Introduction
This article was written at the request of members of the Santa
Cruz County Prostate Cancer Support Group. Its purpose is to explain in layman’s
terms the relationships between hormones and other chemicals in the body as
they relate to Prostate Cancer, and how they may be manipulated to provide
relief from the further advance of the disease. It does not attempt to make
any recommendation as to whether hormone treatment should be used, as opposed
to surgery or radiation.
CAUTION: This article is not intended to
replace medical advice from a health care provider, and the reader is
cautioned not to try any treatment or supplement discussed until he has
discussed it with a health care professional.
What are hormones?
A hormone is simply a chemical messenger which is manufactured by
cells in the body, usually in very tiny amounts, which has the purpose of
influencing some function of the body. In the complex inter-related system
called the human body, there are literally hundreds of hormones, many of which
influence the production and activity of other hormones. In this discussion,
we are not going to worry about any but a very few of these amazing chemicals
– in particular those hormones related to sexuality.
So let’s begin with the most well-known hormone of all:
testosterone. Testosterone is a truly wonderful chemical, for it is what makes
men look like men! Its influence is what causes a man’s muscles and frame to
grow larger than a woman’s, his voice to drop in tone, his beard to grow,
and last but not least his prostate gland to develop. Even in the womb, a baby
boy’s testicles begin to produce a tiny amount of this substance, causing
his development to change from that of a girl. As he reaches puberty, his
testicles increase their output, and even more dramatic changes take place,
including the attraction to loud music, fast cars, and of course, women…
But the news is not all good, for this wonderful chemical has a
dark side. Among other things, it is toxic to some parts of the body, most
commonly the hair follicles on the top of the head. The price we pay in middle
age is male pattern baldness. And like Dr. Jekyll, it has a Mr. Hyde called dihydrotestosterone,
or DHT for short. The potion which creates this “evil counterpart” is
another chemical called “5-alpha-reductase.”
How do hormones work?
How do these little molecules, barely detectable by chemical tests,
have such an impact? Let’s start with the development of a normal prostate.
As the body matures, the prostate must grow from a tiny bump on the bottom of
the bladder, to a muscular organ which is called upon to provide major
components of the semen and pump them out of the body during intercourse. An
important job, if the human race is going to survive! What actually happens is
that the cells of the 
prostate have tiny
receptors in their nucleus. These receptors are like tiny locks waiting for a
key, which when it is inserted in the lock causes the cell to grow and divide.
And of course, the key is testosterone. Actually, DHT seems to be the most
powerful stimulus to cause prostate cells to grow and reproduce, with about
four times the potency of the plain old kind of testosterone. The diagram
shows schematically how the body controls the production and use of
testosterone. Later we will look at some of the details, but for now, just
note that testosterone is only one of several hormones that the body
manufactures that affect the prostate.
Now let’s consider prostate cancer. First and foremost, prostate
cancer is a hormonally driven disease. Like breast cancer in women, prostate
cancer cells require, at least initially, the presence of a chemical to allow
their growth and reproduction. In the case of prostate cancer, this chemical
is the hormone testosterone. As you might have guessed, DHT also is strongly
linked to prostate cancer. It has
been argued that its presence is a major factor in several prostate
conditions, including benign prostate hyperplasia (enlarged prostate).
Testosterone plays an important role in all phases of prostate cancer. First,
it is the fuel that provides the energy to push the cells of the prostate
beyond their normal boundaries. Laboratory and clinical studies have shown
that it is very likely that prostate cancer is the result of a combination of
three factors: genetics, carcinogens and testosterone.
Many men have what is called a “genetic predisposition” to
prostate problems, and particularly prostate cancer.
It has been known for many years that prostate cancer “runs in
families” and is made much more likely by the presence of altered genetic
materials. Another factor which makes prostate cancer more likely is the
presence of carcinogens in the environment. In the Bay Area prostate cancer is
much more prevalent than most of the country and scientific studies have
pointed toward the presence of heavy metals, such as lead, arsenic and mercury
in the water supply. But it is unlikely that these factors alone would be
enough without the presence of testosterone.
