How is Hormone Therapy Used for Prostate Cancer?
Androgens are steroid hormones that are present in both males and females during puberty. Testosterone is one of the most well-known androgens, and plays a role in the development of the male reproductive system and other male secondary sex characteristics, which is why they are considered the male sex hormones. Androgens are also the precursor to the female sex hormones, estrogens. In females, conversion of these androgens to estrogens is crucial for sexual development. Androgens are made in the testicles as well as in the adrenal glands that sit above the kidneys.1,2
What is androgen deprivation therapy (ADT)?
ADT, also known as hormone therapy, is defined as a series of medications or procedures that are intended to lower the level of androgens in the body or prevent androgens from activating their target receptors (thus, making the androgens functionally useless). Prostate cancer tumors are often fueled to grow by androgens, including testosterone. Turning off the body’s ability to produce or respond to testosterone can potentially halt tumor growth. Without these critical hormones, it may be possible to starve off tumor cells. Hormone therapy can be curative or palliative in intent, depending on your specific case. When used as a palliative care option, hormone therapy is typically used for pain or symptom management only. Hormone therapy can also be used as an initial treatment option in some cases, as well as to treat recurrent prostate cancer when other methods haven’t prevented the cancer’s return.1-3
Types of hormone therapy
There are three main types of hormone therapy:
- Orchiectomy - Surgical removal of the testicles
- LHRH agonists or antagonists - Medication to stop the testicles from making testosterone
- Anti-androgens - Oral medication that prevents cancer cells from using or responding to testosterone
The goal of hormone therapy is to reduce the amount or functionality of androgens in the body. There are multiple mechanisms by which medications or procedures aim to do this. Several of these options include:
An orchiectomy is a surgical procedure that may be performed on men with prostate cancer. However, instead of operating on prostate cancer cells or developed tumors, the surgery involves the removal of the testicles or the tissues that line the testicles. Removing the testicles, or the tissue that lines the testicles and produces testosterone, can lower overall levels of testosterone in the body.
Orchiectomies are often inexpensive when compared to other hormonal, surgical, chemotherapy, or radiation treatment options, and the results and side effects are permanent. A man who has had an orchiectomy where the entirety of the testicles are removed may opt to have plastic or reconstructive surgery afterward and have artificial testicles inserted into the scrotum. Although the appearance will remain the same, the artificial testicles will not produce testosterone.1,2
Treatments that reduce the amount of androgens in the body
LHRH agonists or antagonists are drugs that block the activity of human luteinizing hormone-releasing hormone (LHRH). The most common types of medications in this class include gonadotropin-releasing hormone agonists (GnRH agonists, also referred to LHRH agonists), GnRh receptor antagonists, CYP17 inhibitors, and orchiectomy.
GnRH agonists mimic the GnRH receptor’s normal activator, a key component involved in producing testosterone and other androgens. Turning off the body’s ability to produce testosterone, or reducing the amount made can potentially halt tumor growth. These medications continuously activate a key receptor in the pathway for making testosterone, and eventually overwhelms the receptor. When the receptor is overwhelmed, or desensitized, it stops making luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key in making testosterone.
However, a major concern with desensitizing the GnRH receptor is that before the receptor becomes overwhelmed, it will be continuously activated for the first few weeks of treatment. This means that more testosterone will be produced than usual, and could potentially cause a surge in tumor growth, known as Tumor Flare Phenomenon, which can cause pain, neurological symptoms, and other reactions. Examples of GnRH agonists include:
GnRH receptor antagonists block the GnRH receptor, which, as mentioned previously, is a key receptor in the pathway to making testosterone. When this receptor is blocked, it stops making luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are key in making testosterone. When the making of these hormones is suppressed, testosterone production is decreased as well. These medications are typically able to avoid the Tumor Flare Phenomenon as they decrease androgen levels quicker than GnRH agonists. Examples of GnRH receptor antagonists include Degarelix (Firmagon).
CYP17 inhibitors are typically utilized when the cancer is not responding to treatment with androgen receptor antagonists or other first-line androgen deprivation therapies. At this point, the cancer is said to be castrate-resistant. These medications inhibit CYP17, an enzyme critical in the pathways involved in producing androgens, as well as other essential molecules in the body, including steroids. Examples of CYP17 inhibitors include Abiraterone (Zytiga).
