hormones (black text and arrows), and treatments (red text and arrows)
important in hormonal therapy.
Hormonal therapy uses medications or surgery to block prostate cancer cells
from getting dihydrotestosterone (DHT), a hormone produced in the prostate and
required for the growth and spread of most prostate cancer cells. Blocking DHT
often causes prostate cancer to stop growing and even shrink. However, hormonal
therapy rarely cures prostate cancer because cancers which initially respond to
hormonal therapy typically become resistant after one to two years. Hormonal
therapy is therefore usually used when cancer has spread from the prostate. It
may also be given to certain men undergoing radiation therapy or surgery to
help prevent return of their cancer.[104]
Hormonal therapy for prostate cancer targets the pathways the body uses to
produce DHT. A feedback loop involving the testicles, the hypothalamus, and the
pituitary, adrenal, and prostate glands controls the blood levels of DHT.
First, low blood levels of DHT stimulate the hypothalamus to produce
gonadotropin releasing hormone (GnRH). GnRH then stimulates the pituitary gland
to produce luteinizing hormone (LH), and LH stimulates the testicles to produce
testosterone. Finally, testosterone from the testicles and
dehydroepiandrosterone from the adrenal glands stimulate the prostate to
produce more DHT. Hormonal therapy can decrease levels of DHT by interrupting
this pathway at any point. There are several forms of hormonal therapy:
* Orchiectomy is surgery to remove the testicles. Because the testicles
make most of the body's testosterone, after orchiectomy testosterone levels
drop. Now the prostate not only lacks the testosterone stimulus to produce DHT,
but also it does not have enough testosterone to transform into DHT.
* Antiandrogens are medications such as flutamide, bicalutamide,
nilutamide, and cyproterone acetate which directly block the actions of
testosterone and DHT within prostate cancer cells.
* Medications which block the production of adrenal androgens such as DHEA
include ketoconazole and aminoglutethimide. Because the adrenal glands only
make about 5% of the body's androgens, these medications are generally used
only in combination with other methods that can block the 95% of androgens made
by the testicles. These combined methods are called total androgen blockade
(TAB). TAB can also be achieved using antiandrogens.
* GnRH action can be interrupted in one of two ways. GnRH antagonists
suppress the production of LH directly, while GnRH agonists suppress LH through
the process of downregulation after an initial stimulation effect. Abarelix is
an example of a GnRH antagonist, while the GnRH agonists include leuprolide,
goserelin, triptorelin, and buserelin. Initially, GnRH agonists increase the
production of LH. However, because the constant supply of the medication does
not match the body's natural production rhythm, production of both LH and GnRH
decreases after a few weeks.[105]
The most successful hormonal treatments are orchiectomy and GnRH agonists.
Despite their higher cost, GnRH agonists are often chosen over orchiectomy for
cosmetic and emotional reasons. Eventually, total androgen blockade may prove
to be better than orchiectomy or GnRH agonists used alone.
Each treatment has disadvantages which limit its use in certain circumstances.
Although orchiectomy is a low-risk surgery, the psychological impact of
removing the testicles can be significant. The loss of testosterone also causes
hot flashes, weight gain, loss of libido, enlargement of the breasts
(gynecomastia), impotence and osteoporosis. GnRH agonists eventually cause the
same side effects as orchiectomy but may cause worse symptoms at the beginning
of treatment. When GnRH agonists are first used, testosterone surges can lead
to increased bone pain from metastatic cancer, so antiandrogens or abarelix are
often added to blunt these side effects. Estrogens are not commonly used
because they increase the risk for cardiovascular disease and blood clots. The
antiandrogens do not generally cause impotence and usually cause less loss of
bone and muscle mass.
zero...@midsouth.rr.com
High T/Low DHT as you describe it and as Dr. Bob is using it appears
to be a post-(triple) ADT maintenance therapy. What is the scientific
reason for the ADT and could High T/Low DHT possibly be used on its
own in cases where ADT has not yet been started? I.e. in early
recurrences. Also, does your model have implications re the early vs.
late ADT debate?
Bill/Memphis
e...@math.uchicago.edu
> On Fri, 12 Dec 2008 05:37:55 -0800 (PST), e...@math.uchicago.edu wrote:
> >On Dec 12, 12:08 am, DoubleOwSeven <doubleowse...@yahoo.com> wrote:
> >> Q. It took more than thirty years for scientists to learn that
> >> hormones were dangerous for women and caused breast cancer. Isn’t it
> >> possible we’ll eventually find out the same is true for testosterone
> >> and prostate cancer?
