Preventing and Treating the Side Effects of Testosterone Deprivation Therapy in Men with Prostate Cancer A Guide for Patients and Physicians

Edited from PCRI Insights November, 2007 vol. 10, no.4

Brad Guess PA-C Former PCRI Executive Director

In the early 1940s, Drs. Huggins and Hodges discovered that when testosterone was removed by castration, men with advanced metastatic prostate cancer went into remission for 2-3 years. (1) They found that prostate cancer was “sensitive” to testosterone; prostate cancer grew when testosterone was present, and it died or went into remission when it was not. This ultimately led to the development of drugs that could eliminate testosterone and thereby accomplish the same thing without surgically removing the testicles.

Today, Testosterone deprivation therapy (also widely known as Androgen Deprivation Therapy) has largely replaced surgical castration through the use of Testosterone Inactivating Pharmaceuticals (TIP) that eliminate testosterone production or to block it at a cellular level at all stages of prostate cancer. LHRH agonists (Lupron®, Zoladex®, etc.) are drugs that eliminate testosterone. Antiandrogens (Eulexin®, Casodex®, or Nilandron®) block testosterone at a cellular level. This type of treatment is very effective at controlling prostate cancer, often for many years. However, you only have to speak briefly with a man who is taking these drugs to find out that there are a lot of side effects from having no testosterone!

This guide is intended for those men who find themselves on a TIP* for prostate cancer, and may or may not already be experiencing side effects of having no testosterone. Table 1 lists the most common acute side effects and Table 2 lists the most common chronic side effects of TIPs. The guide should not be used as a substitute for medical advice from a qualified medical provider. Rather, prostate cancer patients and their physicians should use the guide to discuss strategies for preventing and treating these side effects.

* Editor’s Note: The acronym TIP describes all testosterone inactivating pharmaceuticals. Hence, in this article use of the acronym TIP may refer to a single pharmaceutical or several pharmaceuticals.


Table 1. Common Acute Side Effects from Testosterone Deprivation Therapy


ACUTE SIDE EFFECTS

(Symptoms usually start to occur within the first 2-3 months after starting testosterone deprivation therapy)

• Loss of Libido (“sexual drive”)
• Loss of nocturnal erections (associated with ED)
• Hot flushes (can affect quality of life in some men)
• Breast tenderness (usually is felt before growth is observed)
• Anemia (a drop in hemoglobin can occur in as quickly as one month)
• Cognition and memory decline (should be assessed on a regular basis)
• Diarrhea (occurs more often with flutamide than with Casodex®)
• Abnormal liver function test results (seen with the testosterone blocking medications, they must be stopped)

Table 2. Common Chronic Side Effects from Testosterone Deprivation Therapy

CHRONIC SIDE EFFECTS

(Symptoms usually start to occur 3-4 months after starting testosterone deprivation therapy and can persist)

• Erectile dysfunction/Disuse atrophy of the penis (probably a result of loss of nocturnal erections)
• Dry ejaculations (from atrophy of prostate)
• Bothersome urinary symptoms (sometimes gets better, sometimes gets worse)
• Bone mineral density loss (4-10% in the first year of a TIP use)
• Loss of muscle strength (will continue without resistance training)
• Joint aches and pains (usually in the hands)
• Breast growth (much worse for men on testosterone blocking monotherapy)
• Fatigue/excessive daytime sleepiness (probably from loss of muscle strength, can get worse with time)
• Changes in metabolism, weight gain, body composition, and lipid profiles
• Depression and emotional distress (patients and their family need to discuss this with their medical providers)
• Changes in blood pressure (up or down)
• Dry skin and loss of body hair
  

Most of the suggestions in the guide are based on clinical research studies; however, since research in the prevention and treatment of certain side effects is often lacking, some of the suggestions are based on my own clinical experience. The references cited in the guide come from a paper I co-wrote entitled “Preventing and Treating the Side Effects of Testosterone Inactivating Pharmaceuticals in Men with Prostate Cancer”, published in Seminars in Preventive and Alternative Medicine, June, 2006.


