Hormone Therapy

In This Section:

• Normal testosterone function and synthesis
• Targeting prostate hormones
• LHRH agonists
• LHRH antagonists
• Antiandrogens
• Androgen synthesis inhibitors (super-antiandrogens)

Normal testosterone function and synthesis

Androgens are male sex hormones. The main androgen circulating in men's blood is testosterone. Testosterone is needed to develop and maintain male sex characteristics. About 85 to 90 percent is made by the testicles and about 10 to 15 percent is made by the adrenal glands and other body cells in healthy adult males.

Testosterone production begins when the hypothalamus in the brain detects low testosterone levels. In response, the hypothalamus releases luteinizing hormone-releasing hormone (LHRH), which is also called gonadotropin-releasing hormone (GnRH). LHRH travels to the pituitary gland, where it binds to LHRH receptors.

The pituitary gland responds by releasing a hormone called luteinizing hormone (LH) that travels to the testicles and stimulates the production of testosterone. When an increase in testosterone is detected by the hypothalamus and the pituitary gland, the release of LHRH and LH stops. When testosterone levels drop again, the cycle begins anew.

Testosterone released into the blood from the testicles can easily enter a prostate cell, bind to receptor proteins in the cytoplasm and enter the cell's nucleus. This androgen receptor complex then binds to specific sequences of DNA to regulate the expression of numerous genes involved in cell growth.

Targeting prostate hormones

Prostate cancer cells that grow in the presence of testosterone are called "androgen-dependent" and "androgen-sensitive." Androgen-dependent means "testosterone-dependent."

Prostate cancer cells that can still grow in the presence of very, very low levels of testosterone are called "castration-resistant" cancers. This type of prostate cancer can grow even when the testicles no longer supply the hormone. The cancer continues to thrive on the residual amount remaining in a patient's body. Other names for "castration-resistant" include androgen-independent, androgen-resistant or androgen-insensitive.

The goal of hormone therapy in prostate cancer is to interfere with the androgen signaling that is critical to the growth of both androgen-dependent and castration-resistant cancer cells.

Hormone therapy has many names. It is also called androgen deprivation therapy, hormonal ablation, androgen ablation, chemical castration, or surgical castration.

Interfering with the androgen signaling needed by prostate cancer to grow can be achieved in several ways. One approach uses agonists to suppress the pituitary gland's call for testosterone, prostate cancer's favorite androgen. These chemicals are called LHRH agonists.

Another technique uses antagonists to stop the production of testosterone in the testes and adrenal glands. These small molecule inhibitors are called LHRH antagonists.

A third therapy uses androgen receptor antagonists to inhibit the action of testosterone that has already been produced in androgen-dependent prostate cancer cells.

Finally, a new FDA-approved approach uses an androgen synthesis inhibitor to stop testosterone production from all sources in the patient's body. This is currently approved for men with castration-resistant prostate cancer.

We will review all four of these approaches in the next sections.

LHRH agonists

Binding of naturally occurring LHRH to its pituitary gland receptor initiates a cell signaling process that results in the release of LH, which in turn leads to testosterone production.

An LHRH agonist is a chemical that mimics naturally occurring LHRH without being identical to it. LHRH agonists are similar enough to the naturally occurring LHRH to bind to the LHRH receptors and produce a physiologic effect. At the same time, they are dissimilar enough to have different binding affinities, and the agonists remain bound to the receptors for a longer time.

As a result of the prolonged presence of the LHRH agonists and persistent release of LH, there is a sudden rise in testosterone. This spike in testosterone level is known as a "hormone flare."

After several days, the LHRH receptors become desensitized and are down-regulated. LH production decreases and testosterone level drops to level seen with surgical removal of the testicles.

LHRH antagonists

Binding of naturally occurring LHRH to its pituitary gland receptor initiates a cell signaling process that results in the release of LH, which in turn leads to testosterone production.

