Overview

Testosterone is an androgen male hormone produced mainly by the testicles. Many organs in the body are composed of cells that respond to or are regulated by exposure to testosterone. Cells in the prostate have testosterone receptors and when exposed to testosterone, are stimulated to grow. When cells that have testosterone receptors become cancerous, the growth of these cancer cells can be increased by exposure to testosterone.

Hormone therapy, also known as androgen-deprivation therapy or (ADT), is designed to stop testosterone from being released or to prevent it from acting on the prostate cells and prevent the growth of cancer. Hormone therapy is primarily cytostatic; it prevents cancer cells from growing.  It is not cytotoxic, like chemotherapy, which kills cancer cells.  Hormone therapy may work for many years but eventually prostate cancer becomes resistant. When prostate cancer cells grow independent of or become insensitive to hormone therapy the cancer is referred to as hormone refractory and is known as hormone-refractory prostate cancer (HRPC).

Hormone therapy is increasingly being used before, during, or after local treatment and is a mainstay of the treatment of advanced prostate cancer. The type and timing of hormone therapy is an individual decision and one that should be discussed with your doctor.  There are two methods of delivering hormone therapy: 1) surgical orchiectomy and 2) medical hormone therapy.

Types of Hormone Therapy

Orchiectomy

Bilateral orchiectomy (castration) is a surgical operation to remove the testicles. By removing the testicles, the main source of testosterone is removed and hormone levels decrease. Orchiectomy is a common treatment for patients with metastatic (stage IV) prostate cancer who will likely require hormone therapy for life. Patients may experience a benefit in symptoms in a matter of days following surgery.

Orchiectomy can cause side effects such as loss of sexual desire, impotence, hot flashes, and weight gain. The operation itself is relatively safe and not associated with severe complications. Orchiectomy is a convenient and less costly method of hormone therapy; however, it is irreversible.

Medical Androgen Deprivation Therapy (ADT)

The second method of hormone therapy is to take medicines that produce the same effect as an orchiectomy. This is referred to as Androgen Deprivation Therapy (ADT).  ADT slows or stops prostate cancer growth by reducing the exposure of the prostate to testosterone.  Medicines that reduce male hormone levels are called LHRH analogues and anti-androgens. Female hormones such as estrogens can also reduce male hormone levels, but can also cause serious side effects and are therefore rarely used.

LHRH Analogues: Drugs that act like luteinizing hormone releasing hormone (LHRH) are known as LHRH analogues  (Note that LHRH is sometimes called gonadotropin-releasing hormone (GnRH). These drugs turn off the signal for testosterone production by the testicles. By turning off the signal, hormone levels are reduced and cancer cells are not exposed to male hormones. LHRH analogues are typically given as a small injection under the skin of the abdomen every month or every three months. These drugs work just as effectively against prostate cancer as bilateral orchiectomy.

LHRH Antagonists—A newer class of medications can block LHRH from stimulating testosterone production without causing an initial testosterone surge. This class includes degarelix, which is given monthly to men as an alternative to orchiectomy or LHRH agonists.1

LHRH analogues can cause side effects such as loss of sexual desire, impotence, hot flashes and the development of osteoporosis, which increases the risk of bone fractures. Because these drugs require an injection every 1 or 3 months, LHRH analogues may not be as convenient as an orchiectomy. Unlike orchiectomy however, these drugs can be discontinued, and male hormone levels gradually return to normal.

LHRH analogues may be used to treat patients with any stage of prostate cancer. When first taken, these drugs may increase prostate cancer growth and make a patient’s symptoms worse. This temporary problem is called “tumor flare.” Gradually, these drugs cause hormone deprivation, shrinkage of prostate cancer, and improvement in symptoms. Tumor flare can be prevented by administering an anti-androgen medication before the LHRH analogue. The LHRH antagonist degarelix, doesn’t cause a flare in testosterone.

  • Leuprolide (Lupron, Eligard)
  • Goserelin (Zoladex)
  • Triptorelin (Trelstar)
  • Histrelin (Vantas)
  • Degarelix (Firmagon)

Anti-androgens: Not all male hormones are made by the testicles.  A small amount of male hormone is made by the adrenal glands, and may not be affected by bilateral orchiectomy or LHRH analogues. An anti-androgen is a medication that can block the effect of the remaining male hormone on prostate cancer cells. Anti-androgens are pills often given to patients in addition to orchiectomy or LHRH agonists. This combination of treatment is known as total or combined androgen blockade (CAB).