Erectile Dysfunction, Loss of Libido, and Loss of Nocturnal Erections

About one-third of men over the age of 40 have some degree of trouble getting and maintaining erections. (2) Since men with prostate cancer tend to be older, many may have erectile dysfunction (ED) prior to starting testosterone deprivation therapy. The loss of testosterone usually makes this situation worse or creates ED for the first time in a man’s life. There are two components to ED in men on a TIP:

The loss of libido (sexual interest) occurs in as many as 8-9 out of 10 men on testosterone deprivation therapy. (3) Many men will lose their libido completely, while others lose it only partially.

The loss of nocturnal erections (the spontaneous erections all men get at night when they sleep), can lead to atrophy (shrinkage) of the penis and progressive difficulty getting erections.

Prevention / Treatment Strategies

Unfortunately, there is no treatment for the loss of libido. However, it usually returns once testosterone deprivation therapy is stopped and testosterone levels return to normal. A four-step prevention and treatment strategy for men with prostate cancer on a TIP is outlined in Table 3. It should be noted that this strategy should be discussed thoroughly with your medical provider, since it potentially involves several different medications. Some men may find this strategy cumbersome, especially if their libido is gone. However, remember that it is a strategy for “maintenance” of erectile function. The idea is to maintain function, so that if the time comes when testosterone deprivation therapy is stopped, things can return to normal.


Table 3.

Four step prevention and treatment strategy for maintenance of erectile function in men receiving TIP.

Step 1: Nightly (every other night when Cialis® is used) low doses of an oral PDE-5 inhibitor. This is used to maintain nocturnal erections.

Step 2: Daily (if possible) use of a vacuum erection device for “exercising” the penis to prevent atrophy.

Step 3: Use an oral PDE-5 inhibitor (men should be encouraged to try each of the available choices to determine which works the best for them) as needed for sexual intercourse. Men can combine the PDE-5 inhibitor and vacuum erection device if needed.

Step 4: Consider the use of Muse® (as an urethral suppository or intercavernosal injection) in cases where an adequate erection for intercourse is not achieved with Step 3. Men can combine Muse® and a PDE-5 inhibitor if needed (only after discussing with their medical provider).


Dry Ejaculation

In men who have an intact prostate and have not had it removed, radiated or frozen, the normal fluid production of the prostate stops while they are on testosterone deprivation therapy. Therefore, when a man ejaculates it will be dry. Some men report that the pleasure of an orgasm with dry ejaculation is reduced.

Prevention / Treatment Strategies

Unfortunately there is no way to prevent or treat this problem. However, once testosterone deprivation therapy is completed and testosterone levels return to normal, the prostate typically begins to produce fluid again and ejaculate returns.


Bothersome Urinary Symptoms

Some men notice that bothersome urinary symptoms (such as a slow urine flow, getting up frequently at night to urinate, and dribbling urine) improve after they are on a TIP. This is probably due to the shrinkage that takes place in the prostate after testosterone is removed. On the other hand, some men have an increase in such bothersome urinary symptoms.

Prevention / Treatment Strategies

Discuss with your doctor a simple test to check your “postvoid urine residual” (how much urine is left in your bladder after you urinate). If the amount is greater than 100 ml (a little less than half a cup), you may benefit from a class of drugs call “alpha blockers”. Examples are Flomax or Uroxatrol. If your postvoid residual urine is less than 100 ml and you are having trouble holding your urine or dribbling, “Kegal” exercises can be helpful (your medical provider can explain these and information about how to do them can be found on the Internet). If Kegel exercises do not help, a number of anticholinergic drugs such as Detrol® or Ditropan® may improve the symptoms.


Bone Mineral Loss

The loss of bone mineral density is usually a silent side effect of testosterone deprivation therapy. It can occur at a rate of 4-10% after the first 12 months of a TIP application. (4) , (5) Given that most men with prostate cancer are older and as many as half of men starting testosterone deprivation therapy may already have some bone mineral loss or even osteoporosis, the risk of a bone fracture warrants serious attention. It is essential that men be screened for osteoporosis with a bone mineral density test prior to starting the application of a TIP or soon after.