An LHRH antagonist is similar in structure to naturally occurring LHRH and competes with it for binding to the LHRH receptors.

Instead of promoting testosterone production, LHRH antagonists are small molecule inhibitors that interfere with the production of testosterone in the testes and adrenal glands.

They do this by preventing naturally occurring LHRH from binding to their receptors.

LHRH receptors with bound LHRH antagonists do not stimulate the release of LH. As a result of this interruption in the release of LH, the testicles stop producing testosterone and the body's androgen levels drop.

In contrast to LHRH agonists, LHRH antagonists do not cause a "hormone flare" because they do not have the same physiologic effect as LHRH.

Antiandrogens

Testosterone binds to androgen receptor proteins in the cytoplasm of prostate cells and enters the cell nucleus. This androgen receptor complex then binds to specific sequences of DNA to regulate the expression of numerous genes involved in cell growth.

Antiandrogens approved for cancer treatment target and inhibit this androgen action within androgen-dependent prostate cells. Antiandrogens are effectively androgen receptor antagonists.

When antiandrogens bind to androgen receptors within the prostate cancer cells, testosterone is unable to bind to its receptors and, in turn, is unable to stimulate cell growth to the same extent. This slows down the growth of prostate cancer.

Antiandrogens are usually given before treatment with, or in combination with, an LHRH agonist.

Androgen synthesis inhibitors (super-antiandrogens)

An androgen synthesis inhibitor is a very recent addition to the treatment arsenal for prostate cancer. This new agent is an improvement to existing hormone therapies because it can drop testosterone levels in a man's body lower than can be achieved by any other known treatment. For this reason, it is being nicknamed a super-antiandrogen.

Castration-resistant prostate cancer is hard to treat because it may grow in the presence of very low levels of testosterone. In these cases, an androgen synthesis inhibitor may be a better treatment option. An androgen synthesis inhibitor, or super-antiandrogen, can lower testosterone levels even more than was previously possible. It is FDA-approved to treat men diagnosed with castration-resistant prostate cancer.

Zytiga™ (abiraterone acetate) is a new androgen synthesis inhibitor. It blocks the synthesis of testosterone from all three locations: the testes, the adrenal glands, and prostate cancer cells themselves.

Zytiga™ works by blocking the action of an enzyme called CYP17. This enzyme plays a central role in allowing the body to produce testosterone from cholesterol.

This new targeted therapy is FDA-approved for use in castration-resistant prostate cancer that has previously been treated with docetaxel.

Self Test

Questions

1. Where does signaling for more testosterone production begin?
   1. In the pituitary gland
   2. In the testes
   3. In the hypothalamus
   4. In the prostate cancer cell
   
   
2. Where does testosterone go once released from a man's testicles?
   1. Into the nucleus of his prostate cells
   2. Into the cytoplasm of his prostate cells
   3. Into the nucleus of prostate cancer cells
   4. All of the above
   
   
3. Which of these are hormone therapy strategies in prostate cancer to deprive testosterone-dependent cancer cells of androgenic stimulation?
   1. Target and suppress the pituitary gland's call for testosterone
   2. Target and inhibit production of testosterone in the testicles and adrenal glands
   3. Target and inhibit androgen action in androgen-dependent prostate cells
   4. All of the above
   
   
4. When a patient's prostate cancer continues to grow even after testosterone has been inhibited, the cancer is called castration-resistant. What other way can this condition be described?
   1. Androgen-independent
   2. Androgen-resistant
   3. Androgen-insensitive
   4. All of the above
   
   
5. Which best describes the binding affinity of LHRH agonists to LHRH receptors on a man's pituitary cells?
   1. In the pituitary gland
   2. They remain bound for a shorter time than normal LHRH
   3. They remain bound for a longer time than LHRH
   4. In the prostate cancer cell
   