>
> >Actually, this is total nonsense. All one has to do is read the
> >article "Disruption of androgen receptor signaling by synthetic
> >progestins may increase risk of developing breast cancer" at
> >own article "Can a single model explain both breast cancer and
> >understand that it is only the synthetic progestin MPA, and not
> >progesterone itself, that causes the increase in breast cancer by
> >increasing anti-apoptotic proteins such as Bcl-2 by blocking the
> >intracellular androgen receptor. All evidence points to the fact that
> >progesterone actually decreases Bcl-2 and thus should greatly reduce
> >the incidence of breast cancer.
>
> >The rest of the article is interesting, but in my opinion, Dr.
> >Morgentaler understates the risk of giving T to men who already have
> >prostate cancer. The earlier the stage of the cancer, the more
> >beneficial T should be, but because of the heterogeneous nature of
> >the population, there is always the risk that some of the cancer
> >cells will thrive in the presence of T, especially if Arimidex is not
> >added to prevent estradiol formation. This risk becomes greater on
> >average the more advance the cancer is.
>
> >Ed Friedman
>
>
> Of course this is keenly interesting to me. Monday I should have my 18
> month post RLRP PSA results and assuming I don't screw the pooch on
> that one or the 24 month screening *and* my T continues to drop, I am
> going to give some strong consideration to "taking some T".
>
> --
If you are serious about taking T and you live anywhere near the
Chicago area, you might want to try contacting the Urology Department
at the University of Chicago. There is at least one researcher there
who is experimenting with giving T to PCa patients, and after a
seminar I attended I overheard him say that he was having trouble
finding volunteers. I spoke with him briefly and learned that he was
using T by itself - a protocol that I disagree with. At a minimum, he
should be using a small enough dose of Arimidex to keep estradiol
levels normal when supplementing with T, as well as being prepared to
add finasteride if there is any indication of the T increasing PSAV.
Ed Friedman
e...@math.uchicago.edu
Bill,
If you look at the web page I cited for Dr. Leibowitz's treatment, you
will see that in fact one patient (himself a doctor), refused ADT and
went directly to high T/low DHT treatment.
with a resulting PSA doubling time of > 15 years. This is only one
case, and obviously more numbers are needed to determine how this
treatment matches up vs. using intermittent ADT first. I would not be
surprised if it turns out that avoiding ADT turns out to be the
superior treatment. Basically, ADT kills those PCa cells which are
easy to kill, i.e. they don't have enough anti-apoptotic protein
production to survive ADT. Following ADT you end up with a population
that is more aggressive than what you started with. Since all of the
PCa are competing with each other for the resources necessary to grow,
it may be beneficial having more non-aggressive PCa cells around, to
"starve" any very aggressive PCa cells that might be embedded deep
inside a tumor mass. However, Dr. Leibowitz currently uses ADT in
order to "debulk" the PCa. In some cases, this is essential, e.g.
with the patient who started with a PSA over 3300 who ended up with a
PSA <1 following his triple ADT. My guess is that whenever there are
definitely metastases present, then the patient should definitely
start with the ADT.
As you probably know, a recent NCI study showed that continual early
ADT resulted in a higher death rate from PCa than waiting until later
for continual ADT. I explain this in a similar vein as above.
Basically, if ADT is maintained long enough, only the highly
aggressive cells will survive. This means that a tumor mass will be
stripped of non-aggressive cells thus releasing aggressive cells that
were buried deep inside the tumor mass. Similarly, I would explain
the results that intermittent ADT and continual ADT result in
approximately the same death rate from PCa in much the same way, with
both procedures killing all of the non-aggressive PCa cells given
enough time. In theory there should be a slight advantage to
intermittent ADT, but if the down-time intervals are short enough, you
won't see much difference in practice.
The latest link for the silybin-phytosome work that I know of is
http://www.springerlink.com/content/48282102832r709q
I don't know how they were able to get the powder that they used in
this paper - the company in question only seems to sell small dose
capsules available at various health food websites. If you do find
out how to get the powder for 13g/day doses, please post it since I as
well as probably others would like to know.
Ed Friedman