Testosterone has the effect of driving prostate cells to grow and
reproduce, and if there is a genetic and/or carcinogenic factor present, then
often the combination will create enough stress in the cells to cause some of
them to fail to reproduce correctly. Usually there is a fail-safe mechanism
which causes the abnormal cells to die. The fancy term for this is “apoptosis.”
But occasionally this fail-safe system itself fails and the abnormal
cells begin to reproduce. A
condition called “Prostatic Intraepithelial Neoplasia”
or PIN for short is believed to be the first sign of this development. PIN is
a recognizable difference in the prostate cells, but isn’t actually cancer,
because it does not exhibit uncontrolled growth and reproduction of cells. But
if the presence of genetics or carcinogens combined with testosterone
continues, they trigger a process called mutation may cause the cells to
progress from PIN to prostate cancer. Mutation is the disturbance of the
genetic material of the cells, either from the chemical action of carcinogens,
or hereditary defects passed on from the parents. And if enough of these
mutations occur, eventually a cell is created which not only is abnormal, but
also reproduces uncontrollably. This, of course, is prostate cancer.
But it doesn’t stop there. Once prostate cancer occurs, the
mutations continue. It is believed that by the time they die (usually of
something else) as many as one out of three men have prostate cancer. And men
may develop early stages of prostate cancer even as young as twenty or thirty
years of age. Why then do so few men die of prostate cancer? The simple answer
is that it takes many stages of mutation until the cancer cells become really
dangerous. This is usually measured in the patient by the familiar “Gleason
Grade” which is used to indicate the degree of abnormal appearance of the
cells. Early prostate cancer, with a Gleason Grade of 1 or 2 is not thought to
be very dangerous. But as the cells mutate more and more, their appearance
becomes more abnormal and cells with a Gleason Grade of 4 or 5 are likely to
go on a rampage, invading other tissue in the body.
The original diagram illustrating the grades by Dr. Donald Gleason
is shown above. Note that the Gleason Grade may be from 1 to 5, but since the
two most prevalent grades are added together, the final number or “Gleason
Sum” may be from 2 to 10. Many people incorrectly refer to the Gleason Sum
as the “grade.”
How can we use hormones to prevent cancer?
Since hormones are one of the three factors which act together to
cause prostate cancer, it makes sense that we could start fighting the cancer
even before it occurs, by some manipulation of the hormone testosterone. There
are two approaches that can help in this way.
First, we can reduce the amount of testosterone the body creates.
This can be done without drugs, by altering the diet. It appears that
testosterone production in the body depends on a number of raw materials, one
of which is animal fat, from red meat in particular. By reducing the intake of
this fat, we can somewhat lower the level of testosterone. Another way to do
this is by the consumption of what are called “phyto-estrogens.”
These are vegetables, such as soy products, which mimic the activity of
the female hormones. When eaten, they act to reduce the production of
testosterone.
The other approach is to reduce the amount of testosterone which is
converted into DHT. Again, this can be accomplished by dietary methods. The
herb saw palmetto has a powerful ability to stop the production of DHT, by
inhibiting 5-alpha-reductase. There are also drugs such as finasteride
(Proscar) which have the same effect. Either or both of these approaches are
helpful to reduce the likelihood of developing prostate cancer, by reducing
the effect of testosterone on the prostate cells.
How can we use hormones to fight cancer?
Once the bridge has been crossed, and a man has prostate cancer,
there are many ways that hormones can be brought into the fight against the
disease. In this case, there are two main objectives in working with hormones:
- Reducing
further mutations of the cancer cells, and
- Stopping
their growth and reproduction.
Fortunately there are many techniques that have been developed in
the last few years to accomplish these goals. We will divide our discussion
into four categories:
Lifestyle,
diet and supplements,
First
line androgen deprivation therapy
Second
line tactics
Hormone-refractory
strategies.
But first we will look at some of the things which make hormone
therapy more of an art than a science.
Some things to keep in mind
The use of hormones against prostate cancer is actually still not
fully understood, even by researchers. This is because no one knows exactly
how the various types of cancer cells all react to the manipulation of
hormones. From the perspective of the patient, this can be frustrating,
because one frequently gets conflicting information from different sources.
