Hormone therapy is also called androgen deprivation therapy (ADT) or androgen suppression therapy. The goal is to reduce levels of male hormones, called androgens, in the body, or to prevent them from reaching prostate cancer cells.

The main androgens are testosterone and dihydrotestosterone (DHT). Androgens, which are made mainly in the testicles, stimulate prostate cancer cells to grow. Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. However, hormone therapy alone does not cure prostate cancer.

Hormone therapy may be used:

• If you are not able to have surgery or radiation or can’t be cured by these treatments because the cancer has already spread beyond the prostate gland
• If your cancer remains or comes back after treatment with surgery or radiation therapy
• Along with radiation therapy as initial treatment if you are at higher risk of the cancer coming back after treatment (based on a high Gleason score, high PSA level, and/or growth of the cancer outside the prostate)
• Before radiation to try to shrink the cancer to make treatment more effective

Types of hormone therapy

Several types of hormone therapy can be used to treat prostate cancer.

Orchiectomy (surgical castration)

Even though this is a type of surgery, its main effect is as a form of hormone therapy. In this operation, the surgeon removes the testicles, where most of the androgens (testosterone and DHT) are made. With this source removed, most prostate cancers stop growing or shrink for a time.

This is done as a simple outpatient procedure. It is probably the least expensive and simplest way to reduce androgen levels in the body. But unlike some of the other methods of lowering androgen levels, it is permanent, and many men have trouble accepting the removal of their testicles.

Some men having the procedure are concerned about how it will look afterward. If wanted, artificial silicone sacs can be inserted into the scrotum. These look much like testicles.

Luteinizing hormone-releasing hormone (LHRH) analogs

These drugs lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes calledchemical castration because they lower androgen levels just as well as orchiectomy.

Even though LHRH analogs (also called LHRH agonists) cost more than orchiectomy and require more frequent doctor visits, most men choose this method. These drugs allow the testicles to remain in place, but the testicles will shrink over time, and they may even become too small to feel.

LHRH analogs are injected or placed as small implants under the skin. Depending on the drug used, they are given anywhere from once a month up to once a year. The LHRH analogs available in the United States include leuprolide (Lupron^®, Eligard^®), goserelin (Zoladex^®), triptorelin (Trelstar^®), and histrelin (Vantas^®).

When LHRH analogs are first given, testosterone levels go up briefly before falling to very low levels. This effect is called flare and results from the complex way in which LHRH analogs work. Men whose cancer has spread to the bones may have bone pain. If the cancer has spread to the spine, even a short-term increase in growth could compress the spinal cord and cause pain or paralysis. Flare can be avoided by giving drugs called anti-androgens for a few weeks when starting treatment with LHRH analogs. (Anti-androgens are discussed further on.)

Luteinizing hormone-releasing hormone (LHRH) antagonists

LHRH antagonists work like LHRH agonists, but they reduce testosterone levels more quickly and do not cause tumor flare like the LHRH agonists do.

Degarelix (Firmagon^®) is an LHRH antagonist used to treat advanced prostate cancer. It is given as a monthly injection under the skin and quickly reduces testosterone levels. The most common side effects are problems at the injection site (pain, redness, and swelling) and increased levels of liver enzymes on lab tests. Other side effects are discussed in detail below.

Anti-androgens

Anti-androgens block the body’s ability to use any androgens. Even after orchiectomy or during treatment with LHRH analogs, the adrenal glands still make small amounts of androgens.

Drugs of this type, such as flutamide (Eulexin^®), bicalutamide (Casodex^®), and nilutamide (Nilandron^®), are taken daily as pills.

Anti-androgens are not often used by themselves. An anti-androgen may be added to treatment if orchiectomy or an LHRH analog is no longer working by itself. An anti-androgen is sometimes given for a few weeks when an LHRH analog is first started to prevent a tumor flare.

Anti-androgen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. This is called combined androgen blockade (CAB). There is still some debate as to whether CAB is more effective in this setting than using orchiectomy or an LHRH analog alone. If there is a benefit, it appears to be small.

Some doctors are testing the use of anti-androgens instead of orchiectomy or LHRH analogs. Several recent studies have compared the effectiveness of anti-androgens alone with that of LHRH agonists. Most found no difference in survival rates, but a few found anti-androgens to be slightly less effective.