Prevention / Treatment Strategies

If osteoporosis is detected with screening prior to the start of testosterone deprivation therapy, it is important that you discuss with your medical provider the potential for other causes of bone mineral loss, besides that which occurs as a part of normal aging. Restricting the excess use of alcohol, tobacco, caffeine, and vitamin A is the first step in preventing and treating bone mineral loss. You should do resistance exercises and supplement your diet with 1200-1500 mg of calcium (preferable calcium citrate) and 2000 IU of Vitamin D should be implemented. If osteoporosis is detected with screening and no other underlying cause has been identified, discuss the use of oral or intravenous bisphosphonates with your medical provider. Bisphosphonates are a class of drugs that inhibit osteoclast-mediated bone resorption (the breaking down process of bone that can occur while on a TIP). Urine tests such as N-telopeptide and Pyrilinks-D can be performed periodically to monitor excessive bone breakdown while on a TIP. Yearly bone mineral density testing is recommended for men on (TIP).


Sarcopenia (Loss of Muscle Strength)

The elimination of testosterone in men leads to a deterioration of lean muscle mass, an increase in fat mass, and a subjective decrease in physical function. In other words, men get weak, gain weight and don’t feel as well when they are on testosterone deprivation therapy. These side effects become evident within the first three or four months after starting on a TIP and progress the longer a man continues treatment.

Prevention / Treatment Strategies

Research shows that strength training can often prevent or reverse the loss of muscle mass and physical well-being associated with the reduction of testosterone. (6) The importance of regular strength training cannot be stressed enough. It should be a priority in any strategy to prevent and treat the side effects of any TIP. The essence of a successful strength-training program is lifting weights to the point of muscle failure. Programs to build muscle need to start slowly for the first few months so that no injuries develop. A professional trainer is highly desirable.


Joint Aches and Pains

Men who are on testosterone deprivation therapy for six months or more will commonly complain of the onset of new joint aches and pains, particularly in the hands but sometimes in other joints.

Prevention / Treatment Strategies

Speak with your medical provider about the use of over the counter preparations such as glucosamine, MSM (methylsulfonylmethane) or nonsteroidal anti-inflammatory drugs (NSAID’s) such as ibuprofen and naproxen (there is weak evidence that chondroiten may not be advisable for men with prostate cancer). Maintaining good muscle strength and tone will provide better joint support and can minimize these aches and pains.


Hot Flushes

Hot flushes are described as sudden, intense warmth in the face, neck and chest, often followed by sweating. Hot flushes are one of the most common side effects in men on testosterone deprivation therapy, occurring in up to 70% of men. (7) Generally, men regard hot flushes as an irritating, but tolerable nuisance. However, some men find that hot flushes have a significant impact on their quality of life, sleep and work.

Prevention / Treatment Strategies

There is no known way to prevent hot flushes in men on a TIP, and treatment for them should generally be reserved for those men with severe hot flushes that affect their daily living. There are several treatments that have been shown to be effective at reducing the number and severity of hot flushes.

1. Acupuncture (twice a week) has been shown to decrease the number of hot flushes by as much as 70%. (8)

2. The use of isolated soy protein powder (40g/day) added to the diet can reduce hot flushes by up to 45% (vs. a 30% reduction with placebo). (9)

3. The most effective treatment for men with severe hot flushes when on a TIP is the hormone progesterone, which is administered as medroxyprogesterone. (10) This medication is given as a shot (400mg) and often is sufficient to control hot flushes for 6-12 months.

4. Another form of the hormone progesterone is progestin megestrol acetate (Megace®); in doses of 20 mg twice per day, it can be very helpful. The most common side effect of progesterone is an increased appetite. A brief word of caution; there has been a single report in the literature of a case of prostate cancer progression associated with the use of progesterone. (11)

5. Low-dose estrogen (1 mg in the form diethylstilbestrol) can improve hot flush symptoms by up to 70%. (12) However, estrogen, even at low doses, can cause breast tenderness and growth, swelling of the lower legs and on rare occasion blood clots. Diethylstilbestrol (DES) is not commercially available at retail pharmacies, but can be obtained relatively inexpensively at most compounding pharmacies.