Some doctors will tell you that hormone therapy is at best a holding action
and will fail in 18 months to three years, while others claim to have “cured”
prostate cancer by using hormone therapy. Probably the truth is somewhere in
between.
The problem is that unlike an infection, cancer is not a simple
disease. It now appears that there may be many different types of cancer cells
in a single tumor, and these cells react differently to hormone manipulation.
Pathologists have identified many different genetic abnormalities or “onco-genes”
which can be present in prostate cancer. These genetic variants each have
their own characteristics, including how dependent they are on testosterone.
To understand what this means, we might use as an example the
observations of the founder of the science of genetics, Charles Darwin. On one
of his expeditions,
Why are we spending so much time on this seemingly academic
subject? Because this effect, called “natural selection” has been observed
many times since in all kinds of organisms, including prostate cancer cells.
The last key to this puzzle is that the variation in prostate cancer cells is
their sensitivity to testosterone. Some cells will actually die if deprived of
testosterone, and if a prostate cancer patient is lucky enough to have all of
these cells, then depriving the cells of testosterone would actually cure him.
Unfortunately the chances of such a situation are very slim. The much more
common situation is that there are a range of cells, some of which are very
dependent on testosterone, and some of which are less so. There also may be
some cells that have no need of testosterone at all.
There is a fairly good correlation between the Gleason Grade of
cancer cells and their dependence on testosterone. It appears that for the
most part, low grade cells are the most dependent, while the high grade cells
are less so. So this is an important factor in predicting the success of
hormone treatment. Another correlating factor is the production of PSA
(prostate specific antigen). Tumors that produce a lot of PSA for a given size
generally seem to be much more responsive to hormone manipulation.
Lifestyle, diet and supplements
No discussion about the treatment of Prostate Cancer would be
complete without mention of the complementary approach. In this case, changes
in diet, lifestyle and nutritional supplements may accomplish many of the same
goals as more formal medical treatment. Of course, all nutritional or
lifestyle modifications should be done under the care of a doctor.
The famous financier Michael Milken was
diagnosed with metastatic prostate cancer in 1993,
and given a year or two to live. He resolved to fight his disease by every
means at his disposal, and immediately began researching the available
treatment options. His conclusion was that he needed to attack cancer on every
level: medical treatment, diet, supplements and exercise. He even hired a
personal chef to make sure his diet was managed in detail and made sweeping
lifestyle changes. Mr. Milken is today a major
philanthropist, heading the Prostate Cancer Foundation. The booklet “Nutrition
and Prostate Cancer” available from the Foundation gives the details of his
approach.
There are many stories like Milken’s
in which men diagnosed with prostate cancer have been successful in controlling
their disease through a holistic approach. If you look at the
approach taken, it usually includes activities that lower the level of
testosterone. It is not the intent of this brief article to cover all of the
nutritional information required to put together a prostate cancer diet, but
there are a wealth of sources on the Internet and from various organizations
such as the American Cancer Society, the Prostate Cancer Foundation, the
Prostate Cancer Research Institute, and others. Even if you don’t believe
that this approach can arrest or cure prostate cancer, there are proven
benefits from diet modification and the use of supplements such as lycopene,
green tea and soy products.
First line androgen deprivation therapy
The initial hormone treatment for prostate cancer is fairly well
defined. It typically consists of one, two or three drugs, as follows:
- An
LHRH agonist or antagonist, which may be combined with,
- An
anti-androgen, which may be combined with
- A
5-Alpha-Reductase Inhibitor
The combination of drugs described has the effect of
reducing the levels of testosterone from the normal range of 200
to 500 ng/ml (nano
grams per milliliter) down to less than 20. Here is a more detailed
description of the roles of each component of this therapy.
LHRH agonists/antagonists
Also called GnRH agonists/antagonists, These
are synthetic hormones which have the ultimate effect of shutting down the
testicles’ production of testosterone. The action of these drugs is to
interfere with the release of the luteinizing
hormone (LH) by the pituitary gland that tells the testicles to produce
testosterone. Examples of such drugs are Lupron (leuprolide
acetate), Zoladex (gosarelin
acetate), Trelstar
(triptorelin) and Plenaxis
(abarelix).