If hormone therapy including an anti-androgen stops working, in some men the cancer will stop growing for a short time from simply stopping the anti-androgen. Doctors call this the anti-androgen withdrawal effect, although they are not sure why it happens.

Other androgen-suppressing drugs

Estrogens (female hormones) were once the main alternative to orchiectomy for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been largely replaced by LHRH analogs and anti-androgens. Still, estrogens may be tried if androgen deprivation is no longer working.

Ketoconazole (Nizoral^®), first used for treating fungal infections, blocks production of androgens. It is most often used to treat men just diagnosed with advanced prostate cancer who have a lot of cancer in the body, as it offers a quick way to lower testosterone levels. It can also be tried if other forms of hormone therapy are no longer effective.

Ketoconazole can block the production of cortisol, an important steroid hormone in the body. People treated with ketoconazole often need to take a corticosteroid (like hydrocortisone) to prevent the side effects caused by low cortisol levels.

Newer forms of hormone therapy

Researchers have developed newer forms of hormone therapy in recent years that may prove to be more effective than some of those now in use.

Abiraterone (Zytiga^®): Drugs such as LHRH agonists can stop the testicles from making androgens, but other cells in the body, including prostate cancer cells themselves, can still make small amounts, which may fuel cancer growth. Abiraterone blocks an enzyme called CYP17, which helps stop these cells from making certain hormones, including androgens.

Abiraterone can be used in men with advanced castrate-resistant prostate cancer (cancer that is still growing despite low testosterone levels either from LHRH agonists or orchiectomy). Abiraterone has been shown to shrink or slow the growth of some of these tumors and help some of these men live longer.

This drug is taken as a pill every day. Since this drug doesn’t stop the testicles from making testosterone, men who haven’t had an orchiectomy need to continue with LHRH agonist therapy. Because abiraterone lowers the level of certain other hormones in the body, prednisone (a cortisone-like drug) needs to be taken as well during treatment.

Enzalutamide (Xtandi^®): This drug is a newer type of anti-androgen. In order for androgens like testosterone to affect prostate cancer cells, they bind to a protein in the cells called the androgen receptor. The receptor then sends a signal for the cells to grow and divide. Enzalutamide (also known as MDV3100) blocks this signal from the androgen receptor to the cell.

In men with castrate-resistant prostate cancer who have already been treated with the chemotherapy drug docetaxel (Taxotere, enzalutamide has been shown to lower PSA levels, shrink or slow the growth of tumors, and help them live longer. This drug is also being studied to see if it can help men earlier in treatment.

Enzalutamide is a pill, with the most common dose being 4 pills each day. In studies of this drug, men stayed on LHRH agonist treatment, so it isn’t clear how helpful this drug would be in men with non-castrate levels of testosterone.

Other new drugs: Other new medicines such as orteronel have shown promise in early studies. They are now being tested against prostate cancer, but are only available through clinical trials at this time. These drugs are discussed in the section, “What’s new in prostate cancer research and treatment?”

Possible side effects of hormone therapy

Orchiectomy, LHRH analogs, and LHRH antagonists can all cause similar side effects due to changes in the levels of hormones such as testosterone and estrogen. These side effects can include:

• Reduced or absent libido (sexual desire)
• Impotence (erectile dysfunction)
• Hot flashes, which may get better or even go away with time
• Breast tenderness and growth of breast tissue
• Osteoporosis (bone thinning), which can lead to broken bones
• Anemia (low red blood cell counts)
• Decreased mental sharpness
• Loss of muscle mass
• Weight gain
• Fatigue
• Increased cholesterol
• Depression

Some research has suggested that the risk of high blood pressure, diabetes, strokes, heart attacks, and even death from heart disease is higher in men treated with hormone therapy, although not all studies have found this.

Anti-androgens have similar side effects. The major difference from LHRH agonists and orchiectomy is that anti-androgens may have fewer sexual side effects. When these drugs are used alone, libido and potency can often be maintained. When these drugs are given to men already being treated with LHRH agonists, diarrhea is the major side effect. Nausea, liver problems, and tiredness can also occur.

Abiraterone does not usually cause major side effects, although it can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea.

