Hormone Treatment Basics
By Doug Thornton
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
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, Darwin observed a small bird called a finch on remote islands in the South Atlantic. Even though the birds were all of the same species there was an interesting variation in the length of their beaks. As the birds migrated from one island to another, their food supply changed. On some islands their normal food of seeds wasn’t plentiful. Now they had to survive by catching insects which burrowed into the bark of trees, and suddenly the few birds with very long beaks had a marked survival advantage, since they could get the insects out of the burrows in the trees. For a time, the population of finches dropped dramatically, but then an interesting thing happened: it began to rise again. What happened was that the environmental pressure of lack of food on the short-billed finches caused a gradual population shift to predominantly long-billed finches, and these began to reproduce and grow successfully.
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. Milkenis 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.
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.
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.
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.
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.
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.
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.