6. The antidepressant venlafaxine (Effexor-XR®) at a dose of 12.5 to 37.5 mg can be very effective at reducing hot flushes. (13) If men also have symptoms of depression while on a TIP, venlafaxine should be considered as the first choice of medication for severe hot flushes.

7. Gabapentin (Neurotin®), an anti-seizure medication, can be tried by men who have failed to respond to other treatments. The commonly used dosage of gabapentin is 300-900 mg divided in two to three does daily.


Breast Tenderness and Growth (Gynecomastia)

Between 13-22% of men treated with a testosterone-lowering drug such as Trelstar® or Zoladex® report having breast growth and or tenderness. (14) This problem can occur in as high as 50-73% of men who are on a testosterone blocking medication alone, such as Casodex® or Eulexin®. (15) , (16 )

Prevention / Treatment Strategies

Breast tenderness and growth can be reduced or prevented if treated before symptoms develop. However, once growth becomes established, the condition is irreversible and can only be corrected with surgery (mastecotomy or liposuction). The following list of treatments can be helpful and should be discussed at length with your medical provider:

1. Radiation to the breast (usually just around the nipples) before the start of testosterone deprivation therapy can reduce the risk of breast growth and tenderness by as much as 65%. (17) This is especially important for a man to discuss with his medical provider prior to starting monotherapy with Casodex® or Eulexin®, because of the high incidence of breast growth and tenderness with this type of testosterone blocking treatment.

2. The medication tamoxifen (Nolvadex®) (used to treat breast cancer) can prevent breast growth and tenderness in over 60% of men on a TIP.18 However, there is some concern that it may increase the risk of a blood clot or hot flashes.

3. The medication letrozole (Femara®) (also used to treat breast cancer), can be very effective and has few side effects. However, there are no clinical studies that have confirmed its effectiveness when used by prostate cancer patients on a TIP. This suggestion is based on the author’s experience.


Fatigue/Excessive Daytime Sleepiness

The main cause of fatigue for men on testosterone deprivation therapy probably comes from the loss of muscle mass and strength. As men loss muscle mass and strength, many also complain of excessive daytime sleepiness.

Prevention / Treatment Strategies

1. The most important strategy for men to prevent or reduce fatigue while on a TIP is a regular strength training program. As mentioned before, this strategy is best accomplished with the help of a qualified personal trainer.

2. The medication modafinil (Provigil®), which is FDA approved for the treatment of narcolepsy, sleep apnea and shift work sleep disorder, can be helpful for men with excessive fatigue and daytime sleepiness. Modafinil has few drug-to-drug interactions and is usually well tolerated, with the most frequent side effect being transient headaches. However, the use of modafinil has not been studied in men with prostate cancer on testosterone deprivation therapy.

3. Low doses (5-10 mg) of the stimulant methylphenidate (Ritalin®) taken in the morning can also be helpful for men with excessive fatigue and daytime sleepiness while on a TIP. Methylphenidate must be used with caution in patients with hypertension or a history of arrhythmias (abnormal heartbeat).


Changes in Metabolism, Body Composition, and Lipid Profiles

Some of the most troubling and often overlooked side effects in men with prostate cancer treated with a TIP are those that can negatively impact cardiovascular health. Studies of men on testosterone deprivation therapy show an increase in weight, body fat, serum levels of glucose and insulin, uric acid, total cholesterol, triglycerides, and the stiffness of arteries.