Anti-androgens can cause side effects such as loss of sexual desire, diarrhea, enlargement of the breasts and occasional impotence. When used alone, these drugs appear to cause impotence much less often than other forms of hormone therapy. On rare occasion, these drugs can cause liver abnormalities, and blood tests can help detect these problems before serious side effects occur. These drugs can also be discontinued, and male hormone levels gradually return to normal.  Anti-androgens are given as oral medications. They are usually prescribed along with an LHRH agonist or before taking an LHRH agonist to decrease risks associated with the hormone flare that can be caused by an LHRH agonist.2

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

Newer hormonal medications that inhibit the synthesis of androgen (abiraterone) and block androgen receptor signaling (enzalutamide) are now FDA-approved for the treatment of metastatic prostate cancer after treatment with chemotherapy, and are being evaluated for use earlier in the disease, like when the PSA begins to rise or before chemotherapy.3, 4, 5, 6, 7, 8

Abiraterone (Zytiga®) Abiraterone is an oral targeted agent that blocks the production of androgens not only by the testes, but also by the adrenal glands and the tumor itself.  Abiraterone when administered with prednisone has been shown to improve quality of live and delay patient-reported pain progression in HRPC patients.  Although this medication is generally well-tolerated, side effects may include fatigue, high blood pressure, and electrolyte or liver abnormalities and patients need to be monitored regularly.3, 5, 6, 7

Enzalutamide (Xtandi®) Enzalutamide targets multiple steps in the androgen-receptor–signaling pathway, interfering with molecular pathways that help the prostate cancer grow. What’s more, the drug does not cause side effects commonly associated with chemotherapy, such as nausea and hair loss. Enzalutamide has been shown to improve survival, reduce the risk of cancer progression, and delay the need for additional chemotherapy in men with HRPC.4, 8

Combined Androgen Blockage

Several clinical studies have directly compared CAB with a single form of hormone therapy (LHRH analogue or orchiectomy) for patients with metastatic prostate cancer. Two large studies conducted in the U.S. and Europe have shown improvement in disease control and survival with CAB.  Most doctors feel CAB controls disease and improves survival better than either an LHRH analogue or orchiectomy alone.9

Intermittent Therapy

Both surgical orchiectomy and standard ADT provide continuous blockade of exposure to testosterone. Some doctors believe that using medical hormone therapy intermittently can decrease the cost and reduce the side effects of treatment. When treatment is withheld for a period of time, sexual function and quality of life may improve. This was recently confirmed in a group of asymptomatic men with rising PSA levels after prostate cancer treatment. Men who received intermittent therapy appeared to have better quality of life, especially in terms of physical function, fatigue, urinary problems, hot flashes, libido, and erectile function and there was no difference in overall survival.10

When to Start Hormonal Therapy

There is general agreement that men with advanced prostate cancer experiencing symptoms from should begin treatment immediately. There has been some disagreement, however, regarding the best time to start hormonal therapy in asymptomatic patients. Studies also suggest that men treated with immediate hormonal therapy lived longer without cancer progression and were less likely to develop significant complications from cancer compared to deferring hormone therapy until they developed symptoms.

Side Effects of Hormonal Therapy

Side effects of hormone therapy for prostate cancer may include the following.  In general, the risk of side effects increases the longer you take hormone therapy medications.

  • Bone thinning-Osteoporosis
  • Erectile dysfunction
  • Fatigue
  • Growth of breast tissue
  • Heart disease
  • Hot flashes
  • Loss of sex drive
  • Loss of muscle mass
  • Memory problems
  • Weight gain

References:

1 Klotz L, Boccon-Gibod L, Shore ND et al. The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer. BJU Int. 2008;102:1531-8.

2 Keating NL, O’Malley AJ, Freedland SJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Journal of the National Cancer Institute. 2010;102:39-46.

3 Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial. The Lancet Oncology. 2013; 14(12):1193-1199.

4 Beer TM, Armstrong AJ, Sternberg CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): Results of phase III PREVAIL study. Presented at the 2014 Genitourinary Cancers Symposium. Journal of Clinical Oncology. 2014; 32 (supplement 4; abstract LBA1).

5 Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Eng J Med 2012; 367: 1187.

6 Carducci M, Nelson JB, Saad F, et al. Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study. Journal of Clinical Oncology, 2004 Annual Meeting Proceedings (Post-meeting edition);22(14S), Abstract #4508.

7 Lipton A, Sleep DJ, Hulting SM, et al. Benefit of Atrasentan in Men with Hormone Refractory Prostate Cancer Metastatic to Bone. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4687.

8 Yount S, Cella D, Mulani P, et al. Impact of atrasentan on prostate-specific outcomes with hormone refractory prostate cancer patients. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4582.

9 Higano C, Shields A, Wood N, et al. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004;64(6):1182-6.

10 Cook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. New England Journal of Medicine. 2012; 367: 895-903.

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