Hormone Therapy for Prostate Cancer
What are male sex hormones?
Hormones are chemicals secreted by certain glands into the bloodstream. They allow organs to communicate with each other. They affect the actions of cells and tissues in the body, often reaching their targets by traveling through the bloodstream.
Androgens (male sex hormones) are a type of hormones that control the development and maintenance of male characteristics. Testosterone and dihydrotesterone (DHT) are the most common androgens in men. Almost all testosterone is produced in the testicles, while a small amount is produced by the adrenal. The prostate cells may produce testosterone.
How do hormones stimulate the growth of prostate cancer?
Androgens are required for normal growth and function of the prostate. Androgens are also necessary for prostate cancers to grow. Androgens promote the growth of both normal and cancerous prostate cells by binding to and activating the androgen receptor, a protein that is expressed in prostate cells (1). Once activated, the androgen receptor stimulates the expression of specific genes that cause prostate cells to grow (2).
At first, prostate cancers need relatively high levels of androgens to grow. Such prostate cancers are referred to as androgen dependent or androgen sensitive because treatments that decrease androgen levels or block androgen activity can inhibit their growth.
Most prostate cancers eventually become “castration resistant,” which means that they can continue to grow even when androgen levels in the body are extremely low or undetectable.
What types of hormone therapy are used for prostate cancer?
- -Block the action of androgens in the body
- -Block the production of androgens throughout the body
Androgen production in men. Drawing shows that testosterone production is regulated by luteinizing hormone (LH) and luteinizing hormone-releasing hormone (LHRH). The hypothalamus releases LHRH, which stimulates the release of LH from the pituitary gland. LH acts on specific cells in the testes to produce the majority of testosterone in the body. Most of the remaining androgens are produced by the adrenal glands. Androgens are taken up by prostate cells, where they either bind to the androgen receptor directly or are converted to dihydrotestosterone (DHT), which has a greater binding affinity for the androgen receptor than testosterone.
Treatments that reduce androgen production by the testicles are the most commonly used hormone therapies for prostate cancer. These include:
- 1)Orchiectomy (removal of the testicles). This can reduce the level of testosterone in the blood by 90 to 95 percent (4). This type of treatment, called surgical castration, is permanent and irreversible.
- 2)Luteinizing hormone-releasing hormone (LHRH) agonists, which prevent the secretion of a hormone called luteinizing hormone. LHRH agonists (LHRH analogs) are synthetic proteins that are structurally similar to LHRH and bind to the LHRH receptor in the pituitary gland. LHRH is also known as gonadotropin-releasing hormone or GnRH, so LHRH agonists are also called GnRH agonists.) Normally, when androgen levels in the body are low, LHRH stimulates the pituitary gland to produce luteinizing hormone, which in turn stimulates the production of androgens by the testicles. LHRH agonists, like the body’s own LHRH, initially stimulate the production of luteinizing hormone. However, the continued presence of high levels of LHRH agonists actually causes the pituitary gland to stop producing luteinizing hormone, which prevents testosterone from being produced. Treatment with an LHRH agonist is called medical castration (sometimes called chemical castration) because it uses drugs to lower androgen levels in the body to the same extent as orchiectomy. But, unlike orchiectomy, the effects of these drugs on androgen production are reversible. Once treatment is stopped, androgen production usually resumes. LHRH agonists are given by injection or are implanted under the skin. Two LHRH agonists, leuprolide and goserelin, are approved to treat prostate cancer in the United States. When patients receive an LHRH agonist for the first time, they may experience a phenomenon called “testosterone flare.” This temporary increase in testosterone level occurs because LHRH agonists briefly cause the pituitary gland to secrete extra luteinizing hormone before blocking its release. The flare may worsen clinical symptoms (for example, bone pain, ureter or bladder outlet obstruction, and spinal cord compression), which can be a particular problem in men with advanced prostate cancer. The increase in testosterone is usually countered by giving another type of hormone therapy called antiandrogen therapy (described below) along with an LHRH agonist for the first few weeks of treatment.
- 3) LHRH antagonists, which are another form of medical castration. LHRH antagonists (also called GnRH antagonists) act by preventing LHRH from binding to its receptors in the pituitary gland, which in turn prevents the secretion of luteinizing hormone, causing the body’s androgen levels to drop. Unlike LHRH agonists, LHRH antagonists do not cause a testosterone flare. One LHRH antagonist, degarelix, is currently approved to treat advanced prostate cancer in the United States. It is given by injection.