Treatments that prevent androgens from working
Androgen receptor inhibitors, also called anti-androgens or a nonsteroidal anti-androgen (NSAA), block testosterone and other androgens from activating the androgen receptors in the body. These medications are typically used in combination with GnRH agonists to counter the effects of Tumor Flare Phenomenon. Although these medications do not stop the body from making androgens, they do act to turn off the body’s ability to respond to them, thus potentially halting tumor growth. Individuals taking NSAAs should be monitored for changes in liver functioning. Examples of NSAAs include:1,2
- Apalutamide (Erleada)
- Nilutamide (Nilandron)
- Flutamide (Eulexin)
- Bicalutamide (Casodex)
- Enzalutamide (Xtandi)
- Darolutamide (Nubeqa)
Other hormone therapies
Ketoconazole (Nizoral) is an antifungal medication that can be used topically to treat athlete’s foot and other minor fungal infections. When prescribed orally in high enough dosages, Nizoral has the capability to prevent the body’s ability to transform cholesterol into other steroid hormones, including testosterone or cortisol. This property of the medication has led to it being considered an anti-androgen. Because the medicine decreases the creation of cortisol, an important glucocorticoid steroid hormone for our everyday functioning, it is often administered with a steroid, to prevent glucocorticoid levels from becoming too low in the body. Individuals taking Nizoral should be monitored for changes in the heart’s electrical activity, as well as for liver function changes.1,2
Corticosteroid medications are a class of drugs designed to mimic naturally occurring corticosteroids produced by the adrenal cortex. Glucocorticoids are a class of corticosteroids commonly used in cancer therapy. For prostate cancer treatment, specific corticosteroids can be prescribed alone or in combination with other therapies to stop the adrenal glands from producing testosterone or to aid in symptom or side-effect management.
Estrogens are commonly known as female sex hormones that regulate the reproductive system, as well as growth and development in females. Estrogens are used for a variety of purposes including birth control, hormone replacement therapy, and can be used to treat prostate cancer. Using estrogens to treat prostate cancer is often used after many other treatment options have failed. When a male is treated with estrogen-containing medications, it can prompt his body to stop making testosterone. This decrease in the important androgen could starve off tumor cells, limiting their ability to grow and spread. Individuals taking estrogen-containing medications should be monitored for blood clots and changes in liver functioning. Common synthetic estrogens include diethylstilbestrol and ethinylestradiol.1,2
Side effects of hormone therapy
The side effects of hormone therapies often vary, but typically align with the male body’s natural response to a decrease in testosterone. Some of these symptoms include:
- Hot flashes
- Swelling of the breast tissue (gynecomastia)
- Thinning of the bones
- Mood changes (mood swings, depression, anxiety)
- Loss of muscle mass
- Erectile dysfunction
- Decreased sex drive
- Nausea or vomiting
- Swelling of the limbs
This is not an exhaustive list of all potential side effects of hormone therapy. Each treatment option will have its own set of side effects. Your provider will help you determine what treatment option is right for you based on the goals of your treatment and your quality of life goals.1,2,4
Areas of research interest
There has been much research performed, and even more in the works, on new hormone therapies, as well as to determine the highest standard of care for individuals with prostate cancer. Some of these topics include when to start hormone therapy (for example, if it’s better to start therapy right away in early prostate cancer cases instead of watchful waiting), how long to continue hormone therapy, how to handle castrate-resistant or hormone-refractory prostate cancer (with the latter representing prostate cancer cases that are unaffected by any hormone therapy, even castrate-resistant therapies), when to combine hormone therapies with one another or with other treatment options such as radiation, surgery, or chemotherapy, and determining what kinds of cases would benefit from intermittent, or non-continuous, hormone therapy.
Another bustling area of research is focusing on how to make castrate-resistant or hormone-refractory prostate cancers sensitive to hormone therapy, even if it has never been in the past. One example of this comes from studies into targeting the ROR-γ protein, a key element in regulating the activity of the androgen receptor. Early evidence has shown that targeting this protein may help re-sensitize prostate cancers to previously used first-line hormone therapies.4-7
In many instances, hormone therapy may be utilized in addition to surgical, radiation, and chemotherapy treatment options. Additionally, as mentioned previously with the GnRH agonists and NSAAs, some of these hormone therapies can be used in conjunction with one another. Each individual with prostate cancer and the exact characteristics of their case are different, making different options and combinations viable to different people. Your provider will help you determine if a combination treatment approach is appropriate for you, and will help instruct you on how to follow your treatment plan appropriately.