Hormone Therapy for Prostate Cancer

Hormone therapy is also called androgen suppression therapy. The goal of this treatment is to reduce levels of male hormones, called androgens, in the body, or to stop them from fueling prostate cancer cell growth.

Androgens stimulate prostate cancer cells to grow. The main androgens in the body are testosterone and dihydrotestosterone (DHT). Most androgens are made by the testicles, but the adrenal glands (glands that sit above your kidneys) as well as the prostate cancer cells themselves, can also make androgens.

Lowering androgen levels or stopping them from getting into prostate cancer cells often makes prostate cancers shrink or grow more slowly for a time. But hormone therapy alone does not cure prostate cancer.

When is hormone therapy used?

Hormone therapy may be used:

• If the cancer has spread too far to be cured by surgery or radiation, or if you can’t have these treatments for some other reason
• If the cancer remains or comes back after treatment with surgery or radiation therapy
• Along with radiation therapy as the 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.

Treatment to lower testicular androgen levels

Androgen deprivation therapy, also called ADT, uses surgery or medicines to lower the levels of androgens made by the testicles.

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 (such as testosterone and DHT) are made. This causes most prostate cancers to stop growing or shrink for a time.

This is done as an outpatient procedure. It is probably the least expensive and simplest form of hormone therapy. But unlike some of the other treatments, it is permanent, and many men have trouble accepting the removal of their testicles. Because of this, they may choose treatment with drugs that lower hormone levels (such as an LHRH agonist or antagonist) instead.

Some men having this surgery are concerned about how it will look afterward. If wanted, artificial testicles that look much like normal ones can be inserted into the scrotum.

LHRH agonists

Luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or GnRH agonists) are drugs that lower the amount of testosterone made by the testicles. Treatment with these drugs is sometimes called medical castration because they lower androgen levels just as well as orchiectomy.

With these drugs, the testicles stay in place, but they will shrink over time, and they may even become too small to feel.

LHRH agonists 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 every 6 months. The LHRH agonists available in the United States include:

• Leuprolide (Lupron, Eligard)
• Goserelin (Zoladex)
• Triptorelin (Trelstar)
• Leuprolide mesylate (Camcevi)

When LHRH agonists are first given, testosterone levels go up briefly before falling to very low levels. This effect, called tumor flare, results from the complex way in which these drugs work. Men whose cancer has spread to the bones may have bone pain. Men whose prostate gland has not been removed may have trouble urinating. If the cancer has spread to the spine, even a short-term increase in tumor growth as a result of the flare could press on the spinal cord and cause pain or paralysis. A flare can be avoided by giving drugs called anti-androgens (discussed below) for a few weeks when starting treatment with LHRH agonists.

LHRH antagonists

LHRH antagonists can be used to treat advanced prostate cancer. These drugs work in a slightly different way from the LHRH agonists, but they lower testosterone levels more quickly and don’t cause tumor flare like the LHRH agonists do. Treatment with these drugs can also be considered a form of medical castration.

• Degarelix (Firmagon) is given as a monthly injection under the skin. Some men may notice problems at the injection site (pain, redness, and swelling).
• Relugolix (Orgovyx) is taken as pills, once a day, so it might allow for less frequent office visits.

Possible side effects

Orchiectomy and LHRH agonists and antagonists can all cause similar side effects from lower levels of hormones such as testosterone. These side effects can include:

• Reduced or absent sexual desire
• Erectile dysfunction (impotence)
• Shrinkage of testicles and penis
• Hot flashes, which may get better or go away with time
• Breast tenderness and growth of breast tissue (gynecomastia)
• 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 levels
• 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.

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

• Hot flashes can often be helped by treatment with certain antidepressants or other drugs.
• Brief radiation treatment to the breasts can help prevent their enlargement, but this is not effective once breast enlargement has occurred.
• Several drugs can help prevent and treat osteoporosis.
• Depression can be treated with 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 thinking, concentrating, and/or with memory, but this has not been studied thoroughly. 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.

Treatment to lower androgen levels from other parts of the body

LHRH agonists and antagonists can stop the testicles from making androgens, but cells in other parts of the body, such as the adrenal glands, and prostate cancer cells themselves, can still make male hormones, which can fuel cancer growth. Some drugs can block the formation of androgens made by these cells.

Abiraterone (Zytiga) blocks an enzyme (protein) called CYP17, which helps stop these cells from making androgens.

Abiraterone can be used in men with advanced prostate cancer that is either:

• High risk (cancer with a high Gleason score, spread to several spots in the bones, or spread to other organs) 
• Castration-resistant (cancer that is still growing despite low testosterone levels from an LHRH agonist, LHRH antagonist, or orchiectomy)

This drug is taken as pills every day. It doesn’t stop the testicles from making testosterone, so men who haven’t had an orchiectomy need to continue treatment with an LHRH agonist or antagonist. Because abiraterone also lowers the level of some other hormones in the body, prednisone (a corticosteroid drug) needs to be taken during treatment as well to avoid certain side effects.

Ketoconazole (Nizoral), first used for treating fungal infections, also blocks production of androgens made in the adrenal glands, much like abiraterone. It's 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 working.