- 4) Estrogens (hormones that promote female sex characteristics). Although estrogens are also able to inhibit androgen production by the testicles, they are seldom used today in the treatment of prostate cancer because of their side effects.
Treatments that block the action of androgens in the body include antiandrogens, which are drugs that compete with androgens for binding to the androgen receptor. By competing for binding to the androgen receptor, antiandrogens reduce the ability of androgens to promote prostate cancer cell growth. Because antiandrogens do not block androgen production, they are rarely used on their own to treat prostate cancer. Instead, they are used in combination with orchiectomy or an LHRH agonist. Use of an antiandrogen drug in combination with orchiectomy or an LHRH agonist is called combined androgen blockade, complete androgen blockade, or total androgen blockade. Antiandrogens that are approved in the United States to treat prostate cancer include flutamide, enzalutamide, bicalutamide, and nilutamide. Antiandrogens are given as pills to be swallowed.
Treatments that block the production of androgens throughout the body include:
- Drugs that prevent the production of androgens by the adrenal glands and prostate cancer cells themselves, as well as by the testicles. Neither medical nor surgical castration blocks the adrenal glands and prostate cancer cells from producing androgens. Even though the amounts of androgens they produce are small, these amounts can be enough to support the growth of some prostate cancers. Drugs that prevent the adrenal glands (as well as the testicles and prostate cancer cells) from making androgens, which are called androgen synthesis inhibitors, can lower testosterone levels in a man’s body to a greater extent than any other known treatment. These drugs block testosterone production by inhibiting an enzyme called CYP17. This enzyme, which is found in testicular, adrenal, and prostate tumor tissues, plays a central role in allowing the body to produce testosterone from cholesterol. Three androgen synthesis inhibitors are approved in the United States. All are given as pills to be swallowed. Two of these, ketoconazole and aminoglutethimide, are approved for indications other than prostate cancer but are sometimes used as second-line treatments for castration-resistant prostate cancer. The third, abiraterone acetate, is approved to treat metastatic castration-resistant prostate cancer.
How is hormone therapy used to treat prostate cancer?
- 1)Adjuvant hormone therapy. Hormone therapy that is given after other primary treatments to lower the risk that prostate cancer will come back is called adjuvant hormone therapy. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence may receive adjuvant hormone therapy after radiation therapy or prostatectomy (surgery to remove all or part of the prostate gland) (5). Factors that are used to determine the risk of prostate cancer recurrence include the tumor’s grade (as measured by the Gleason score), the extent to which the tumor has spread into surrounding tissue, and whether or not tumor cells are found in nearby lymph nodes. Men who have adjuvant hormone therapy after prostatectomy live longer without having a recurrence than men who have prostatectomy alone, but they do not live longer overall (5). Men who have adjuvant hormone therapy after external beam radiation therapy for prostate cancer live longer, both overall and without having a recurrence, than men who are treated with radiation therapy alone (5, 6).
- 2) Neoadjuvant hormone therapy. Hormone therapy given before other treatments is called neoadjuvant hormone therapy. Men with early-stage prostate cancer that has an intermediate or high risk of recurrence often receive hormone therapy before or during radiation therapy, in addition to receiving hormone therapy after radiation therapy. Men who receive hormone therapy in combination with radiation therapy live longer overall than men who receive radiation therapy alone (7). The use of neoadjuvant hormone therapy (alone or in combination with chemotherapy) before prostatectomy has not been shown to prolong survival and is not a standard treatment.
- 3) Hormone therapy alone. Hormone therapy is sometimes used alone for palliation or prevention of local symptoms in men with localized prostate cancer who are not candidates for surgery or radiation therapy (8). Such men include those with a limited life expectancy, those with advanced local tumor stage, and/or those with other serious health conditions. Hormone therapy used alone is also the standard treatment for men who have a prostate cancer recurrence documented by CT, MRI, or bone scan after treatment with radiation therapy or prostatectomy. Hormone therapy is often recommended for men who have a “biochemical” recurrence—a rapid rise in prostate-specific antigen (PSA) level—especially if the PSA level doubles in fewer than 12 months. However, a rapid rise in PSA level does not necessarily mean that the prostate cancer itself has recurred. The use of hormone therapy in the case of a biochemical recurrence is somewhat controversial. Finally, hormone therapy used alone is also the standard treatment for men who are found to have metastatic disease (i.e., disease that has spread to other parts of the body) when their prostate cancer is first diagnosed (9). Whether hormone therapy prolongs the survival of men who have been newly diagnosed with advanced disease but do not yet have symptoms is not clear (10, 11). Moreover, because hormone therapy can have substantial side effects, some men prefer not to take hormone therapy before symptoms develop.