Prevention / Treatment Strategies

Prostate cancer patients who are on a TIP should regularly have their weight, blood pressure, lipid profile, homocysteine and C-reactive protein monitored. Patients in collaboration with their medical providers should thoroughly review the role and appropriateness of antioxidants, low dose aspirin, vitamin B-12, folic acid, fish oil, low glycemic index diets, and statin drugs. Screening for cardiovascular disease with an exercise stress test or a coronary artery calcification scan should be considered. (18)


Anaemia

The development of anemia (low red blood cell counts) is common in prostate cancer patients treated with a TIP. Fortunately, most men have no symptoms and do not require treatment for anemia related to testosterone elimination. However, about 15% of men will have symptoms such as fatigue, shortness of breath, and a decrease in quality of life. (19) So anemia should be discussed at length with your medical provider.

Prevention / Treatment Strategies

For those men who are symptomatic from anemia while on a TIP, an evaluation of other potential causes of anemia such as bleeding, iron, B-12 or folate deficiencies should be considered. Anemia related to testosterone elimination is not related to deficiencies of iron, B-12 or folate and can be treated and reversed quickly with low doses of synthetic erythropoietin (Procrit®, Aranesp®).


Cognition and Memory Decline

Research on the effects of testosterone deprivation therapy in men with prostate cancer on cognition and memory is limited and inconclusive. However, many men do complain, “my memory is just not what it used to be” or “I’m just not able to concentrate as I used to”.

Prevention / Treatment Strategies

The importance of keeping intellectually stimulated and mentally active during treatment with a TIP cannot be underestimated. Because most men treated with a TIP are elderly, it is important for medical providers to assess whether negative changes in cognition and memory represent early signs of Alzheimer’s, vascular dementia, or other cognitive disorders.


Depression and Emotional Distress

Prostate cancer patients on testosterone deprivation therapy report feeling depressed and having wide emotional swings (crying one minute and being angry the next. The cause of this is unknown, and no research exists to answer the question

Prevention / Treatment Strategies

If men develop depression and or emotional swings after starting, it is important for them or their family to discuss the problem with their medical providers, because depression and emotional swings can have a significant negative impact on quality of life. The group of antidepressants called selective serotonin reuptake inhibitors (SSRIs ex: Prozac®) and selective serotonin and norepinephrine reuptake inhibitors (SSNRIs ex: Effexor®) are often effective in this situation. As previously mentioned, if a man has significant hot flashes in addition to feelings of depression or emotional swings while on a TIP, the medication venlafaxine (Effexor®) may the best first choice for treatment. Individual psychotherapy with a licensed clinical psychologist can also be very helpful for some patients. The combination of an SSRI and individual psychotherapy is the most effective treatment for men with moderate to severe depression.


Changes in Blood Pressure

Changes in blood pressure, both upward and downward, have been observed in men on testosterone deprivation therapy. However, there is no research available to validate these observations.

Prevention / Treatment Strategies

Regular blood pressure measurements should be performed on men receiving a TIP. Standard management similar to that used for patients who are not on testosterone deprivation therapy (the addition or removal of blood pressure medications) is effective.


Diarrhea

Flutamide causes diarrhea in approximately 6.1% of men and Casodex® causes diarrhea in 0.5% of men. (20)

Prevention / Treatment Strategies

Diet modification and symptomatic treatment with anti-diarrhea medication may be helpful. However, the medication almost always has to be stopped. In my experience, if patients develop diarrhea with one of the testosterone blocking medications, they can usually switch to other medications with little difficulty.


Abnormal Liver Function Test Results (Liver Toxicity)

Liver toxicity can occur in approximately 2.5 and 1.4% of men taking the testosterone blocking medications flutamide and Casodex®, respectively. (20)

Prevention / Treatment Strategies

Routine monitoring of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will detect liver toxicity early. Usually it is necessary to stop the medication. However, in mild cases, the problem may be transient and may cease when the medication is stopped or the dose is reduced. Men who have liver toxicity from one testosterone blocking medication can usually be safely treated when taking another. Some evidence exists that milk thistle (Silybum marianum) may have a protective effect on the liver and may possibly be beneficial for reducing ALT, although this has not been clearly established. Fortunately, available evidence does suggest that milk thistle is associated with few, generally minor adverse effects. The usual dose of milk thistle is 200 mg taken three times a day.


