How Does Androgen Deprivation Therapy (ADT) Work? 13 Side Effects

Knowing the dangers and advantages of ADT can help you make an educated decision about how to proceed with therapy.

Androgen deprivation therapy (ADT) is a type of treatment for prostate cancer that uses medications or surgery to lower the levels of male hormones or androgens made by the testicles.

ADT works in two ways by:

1. Reducing the androgen levels in the body
2. Blocking the action of androgens

The prostate is a part of the male reproductive system where semen is produced. Semen is the fluid that helps with mobility of the sperms and even provides the sperm with necessary nutrition.

If the growth of prostate cancer is inhibited by ADT, such cancers are called castration-sensitive, androgen-dependent, or androgen-sensitive.

However, most prostate cancers ultimately become castration-resistant and stop responding to hormone treatment. They continue to develop even when the body's androgen levels are extremely low or undetectable.

• These tumors were earlier referred to be hormone-resistant, androgen-independent, or hormone-refractory. However, these words are no longer often used because the tumors are not genuinely independent of androgens for growth.
• Various new therapies were developed to be used to treat tumors that have become castration-resistant.

What are androgens?

Androgens are male sex hormones that are essential for:

• The growth and functionality of the prostate
• Normal reproductive and sexual function in men
• Development of secondary sexual characteristics during puberty

Androgens promote the growth of cancerous cells of the prostate by binding to and activating androgen receptors on prostate cells.

What are the various hormone therapies used against prostate cancer?

Treatments that reduce androgen production by the testicles

Androgen deprivation therapy (ADT) is the most often utilized hormone treatment for prostate cancer and the initial form of hormone therapy. ADT comprises the following:

1. Orchiectomy
   • This is the surgical removal of one or both testicles. Surgical castration or the removal of the testicles can lower testosterone levels in the blood by 90 to 95 percent. A subcapsular orchiectomy removes only the tissue in the testicles that generates androgens, rather than the complete testicle. Orchiectomy is a permanent and irreversible procedure.
2. LHRH agonists
   • Luteinizing hormone-releasing hormone (LHRH) agonists or LHRH analogs are synthetic proteins that are structurally identical to LHRH and bind to the pituitary gland’s LHRH receptor. When androgen levels in the body are low, the hypothalamus normally releases LHRH. This causes the pituitary gland to release luteinizing hormone (LH), which causes the testicles to make androgens.
   • LHRH agonists, like the body's natural LHRH, boost luteinizing hormone synthesis at first. The presence of large amounts of LHRH agonists, however, leads the pituitary gland to discontinue generating luteinizing hormone. As a result, no androgens are produced by the testicles.
   • The use of an LHRH agonist is referred to as medical castration or chemical castration. However, unlike surgical castration (orchiectomy), the effects of LHRH agonists on testosterone production are reversible. Androgen production normally restarts once the medication is discontinued.
3.  LHRH antagonists
   • LHRH antagonists (also called gonadotropin-releasing hormone antagonists) block LHRH from binding to its pituitary gland receptors. This inhibits luteinizing hormone secretion, which prevents the testicles from creating androgens.
   • LHRH antagonists, unlike LHRH agonists, do not generate an initial testosterone surge.
4. Estrogens (female sex hormone)
   • Although estrogens can decrease androgen synthesis in the testicles, they are rarely utilized in the treatment of prostate cancer due to their negative effects.

Treatments that block the action of androgens

This type of treatment is used when ADT does not seem to work:

1. Androgen receptor blockers
   • Androgen receptor antagonists (also called androgen receptor blockers) are medications that compete with androgens to bind to the androgen receptor. These medicines limit androgens' potential to drive prostate cancer growth by competing to bind to the androgen receptor.
   • Because androgen receptor blockers do not reduce testosterone production, they are rarely used alone to treat prostate cancer. They are frequently used in conjunction with ADT (either orchiectomy or an LHRH agonist). 
   • Combination androgen blockade, full androgen blockade, or total androgen blockade refers to the use of an androgen receptor blocker along with orchiectomy or an LHRH agonist.

Treatments that block the production of androgens in the body

1. Androgen synthesis inhibitors
   • Androgen synthesis inhibitors are medications that suppress the production of androgens by all tissues that manufacture them. Neither medicinal nor surgical castration inhibits the production of androgens by the adrenal glands or prostate cancer cells.
   • Even though these cells generate only trace levels of androgens, they can be sufficient to fuel the growth of some prostate tumors.
   • Androgen synthesis inhibitors suppress testosterone levels in males more than any other recognized medication. They accomplish this by blocking an enzyme called CYP17. This enzyme, present in testicular, adrenal, and prostate tumor tissues, is required for the body to synthesize testosterone from cholesterol.

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13 possible side effects of ADT

The negative effects of hormone treatment medication in males worsen over time. Some of the negative effects will disappear after the individual discontinues taking the medication. Surgical castration, however, is not reversible.

Possible side effects associated with androgen deprivation therapy (ADT) include:

1. Erectile dysfunction
2. Hot flashes
3. Osteoporosis (bone density reduces and the bones become porous and weak)
4. Fatigue
5. Increased body fat and body mass index
6. Reduced or absent sex drive
7. Muscle mass reduction
8. Increased risk of heart diseases and diabetes
9. Shrinkage of testicles and penis
10. Growth of breast tissue and breast tenderness
11. Anemia (low red blood cell count)
12. Changes in mood
13. Depression

The side effects of hormone treatment for prostate cancer can have a severe influence on a man's quality of life. However, some therapies can help minimize some of the negative effects.

Lifestyle modifications, including exercise, can assist to offset muscle mass loss and tiredness. Hot flashes, nausea, diarrhea, and bone loss can be treated with medication. Tamoxifen or low-dose radiation may help prevent or minimize breast enlargement. Counseling and medication may be beneficial for males suffering from depression.

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3 alternate therapies for ADT

1. Intermittent androgen deprivation therapy
   • Intermittent androgen deprivation treatment (IADT) has been offered as an alternate way to minimize long-term negative effects and delay the development of androgen independence in cancer cells.
   • The suggested strategy involves cyclic hormone suppression, with induction therapy for a predetermined interval or until the maximal response is obtained. The medication is stopped and restarted depending on the values of prostate-specific antigen values. IADT seeks to decrease treatment-related symptoms after androgen deprivation treatment (ADT) discontinuation by restoring the body's hormonal axis.
   • The usage of IADT has resulted in significant improvements in quality of life because the side effects were reduced drastically in most people.
   • However, the use of IADT remains controversial because its influence on disease management and survival relative to continuous ADT is unknown.
2. Sequential androgen blockade
   • A 5-alpha-reductase inhibitor, such as finasteride, is used along with an antiandrogen, such as cyproterone acetate, to block the conversion of testosterone to its active metabolite dihydrotestosterone.
   • They prevent testosterone and dihydrotestosterone from binding to the androgen receptor.
   • This method is currently in the trial phase and is considered experimental.
3. Delayed treatment
   • There is no clear advantage of starting ADT right away after diagnosis of prostate cancer (early treatment) when compared to delayed treatment (postponement of treatment until the patient develops symptoms).
   • The initiation of ADT is to be done after comparing the chances of lowering disease progression and problems related to progression by early treatment to the possible benefits on quality of life achieved by delaying medication.

Bottom line

• The use of androgen deprivation treatment (ADT) as part of a prostate cancer treatment strategy is a personal decision that is influenced by several circumstances.
• Knowing the dangers and advantages of ADT can help you make an educated decision about how to proceed with therapy.
• It is vital to consult with your doctor and understand the complete information relevant to your specific situation before making any major decisions.