The length of treatment with hormone therapy for prostate cancer depends on a man’s risk of recurrence, which is based on the clinical stage (the amount or spread of cancer in the body), Gleason score (system of grading prostate cancer tissue based on how it looks when examined under a microscope), and PSA level. For men with intermediate-risk prostate cancer, hormone therapy is generally given for 4 to 6 months; for men with high-risk disease it is generally given for 18-24 months.
Many prostate cancers that initially respond to hormone therapy with LHRH agonists, LHRH antagonists, or orchiectomy eventually stop responding to this treatment. This is referred to as castration-resistant prostate cancer. Castration-resistant prostate cancers need much lower levels of androgen to grow than androgen-sensitive cancers.
Several potential mechanisms may allow prostate cancer cells to grow even when androgen levels are very low, including increased production of androgen receptor molecules within the cells (either through an increase in the expression of the androgen receptor gene or an increase in the number of copies of the androgen receptor gene per cell), a change in the androgen receptor gene such that it produces a more active protein, and changes in the activities of proteins that help control the function of the androgen receptor (12,13).
Doctors cannot predict how long hormone therapy will be effective in suppressing the growth of any individual man’s prostate cancer. Therefore, men who take hormone therapy for more than a few months will be regularly tested to determine the level of PSA in their blood. An increase in PSA level may indicate that a man’s cancer has started growing again. A PSA level that continues to increase while hormone therapy is successfully keeping androgen levels extremely low is an indicator that a man’s prostate cancer has become resistant to the hormone therapy that is currently being used.
What are the treatment options for castration-resistant prostate cancer?
Treatments for castration-resistant prostate cancer include:
- 1) Antiandrogens, such as flutamide, bicalutamide, nilutamide, and enzalutamide
- 2) Androgen synthesis inhibitors, such as ketoconazole, aminoglutethamide, and abiraterone acetate
- 3) Immunotherapy using a cell-based vaccine called sipuleucel-T. This vaccine uses a man’s own immune cells to fight metastatic prostate cancer that has become resistant to hormone therapy.
- 4) Chemotherapy, most commonly with the drug docetaxel. Another drug, cabazitaxel, is approved for the treatment of metastatic castration-resistant prostate cancer that was previously treated with docetaxel.
- 5) Radium 223 dichloride, a radiopharmaceutical approved to treat men with castration-resistant prostate cancer that has metastasized (spread) to the bones and is causing symptoms but has not spread to other organs. This drug collects in certain areas of bone, such as bone metastases, and gives off radiation that kills cancer cells.
Men with castration-resistant prostate cancer who receive these treatments will continue to take first-line hormone therapy (e.g., an LHRH agonist) to avoid an increase in testosterone level, which may lead to tumor progression in some men (14).
Randomized clinical trials have demonstrated that treatment with abiraterone acetate or enzalutamide prolongs survival among men with metastatic castration-resistant prostate cancer, whether or not they have previously received chemotherapy (15–18).
What are the side effects of hormone therapy for prostate cancer?
Both medical castration and surgical castration greatly reduce the amount of androgens produced by the body. Because androgens are used by many other organs besides the prostate, medical or surgical castration can have a wide range of side effects (3,19):
- -Loss of interest in sex (lowered libido)
- –Erectile dysfunction
- –Hot flashes
- -Loss of bone density
- -Bone fractures
- -Loss of muscle mass and physical strength
- -Changes in blood lipids
- –Insulin resistance
- -Mood swings
-Growth of breast tissue (gynecomastia)
Drugs that stop the adrenal glands from making androgens (i.e., the androgen synthesis inhibitors ketoconazole, aminoglutethimide, and abiraterone acetate) can cause diarrhea, itching and rashes, fatigue, erectile dysfunction (with long-term use), and, potentially, liver damage.