Dry Skin and Loss of Body Hair

Men on testosterone deprivation therapy often complain of dry skin and generalized loss of body hair.

Prevention / Treatment Strategies

The regular use of moisturizing lotion will reduce the bother of dry skin. These side effects cease with the end of treatment, when testosterone levels return to normal.


Conclusion

The medical evidence that testosterone deprivation therapy has substantial anti-prostate cancer effects continues to mount. Consequently, its use has become increasingly more common for all stages of prostate cancer. However, the potential for significant side effects that can dramatically reduce a man’s quality of life are a real concern with this type of therapy. Unfortunately, little attention has been given to the prevention and treatment of these side effects. It is my hope that this guide will open the lines of communication between men and their medical providers, and provide a tool to help them prevent and treat these side effects effectively, so that men can gain the full benefit of this treatment and still maintain a good quality of life.

Editor’s Note: This guide was the last document written by Brad before his untimely death from a heart attack in June 2006.

References:

1. Huggins C, Hodges C: Studies on prostate cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma on the prostate Cancer Res 1:293-297, 1941

2 Feldman H, Goldstein I, Hatzichristou D, et al: Impotence and its medical and psychosocial correlates: Results of the Massachusetts Male Aging Study. J Urol 151:54-61, 1994

3. Potoshy AL, Knoph K et al. Quality-of-Life outcomes after primary androgen deprivation therapy: Results from the Prostate Cancer Outcomes Study. J Clin Onc 19:3750-57, 2001

4. Daniell H, Dunn S, Ferguson D, et al: Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 163:181-186, 2000

5. Goldray D, Weisman Y, Jaccard N, et al: Decreased bone density in elderly men treated with a gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab 76:288-290, 1993

6. Segal R, Reid R, et al: Resistance exercise in men receiving androgen deprivation therapy for prostate cancer. J Clin Oncol 21:1653-1659, 2003

7. Karling P, Hammar M, Varenhorst E: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J Urol 152:1170-1173, 1994

8. Hammar M, Frisk J, Grimas O, et al: Acupuncture treatment of vasomotor symptoms in men with prostatic carcinoma: A pilot study. J Urol 161:853-856, 1999

9. Albertazzi P, Pansini F, Bonaccorsi G, et al: The effect of dietary soy supplementation on hot flushes. Obstet Gynecol 91:6-11, 1998

10. Langenstroer P, Kramer B, Cutting B, et al: Parenteral medroxyprogesterone for the management of luteinizing hormone releasing hormone induced hot flashes in men with advanced prostate cancer. J Urol 174: 642-645, 2005

11. Sartor O, Eastham J: Progressive prostate cancer associated with use of megestrol acetate administered for control of hot flashes. South Med J 92:415-416, 1999

12. Smith JJR: A prospective comparison of treatments of symptomatic hot flushes following endocrine therapy for carcinoma of the prostate. J Urol 152:132-134, 1994

13. Quella S, Loprinzi C, Sloan J, et al: Pilot evaluation of venlafaxine for the reatment of hot flashes in men undergoing androgen ablation therapy for prostate cancer. J Urol 162:98-102, 1999

14. McLeod D, Iversen P: Gynecomastia in patients with prostate cancer: A review of treatment options. Urology 56:713-720, 2000

15. Iversen P, Tyrrell C, Kaisary A, et al: Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advance prostate cancer: 6.3 years of follow-up. J Urol 164:1579-1582, 2000.

16. Boccardo F, Rubagotti A, Battaglia M, et al: Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 23:808-815, 2005

17. Widmark A, Fossa S, Lundmo P, et al: Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3. Urology 61:145-151, 2003

18. Nishiyama T, Ishizake F, Anraku T, et al: The influence of androgen deprivation therapy on metabolism in patients with prostate cancer. J Clin Endocrinol Metab 90:657-660, 2005

19. Strum S, McDermed J, Scholz M, et al: Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol 79:933-941, 1997

20. Schellhammer P, Sharifi R, Block N, et al: Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: Final report of a double blind, randomized, multicenter trial. Urology 50:330-336, 1997