   
6. When LHRH antagonists bind to the LHRH receptors and prevent naturally occurring LHRH from doing so, what effects does this have?
   1. There is an increase in the release of LH
   2. The testicles stop producing testosterone
   3. The androgen levels drop
   4. There is a "hormone flare"
   5. Both B and C
   
   
7. How do antiandrogens slow the growth of prostate cancer cells?
   1. They slow testosterone binding to its receptor, which inhibits cell growth
   2. They stop the production of testosterone
   3. They prevent testosterone from signaling the hypothalamus
   4. They bind to testosterone directly so testosterone can't bind to other receptors
   
   
8. A new drug named abiraterone acetate is called a super-antiandrogen because it blocks testosterone in which of these locations?
   1. In the testes
   2. In the adrenal glands
   3. In prostate cancer cells
   4. All of the above
   
   

Answers

1. Correct answer to Question 1: c
   1. In the pituitary gland. Although the pituitary gland is involved in the signaling pathway, signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
   2. In the testes. The signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
   3. In the hypothalamus. The signaling for more testosterone production begins when the hypothalamus in the brain detects low testosterone levels.
   4. In the prostate cancer cell. The signaling begins when the hypothalamus in the brain detects low testosterone levels.
   
   
2. Correct answer to Question 2: d
   1. Into the nucleus of his prostate cells. There is a better answer.
   2. Into the cytoplasm of his prostate cells. There is a better answer.
   3. Into the nucleus of prostate cancer cells. There is a better answer.
   4. All of the above. Testosterone released into the blood from the testicles can easily enter prostate cells (cancerous and noncancerous), bind to receptor proteins in the cytoplasm, and enter the cell nucleus.
   
   
3. Correct answer to Question 3: d
   1. Target and suppress the pituitary gland's call for testosterone. There is a better answer.
   2. Target and inhibit production of testosterone in the testicles and adrenal glands. There is a better answer.
   3. Target and inhibit androgen action in androgen-dependent prostate cells. There is a better answer.
   4. All of the above. The goal of hormone therapy in prostate cancer is to interfere with the androgen signaling that is critical to the growth of testosterone-dependent cancer cells. Interfering with the androgen signaling can be achieved in several ways.
   
   
4. Correct answer to Question 4: d
   1. Androgen-independent. There is a better answer.
   2. Androgen-resistant. There is a better answer.
   3. Androgen-insensitive. There is a better answer.
   4. All of the above. Correct.
   
   
5. Correct answer to Question 5: c
   1. In the pituitary gland. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
   2. They remain bound for a shorter time than normal LHRH. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
   3. They remain bound for a longer time than LHRH. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
   4. In the prostate cancer cell. The answer is C. LHRH agonists are similar enough to bind to LHRH receptors and produce a physiological effect, but they are dissimilar enough to remain bound for a longer time than naturally occurs.
   
   
6. Correct answer to Question 6: e
   1. There is an increase in the release of LH. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
   2. The testicles stop producing testosterone. Partially correct. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
   3. The androgen levels drop. Partially correct. The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
   4. There is a "hormone flare". The answer is E (both B and C). When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
   5. Both B and C. When LHRH antagonists are given, there is a decrease in the release of LH. The testicles then stop producing testosterone, androgen levels drop, and there is no "hormone flare."
   
   
7. Correct answer to Question 7: a
   1. They slow testosterone binding to its receptor, which inhibits cell growth. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
   2. They stop the production of testosterone. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
   3. They prevent testosterone from signaling the hypothalamus. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
   4. They bind to testosterone directly so testosterone can't bind to other receptors. The answer is A. Antiandrogens bind to androgen receptors within prostate cancer cells, leaving fewer sites available for testosterone binding. As a result, the androgen receptor complex is unable to stimulate cell growth to the same extent.
   
   
8. Correct answer to Question 8: d
   1. In the testes. There is a better answer.
   2. In the adrenal glands. There is a better answer.
   3. In prostate cancer cells. There is a better answer.
   4. All of the above. Correct.