Estrogens avoid the bone loss seen with other kinds of hormone therapy, but they increase the risk of cardiovascular side effects, including heart attacks and strokes. Because of these side effects, estrogens are rarely used today as hormone therapy for prostate cancer.
Having adjuvant hormone therapy after radiation therapy worsens some adverse effects of radiotherapy, particularly sexual side effects and vitality (20). Many of the side effects of ongoing hormone therapy also become stronger the longer a man takes hormone therapy (19).
How can we reduce the side effects of hormone therapy?
Men who lose bone mass during long-term hormone therapy may be prescribed drugs to slow or reverse this loss. The drugs zoledronic acid and alendronate (which belong to a class of drugs called bisphosphonates) increase bone mineral density in men who are undergoing hormone therapy (21, 22). A newer drug, denosumab, which increases bone mass through a different mechanism than bisphosphonates (23), was approved in 2011 for use in men undergoing hormone therapy for prostate cancer. However, bisphosphonates and denosumab are associated with a rare but serious side effect called osteonecrosis of the jaw (14).
Exercise may help reduce some of the side effects of hormone therapy, including bone loss, muscle loss, weight gain, fatigue, and insulin resistance (14, 24). Several clinical trials are examining whether exercise is an effective strategy to reverse or prevent side effects of hormone therapy for prostate cancer.
The sexual side effects of hormone therapy for prostate cancer can be some of the most difficult to deal with. Erectile dysfunction drugs such as sildenafil citrate (Viagra®) do not usually work for men undergoing hormone therapy because these drugs do not affect loss of libido (sexual desire).
When most men stop taking a reversible hormone therapy, the sexual and emotional side effects caused by low levels of androgens will eventually go away. However, if a man has been taking hormone therapy for many years, these side effects may not disappear completely. Some physical changes that have developed over time, such as bone loss, will remain after stopping hormone therapy.
Patients should be sure to tell their doctor about all medications they are taking, including over-the-counter herbal medicines. Some herbal medicines interact with drug-metabolizing enzymes in the body, which can adversely affect hormone therapy (25).
Does a reversible hormone therapy have to be taken continuously?
Researchers have investigated whether a technique called intermittent androgen deprivation can improve the effectiveness of hormone therapy for prostate cancer—that is, whether it delays the development of hormone resistance. With intermittent androgen deprivation, hormone therapy is given in cycles, with breaks between drug administrations, rather than continuously. An additional potential benefit of this approach is that the temporary break from the side effects of hormone therapy may improve a man’s quality of life.
Two clinical trials of intermittent versus continuous androgen deprivation found that intermittent therapy reduced some of the side effects of hormone therapy, including those involving sexual function. However, the trials did not show any improvement in overall survival with intermittent therapy (26, 27).
How is hormone therapy being tested in clinical trials?
Treatment in a clinical trial is an option for men with any stage of prostate cancer. Many questions about the best uses of hormone therapy still need to be answered. These include whether hormone therapy added to brachytherapy, a type of internal radiation therapy, can help improve survival for men with early-stage prostate cancer. Other questions include whether newer intensive hormone therapies may improve the outcome of men who are receiving surgery or radiation therapy for high-risk disease. Researchers are also testing new hormone therapies to treat castration-resistant prostate cancer. These include TAK-700 and VT-464 (28), which work in a way similar to abiraterone acetate.
Another question is the possible value of adding chemotherapy to hormone therapy as initial treatment for men with hormone-sensitive metastatic prostate cancer. Currently, chemotherapy is not used in these men until their disease progresses on hormone therapy (i.e., until it becomes hormone resistant). Early results of an NCI-sponsored trial that was conducted by two cancer cooperative groups—the Eastern Cooperative Oncology Group (ECOG) and the American College of Radiology Imaging Network (ACRIN)—suggest that men with hormone-sensitive metastatic prostate cancer who receive the chemotherapy drug docetaxel at the start of standard hormone therapy live longer than men who receive hormone therapy alone. The trial results suggested that men with the most extensive metastatic disease benefit the most from the early addition of docetaxel. A follow-up analysis will be performed to clarify the effect of this treatment on men with less extensive metastatic disease.
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- Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncology 2010; 11(11):1066-1073. [PubMed Abstract]
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