One problem with the older “agonist” drugs, including Lupron,
Zoladex and Trelstar,
is that because of a complex hormonal interaction, there is an initial “surge”
of testosterone when they are first administered. This surge may result in a
flare-up of the prostate cancer, possibly resulting in life-threatening
symptoms such as kidney failure or spinal cord compression. This surge can be
dealt with effectively by using an anti-androgen for several weeks prior to
starting the agonist drug. The newer antagonist drug Plenaxis
does not appear to have this problem. Unfortunately due to business problems
within the company that provides this drug, it is no longer available except
to current users.
These
drugs are all administered by injection, and are designed to remain active for
a month or more in the body. Some are available in a 3 or 4 month injection,
but some research has shown that by the end of this time, the activity of the
drug has decreased, and there may be some danger of increase in levels of
testosterone.
The disappearance of testosterone caused by these drugs can have
many undesirable side effects. These include osteoporosis, the weakening of
the skeletal bones, as well as weight gain, general lowering of energy level
and lethargy. These can be treated with drugs, diet modification and exercise.
It is also important to know that these drugs do not completely
eliminate all of the testosterone in the body. This is because the adrenal
glands, a pair of small glands attached to the kidneys, also make a small
amount of a testosterone precursor called DHEA, some of which is converted to
testosterone by the prostate. After a period ranging from months to years, it
may be possible for some cancer cells which are exceptionally sensitive to
testosterone to begin to grow rapidly in this environment, and the PSA will
begin to rise.
Anti-Androgens
This family of drugs acts directly on the prostate cancer cells. As
mentioned earlier, prostate cells (both cancerous and normal) have tiny
receptors in their nucleus which are activated by testosterone, causing them
to grow and divide. Anti-androgens are designed to look to like testosterone
molecules to these receptors. But the drug molecules do not activate the
growth and division of the cell. Instead they “plug up” the receptors so
testosterone molecules cannot get in. This effectively prevents the normal
cell division process. Examples of these drugs are Eulixin
(flutamide), Casodex (bicalutamide)
and Nilandron (nilutamide).
These drugs are normally taken by mouth one or more times a day. Because they
are all somewhat toxic to the liver, the patient should have blood work done
to monitor liver function on a regular basis.
5-Alpha-Reductase Inhibitors
As mentioned above, these drugs block the conversion of normal
testosterone to the more active DHT. By doing this, the effective amount of
testosterone is reduced. Examples of these drugs are Proscar (finasteride)
and Avodart (dutasteride).
There is some controversy in the medical profession as to whether
it is appropriate to use these drugs in combination with the other two types,
and also whether they should be continued after hormone therapy is stopped.
One line of reasoning is that these drugs may “artificially” lower the PSA
and give a false sense of security to the patient. However, the logic of this
position is questionable, as PSA is an indication of tumor activity and as
such, lower PSA is probably indicates a lower tumor burden. On
the other hand, some researchers believe that 5-alpha-reductase inhibitors
modify the hormonal environment in such a way as to promote the growth of more
dangerous cancer cells. At this point the answer to this question has not been
agreed to.
Intermittant Hormone Therapy
Another version of first line hormone therapy is what is called “intermittent
hormone therapy.” This is simply an interrupted or cycled version of hormone
therapy, in which the therapy is stopped after the PSA drops to an “undetectable”
level, and is re-started when it rises to a predetermined trigger point. There
is a great deal of discussion over what these levels and trigger points should
be, but many authorities agree that the PSA should bottom out for at least two
or three months, and the treatment should resume when the PSA reaches one-half
the pre-treatment value. There are two arguments for using intermittent
therapy:
It allows the patient to enjoy the benefits of testosterone for at
least part of the time, and It may postpone the
time when hormone therapy fails.