Enzalutamide can cause diarrhea, fatigue, and worsening of hot flashes. This drug can also cause some neurologic side effects, including dizziness and, rarely, seizures. Men taking this drug are more likely to have problems with falls, which may lead to injuries.

Many side effects of hormone therapy can be prevented or treated. For example:

• Hot flashes can often be helped by treatment with certain antidepressants.
• Brief radiation treatment to the breasts can help prevent their enlargement, but it is not effective once breast enlargement has occurred.
• Several different drugs are available to help prevent and treat osteoporosis.
• Depression can be treated by antidepressants and/or counseling.
• Exercise can help reduce many side effects, including fatigue, weight gain, and the loss of bone and muscle mass.

There is growing concern that hormone therapy for prostate cancer may lead to problems with thinking, concentration, and/or memory. But this has not been studied well in men getting hormone therapy for prostate cancer. Studying the possible effects of hormone therapy on brain function is hard, because other factors may also change the way the brain works. A study has to take all of these factors into account. For example, both prostate cancer and memory problems become more common as men get older. Hormone therapy can also lead to anemia, fatigue, and depression – all of which can affect brain function. Still, hormone therapy does seem to lead to memory problems in some men. These problems are rarely severe, and most often affect only some types of memory. More studies are being done to look at this issue.

Current issues in hormone therapy

There are many issues around hormone therapy that not all doctors agree on, such as the best time to start and stop it and the best way to give it. Studies are now looking at these issues. A few of them are discussed here.

Treating early stage cancer: Some doctors have used hormone therapy instead of watchful waiting or active surveillance in men with early (stage I or II) prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who do not receive any treatment at first, but instead wait until the cancer progresses or symptoms develop. Because of this, hormone treatment is not usually advised for early stage prostate cancer.

Early versus delayed treatment: For men who need (or will eventually need) hormone therapy, such as men whose PSA level is rising after surgery or radiation or men with advanced prostate cancer who do not yet have symptoms, it is not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if it is started as soon as possible, even if a man feels well and is not having any symptoms. Some studies have shown that hormone treatment may slow down the disease and perhaps even lengthen survival.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the likely side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment should not be started until a man has symptoms from the cancer. Studies looking at this issue are now under way.

Intermittent versus continuous hormone therapy: Nearly all prostate cancers treated with hormone therapy become resistant to this treatment over a period of months or years. Some doctors believe that constant androgen suppression may not be needed, so they advise intermittent (on-again, off-again) treatment.

In one form of intermittent therapy, hormone treatment is stopped once the PSA drops to a very low level. If the PSA level begins to rise, the drugs are started again. Another form of intermittent therapy uses hormone therapy for fixed periods of time – for example, 6 months on followed by 6 months off.

Clinical trials of intermittent hormonal therapy are still in progress. It is too early to say whether this new approach is better or worse than continuous hormonal therapy. However, one advantage of intermittent treatment is that for a while some men can avoid the side effects of hormonal therapy such as decreased energy, impotence, hot flashes, and loss of sex drive.

Combined androgen blockade (CAB): Some doctors treat patients with both androgen deprivation (orchiectomy or an LHRH agonist or antagonist) plus an anti-androgen. Some studies have suggested this may be more helpful than androgen deprivation alone, but others have not. Most doctors are not convinced there’s enough evidence that this combined therapy is better than one drug alone when treating metastatic prostate cancer.

Triple androgen blockade (TAB): Some doctors have suggested taking combined therapy one step further, by adding a drug called a 5-alpha reductase inhibitor – either finasteride (Proscar) or dutasteride (Avodart) – to the combined androgen blockade. There is very little evidence to support the use of this “triple androgen blockade” at this time.

“Castrate resistant” vs. “hormone refractory” prostate cancer: These terms are sometimes used to describe prostate cancers that are no longer responding to hormones, although there is a slight difference between the two.

“Castrate resistant” means the cancer is still growing despite the fact that hormone therapy (either an orchiectomy or an LHRH agonist or antagonist) is keeping the testosterone in the body at very low, “castrate” levels. Some men may be uncomfortable with this term, but it is specifically meant to refer to these cancers, some of which may still be helped by other forms of hormone therapy (and are therefore not completely “hormone refractory”).

“Hormone refractory” refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.