Ketoconazole also can block the production of cortisol, an important steroid hormone in the body, so men treated with this drug often need to take a corticosteroid (such as prednisone or hydrocortisone).

Possible side effects: Abiraterone can cause joint or muscle pain, high blood pressure, fluid buildup in the body, hot flashes, upset stomach, and diarrhea. Ketoconazole can cause elevated liver blood tests, nausea, vomiting, gynecomastia (enlargement of breast tissue in men) and a skin rash.

Drugs that stop androgens from working

Anti-androgens

For most prostate cancer cells to grow, androgens have to attach to a protein in the prostate cancer cell called an androgen receptor. Anti-androgens are drugs that also connect to these receptors, keeping the androgens from causing tumor growth. Anti-androgens are also sometimes called androgen receptor antagonists.

Drugs of this type include:

• Flutamide (Eulexin)
• Bicalutamide (Casodex)
• Nilutamide (Nilandron)

They are taken daily as pills.

In the United States, anti-androgens are not often used by themselves:

• An anti-androgen may be added to treatment if orchiectomy or an LHRH agonist or antagonist is no longer working by itself.
• An anti-androgen is also sometimes given for a few weeks when an LHRH agonist is first started. This can help prevent a tumor flare.
• An anti-androgen can also be combined with orchiectomy or an LHRH agonist 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 agonist alone. If there is a benefit, it appears to be small.
• In some men, if an anti-androgen is no longer working, simply stopping the anti-androgen can cause the cancer to stop growing for a short time. This is called the anti-androgen withdrawal effect, although it is not clear why it happens.

Possible side effects: Anti-androgens have similar side effects to LHRH agonists, LHRH antagonists, and orchiectomy, but they may have fewer sexual side effects. When these drugs are used alone, sexual desire and erections 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.

Newer anti-androgens

Enzalutamide (Xtandi), apalutamide (Erleada) and darolutamide (Nubeqa) are newer types of anti-androgens. They can sometimes be helpful even when older anti-androgens are not.

• All of these drugs can be helpful in men with cancer that has not spread but is no longer responding to other forms of hormone therapy (known as non-metastatic castration-resistant prostate cancer (CRPC), described below).
• Enzalutamide can also be used for metastatic prostate cancer (cancer that has spread), whether it is castration-resistant or castration-sensitive (still responding to other forms of hormone therapy).
• Apalutamide and darolutamide can also be used for metastatic castration-sensitive prostate cancer (CSPC), also known as hormone-sensitive prostate cancer (HSPC), described below.

These drugs are taken as pills each day.

Side effects can include diarrhea, fatigue, rash, and worsening of hot flashes. These drugs can also cause some nervous system side effects, including dizziness and, rarely, seizures. Men taking one of these drugs are more likely to fall, which may lead to injuries. Some men have also had heart problems when taking these newer types of anti-androgens.

Other androgen-suppressing drugs

Estrogens (female hormones) were once the main alternative to removing the testicles (orchiectomy) for men with advanced prostate cancer. Because of their possible side effects (including blood clots and breast enlargement), estrogens have been replaced by other types of hormone therapy. Still, estrogens may be tried if other hormone treatments are no longer working.

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 observation or active surveillance in men with early-stage prostate cancer who do not want surgery or radiation. Studies have not found that these men live any longer than those who don’t get any treatment 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 levels are rising after surgery or radiation or men with advanced prostate cancer who don’t yet have symptoms, it’s not always clear when it is best to start hormone treatment. Some doctors think that hormone therapy works better if it’s 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 the disease down and perhaps even help men live longer.

But not all doctors agree with this approach. Some are waiting for more evidence of benefit. They feel that because of the side effects of hormone therapy and the chance that the cancer could become resistant to therapy sooner, treatment shouldn’t be started until a man has symptoms from the cancer. This issue is being studied.

Intermittent versus continuous hormone therapy

Most 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 might not be needed, so they advise intermittent (on-again, off-again) treatment. This can allow for a break from side effects like decreased energy, sexual problems, and hot flashes.

In one form of intermittent hormone therapy, 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.

At this time, it isn’t clear how this approach compares to continuous hormone therapy. Some studies have found that continuous therapy might help men live longer, but other studies have not found such a difference.

Combined androgen blockade (CAB)

Some doctors treat patients with 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 starting with one drug alone when treating prostate cancer that has spread to other parts of the body.

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.

Castration-sensitive, castration-resistant, and hormone-refractory prostate cancer

These terms are sometimes used to describe how well a man's prostate cancer is responding to hormone therapy.

• Castration-sensitive prostate cancer (CSPC), also known as hormone-sensitive prostate cancer (HSPC), means the cancer is being controlled by keeping the testosterone level as low as what would be expected if the testicles were removed by castration. Levels can be kept this low with an orchiectomy, or by taking an LHRH agonist or an LHRH antagonist.
• Castration-resistant prostate cancer (CRPC) means the cancer is still growing even when the testosterone levels are at or below the level that would be expected with castration. Some of these cancers might still be helped by other forms of hormone therapy, such as abiraterone or one of the newer anti-androgens.
• Hormone-refractory prostate cancer (HRPC) refers to prostate cancer that is no longer helped by any type of hormone therapy, including the newer medicines.