I have been fascinated by the treatments for prostate cancer (CaP)
reported by Dr. Robert Liebowitz.  By targeting dihydrotestosterone
(DHT) instead of (T), he now has published the only study done with
early stage (T1-T3) CaP which has a realistic chance of producing a 100%
cure rate.  What astonishes me is how almost all of the other urologists
are ignoring his work.  I know that Dr. Liebowitz is still 7.5 years
away from the 15 year mark which is used as the standard time frame for
determining a cure rate, however, I am unaware of any other study that
is anywhere near as promising as his  (e.g., the recent Swedish study in
the NEJM had over 4% CaP deaths for T1-T2 patients after 6.2 years
following RP). The question is, has Dr. Liebowitz lost credibility with
other urologist because he questions
(http://www.prostatepointers.org/prostate/leibowitz/HDTRT8.html) the
classic work of Fowler and Whitmore from 1981, which "proves" that T is
always bad for CaP?

Recently I read the Fowler and Whitmore article in order to decide for
myself where the truth lies.  For those of you who haven't read it, it
basically treats men with metastatic CaP by injecting them all with an
identical dose of testosterone propionate.  The results ranged from bad
to horrific.  Bone pain increased, all indications were that CaP was
growing at a faster rate, and in each case the patient had to stop the
treatment after a week or two.

Also in this article was a table listing all of the previous known
studies done with T and CaP, and summarizing their findings.  In almost
all of the cases, similar horrible pain and suffering was observed.

I am not a MD, but I can understand that those people who become MD's do
so to ease the pain and suffering in other people, and after reading the
Fowler and Whitmore article would vow never to inflict that onto any of
their patients.  However, I am a PhD in Biophysics and Theoretical
Biology, and I am capable of reading a scientific article in a more
objective manner.

So with that in mind, let's first examine the methodology of the
experiment.  To start with, let's look at some of the nitpicking
details. The study was not done using standard double blind technique,
nor even single blind, nor with any controls (e.g., no indication of
what effect, if any, the propionate had).

Next let's examine their protocol.  The best way to describe it is to
give an analogy.  Imagine that you are writing a paper with the goal of
demonizing the use of insulin for diabetics.  One way to do this in a
"believable" fashion would be not to measure the blood sugar before or
during treatment in any of the patients and to give them all the same
dosage of insulin at each meal.  The results would be almost uniformally
terrible.  Well, looking at the Fowler and Whitmore paper, they did not
measure the level of T before or during treatment in any of their
patients and gave them all the same dosage of T, and the results are
almost uniformally terrible.

Finally, if we continue the analogy of demonizing insulin for diabetics,
the flaw in the setup is that if you look at enough patients,
occasionally you will by random chance administer the correct dosage for
a small number of patients and their results would be extremely
positive.  This would definitely be hard to explain if your model is
that insulin is bad for all diabetics.  However, one neat solution is to
omit a column heading for positive results when you summarize all of the
results of other researchers (who used that same protocol).  Therefore,
anyone reading your paper will see nothing but horrible things about the
effects of insulin on diabetics, and you will have a very neat and tidy
model.  Well, looking at  the Fowler and Whitmore paper, they omitted a
column heading for positive results when they summarized the results of
other researchers.  In looking at the references they used, you will
find a small number of extremely positive results when T was
administered to CaP patients.  One patient that sticks in my mind was
one who had lost over 30 lbs. in weight, had pain throughout his bones
due to metastases, and following administration of T his pain went away,
his weight returned to normal and he ended up living over a year before
finally passing away from CaP.

Now let us compare the model of most urologists (which I will call the T
model) in which T is bad for CaP patients under all circumstances with a
model that I will make up (which I will call the DHT model) in which T
actually kills cancer cells and DHT is what is bad for CaP patients
under all circumstances.

First lets look at the patients who did poorly as reported in the Fowler
and Whitmore paper.  The T model explains this easily, since they were
all administered T.  The DHT model also explains this, since T is
converted to DHT, and nothing was done in this experiment to prevent the
conversion.

Next lets look at the few patients who did extremely well when T was
administered.  The T model really can't explain this at all.  The DHT
model can explain it by saying that if you have enough T, you can
counteract the bad effects of DHT.  E.g., let's pull some numbers out of
the air, since none were reported in the actual papers.  Let's assume
that a serum level of T of 500-600 ng/dL produces the maximum amount of
DHT and thus maximizes CaP growth.  If the testosterone injections
increased the serum level by 500 ng/dL on average, then let's assume
that those patients with the worst response all had initial levels of T
of less than 100.

Now let's assume that the level of T necessary to counteract the effect
of maximum DHT is 1200 and that those who experienced positive response
started with an initial level of 700-800.  Then the T would be above the
level necessary to counter the DHT, and would start to kill the CaP for
those patients.  It is known that when T is administered externally, the
maximum total serum level of T is  observed 2-6 weeks after the start of
treatment.  After that, the body produces less T internally, resulting
in a lower total level of T, so that administering the same dosage of T
(without doing serum measurements to maintain a constant serum level of
T) is almost guaranteed to soon bring the level of total T low enough
for the CaP to start growing again.

So just looking at the data presented in the original Fowler and
Whitmore paper (and their references) it is clear that the T model is
scientifically impossible, whereas the DHT model fits the observed data.

Now lets look at some other data not included in their paper.  First,
men with genetic mutations that prevent DHT formation do not get CaP
(and do not lose their hair).  This finding has no explanation in the T
model, but is totally expected in the DHT model.

Next, CaP is most common in men when their T/DHT ratio becomes too low.
 As men age, they produce less T, but more DHT.  In the teenage years,
when T is at its highest (in some cases over 2000), CaP is unknown.  The
T model again fails to explain this, while the DHT model succeeds.

In summary, the T model, which seems to be universally accepted by
urologists today, has no scientific basis to support it.  (If anyone
knows of any studies done in which T accelerates CaP growth which also
rule out other possible explanations, such as conversion of T to DHT or
T to estrogen, please let me know.)  The DHT model also does not have
enough scientific basis to support it, but it at least fits the known
data.  In order for a true model to be made, much more complex
experiments would have to be carried out, measuring serum and saliva
level of all of the known androgens (T, free T, DHT, DHEA, estrogen,
2-hydroxyestrone, 16alpha-hydroxyestrone, 4-hydroxyestrone) and
cross-referencing them to PSA, examining patients known to be
hormone-sensitive, hormone resistant, and hormone refractory, as well as
checking every stage of CaP.

Also, nobody should try to self-medicate themselves with T as a result
of what I have written here.  Again, if you use the insulin model as an
example, even if T is helpful, it must be used in the proper dosage, and
that dosage has yet to be determined.  Also, I do not wish to be seen as
questioning the integrity of Fowler and Whitmore.  Although their work
does not hold up to modern scrutiny, they were imitating the protocols
used by others in that field and were working in a time when not even
PSA testing was available.  The real tragedy is that their summary
stated that T should be "used with caution" with men with metastatic
CaP.  What they should have said is that T is the only chemical produced
  inside men that has been shown in some isolated instances to have
incredible potential for treating CaP.  However, since in most cases it
causes extremely harmful effects, it should be used with extreme
caution, but more research is definitely warranted.

So, getting back to the original point of this post, if urologists are
ignoring Dr. Liebowitz's results because he rejects the T model that
they hold so dear, then they don't have a scientific leg to stand on.

Ed Friedman