Second line tactics
At some point after months to years of hormone therapy, the PSA may
slowly begin to rise. This is frequently mistaken for “hormone refractory”
or “androgen independent” disease. But in fact this may not be the case at
all. What may be closer to the truth is that many of the cancer cells are so
sensitive to testosterone that they can survive on the very low levels
achieved with first line hormone therapy. Another possibility is that the
cells have adapted to use the anti androgen in place of testosterone.
There are usually a few cells that are completely fooled by the drug
molecules – that is, they actually are triggered by the drug just like they
are by testosterone. Gradually, by natural selection, these cells begin to
increase in numbers, and after a period of months to years, dominate the
cancer cell population. This is referred to as “receptor mutation” and at
this point, one will begin to see an increase in PSA.
AAWR and Anti-Androgen Substitution
It may be possible to trick these cells by stopping the
anti-androgen. This sometimes has the same effect as reducing testosterone,
and the PSA falls as the cells are suppressed. This is referred to as an “anti-androgen
withdrawal response” or AAWR. If this approach does not work or stops
working after a short time, the next tactic is to substitute a different
anti-androgen drug. For example, if you were taking Casodex and it failed, you
might have a response from Nilandron or Eulexin.
Some patients are able to get one or more additional years of response from
this drug switching tactic.
Ketoconazole
If the removal or switching of anti-androgens does not prove
successful, or fails after a time, then the next thing to try is to reduce
testosterone virtually to zero. This can be accomplished by changing from
anti-androgen to a drug called ketoconazole which
suppresses the production of the testosterone precursor DHEA by the adrenal
glands. Ketoconazole also suppresses production of
testosterone by the testicles, but many authorities advise continuing with
LHRH agonist/antagonist treatment as well.
Ketoconazole,
which has a trade name of Nizoral, was originally
sold as a systemic anti-fungal medication. It is taken by mouth, and should be
accompanied by a small dose of cortisone to replace the natural cortisone no
longer produced by the adrenal glands. Ketoconazole
is normally taken in a daily dose of 1200 milligrams divided into three parts,
and accompanied by a daily divided dose of 30 milligrams of cortisone.
Incidentally, pharmacists frequently balk at filling a prescription for such a
large dose, and often will require confirmation from the oncologist. Ketoconazole
should ideally be taken with an acidic type of food such as orange juice or tomatoes,
which helps the body absorb the medication. It is also important to
monitor the liver function, as ketoconazole can be
toxic to the liver. Ketoconazole also may have
other side effects such as anorexia and sticky skin.
The response from ketoconazole has been
observed to last from a few months to as much as two years, depending on the
types of cancer cells present. If problems such as liver toxicity occur with
the high dosage mentioned above, some success has been achieved with a reduced
dosage of about one-half the normal amount. This “low-dose keto”
approach could be considered as an alternative.
Estrogen
One other treatment that is sometimes used successfully in a second
line situation is some form of estrogen (female hormone), usually diethyl stilbesterol
or DES. This has a powerful suppressing action on prostate cancer. For reasons
which are not completely understood, DES works in many cases after the normal
hormone treatment fails. However it also has the dangerous property of causing
blood clots and what is called deep vein thrombosis. This danger can be
alleviated somewhat by the used of anti clotting agents such as coumadin.
Because of this danger, the manufacture of DES was stopped some years
ago, and now the only sources of the drug are hard-to-find compounding
pharmacies.
Hormone refractory strategies
At some point, cancer cells which have no need for testosterone
will, by natural selection, begin to dominate the population of the tumor.
This is usually indicated by a rising PSA, despite any kind of hormonal
treatment, and typically this is the point at which oncologists recommend the
use of chemotherapy. However, even though the hormone therapy appears not to
be working, it does not necessarily make sense to discontinue it. The logic
here is that there are still a large number of cancer cells which are
sensitive to testosterone, that have become dormant or inactive. Allowing the
testosterone to be replenished could trigger renewed activity of these dormant
cells, and greatly increase the active tumor cell population.
Another factor is the evidence that ketoconazole
is actually toxic to cancer cells, and may help to increase the effectiveness
of other treatments such as chemotherapy. So it may make sense to continue its
use after the PSA begins to rise. In the final analysis, one should always
weigh the benefits of any treatment against the side effects and risks of
continuing it.