By: Mark Scholz, M.D.
Prostate Oncology Specialists
Testosterone inactivating pharmaceuticals (TIP) prolong survival in randomized prospective trials. TIP, when used after surgery in men with lymph node metastasis, decreases mortality seven fold when used immediately rather than being delayed to the time of disease progression.1 TIP administered with radiation reduces prostate cancer mortality.2 The early use of TIP also delays prostate cancer progression when started at the first sign of relapse rather than delaying its use until clinical disease progression, such as bone metastasis or lymph node enlargement.3 Clearly TIP has tremendous utility in modern prostate cancer management.
The most logical approach for selecting the type and duration of TIP is to modulate the intensity of TIP treatment in accordance with the degree of prostate cancer risk. In other words, men should receive stronger treatment when they have more aggressive disease and use milder treatment in patients with low grade disease or in men who elderly and frail. The process of selecting treatment intensity is derived from the judgment and experience of the treating physician and tempered by the individual patient's own attitudes and desires.
The selection of treatment intensity has little meaning if the patient is not familiar with the advantages of the treatment and a good understanding of all the potential side effects. Many of the side effects of TIP are reversible or preventable with simple measures. Side effects that are not completely reversible should receive much more attention than those that are. Side effects of minor consequence (i.e. dry skin or loss of body hair) are not going to be addressed in this article.
Loss of Libido
Libido is a passionate attraction to the opposite sex (in most cases) and needs to be contrasted with potency, which is the ability to get an erection. Libido can exist without potency and potency can exist without libido. This latter reality was studied at Prostate Oncology Specialists by using Viagra® in 20 men who were potent prior to starting TIP.4 Nineteen of the 20 men on TIP who were administered Viagra were able to get an adequate erection.
However, relatively few men on TIP use Viagra while on TIP because of their absence of desire. In our experience libido is completely lost in 90% of men over age 70. Men between age 60 and 70 retain libido 15% of the time. Men less than age 50 retain libido as much as half the time. Generally libido returns to normal levels when testosterone recovers. However even after testosterone recovery about 25% of men over age 65 describe their libido as diminished compared to before TIP.
About 25% of men over age 70 who are treated with more than two years of TIP will not recover testosterone production. This risk is much less common in younger men and in men treated for shorter periods. The implications of testosterone production failure are not irretrievable because testosterone replacement can be conveniently administered by the daily application of a testosterone gel to the skin.
The loss of libido and the subsequent temporary cessation of sexual activity have wide ranging ramifications far beyond the intended scope of this article. Briefly, healthy men have an average of 3-5 erections while sleeping every night. The cessation of this "exercise" can cause permanent penile atrophy. So whether or not couples continue to have sexual intercourse during TIP, we counsel our patients to induce erections two to three times a week with Viagra, a pump, or with injections.
Loss of Muscle Mass
TIP causes tiredness and weakness. This side effect is much more common when the TIP is administered for more than 6 months. The degree of tiredness and weakness vary from nonexistent to incapacitating. Most commonly this side effect is described by patients as being noticeable, unpleasant, but tolerable. Examples of this effect would be a loss of 20-30 yards on the distance of their golf drive. Tennis players lose some of the power on their serves. Some men start requiring a short nap in the afternoon.
The tiredness results from a loss of muscle mass. The exciting thing is that the muscle loss problem can be reversed with a strength training program. Unfortunately typical aerobic exercise programs are not sufficient to sustain muscle mass during the TIP treatment. Walking, aerobics, and stretching are healthy things to do, but they accomplish little toward building muscle mass.
The basis of strength training is lifting weights to the point of muscle failure. A professional trainer is highly desirable you can afford it. Typically, strength training can be accomplished in a one-hour session twice a week. Strength training exercises are intense, so a day or two of rest is needed after each session. During each one-hour session all the major muscle groups are exercised: Pectorals, deltoids, biceps, triceps, latissimus dorsi, upper and lower back muscles, abdominals, gluteus, quadriceps, hamstrings, and calf muscles. Usually three sets of 10-12 repetitions are done with weights selected to result in muscle failure toward the end of the third set (once the break-in period is completed so no injury occurs).
Strength training is so effective that patients on TIP can actually increase their muscle mass.5 We find that the secondary side effect of tiredness and weakness from TIP can be greatly minimized.
Hot flashes from TIP are irritating but are usually tolerable. They occur in about two-thirds of men treated with TIP. Ten to twenty percent of men on TIP are really bothered by them. Several measures are available. The most effective are progesterone or estrogen. Eighty percent of men treated with progesterone or estrogen have a dramatic reduction in the incidence and intensity of the hot flashes.
One convenient mode of administration is a long-acting shot called Depo-Provera. Usually a single injection is sufficient. The side effects of progesterone are possible increased appetite and some vague questions regarding its effect on prostate cancer. In one study of progesterone as treatment for 159 men with prostate cancer there was minimal anticancer activity. Nor was there any clear evidence it made the cancer worse.6
Estrogen patches are also effective. However, there is some risk of breast enlargement and in some cases prophylactic breast radiation may be required (see below).
Effexor®, a medication approved for the treatment of depression, seems to reduce hot flashes in about 50% of men treated. Neurontin®, which is used in high doses to suppress seizures, seems to reduce hot flashes when used in low doses. Both of these drugs seem to have a fairly low incidence of side effects.
The loss of testosterone, as well as the loss of muscle mass, slow the rate of body metabolism. Without careful discipline in regard to diet, TIP will result in weight gain. The time to take note of this problem is before the weight has accumulated. Following a diet to keep a stable weight is easier to accomplish than initiating a diet to lose weight. It is wise to evaluate your diet for evidence of excess fat and sugar intake at the time of starting TIP.
Breast growth occurs in more that 50% of men on anti-androgen monotherapy7 (see our article on this topic for further information). It occurs to a milder degree in about one-third of men treated with other forms of TIP. Men on anti-androgen monotherapy typically have to be treated with preventative radiation therapy to the breast area or with estrogen blocking pills such as Femara®.
Accelerated calcium loss from the bones occurs in men deprived of testosterone just as with post-menopausal women deprived of estrogen. Untreated bone loss can result in hip and spine fractures. Men who fracture their hips have a 50% mortality rate. Fortunately osteoporosis is reversible or preventable with common medications from a class of medications termed bisphosphonates. Common trade names are Fosamax®, Boniva®, Actonel® and Zometa®. These medications are administered as a pill once a week, once a month, or in the case of Zometa, intravenously.
Some men already have osteoporosis before starting TIP. Therefore, prior to starting TIP, men should obtain a baseline bone density test. We recommend starting a bisphosphonate at the same time TIP is initiated as a preventative measure. Men who have preexisting osteoporosis or who continue to have bone loss while on oral bisphosphonates are usually treated with an intravenous bisphosphonates such Zometa. Vitamin D and calcium supplementation is also required. For a more complete treatment of this subject see Bisphosphonates, Osteoporosis and Bone Metastasis at www.pcri.org.
Some men on TIP complain about problems with "word finding" and remembering names. Perhaps 10% of men treated with TIP will mention a problem remembering words. The problem reverses when the TIP is stopped. A good memory is directly related to one's overall strength and conditioning. Some of the difficulties with memory may occur because of "just feeling tired out." Complaints of memory problems occur less frequently with regular strength training.
Blood is a mixture of red cells and "serum" (water). When the proportion of red cells in the blood is diminished this is called "anemia." Red cells carry oxygen so when anemia becomes severe the most common side effect is shortness of breath. A milder degree of anemia can contribute to a feeling of tiredness. As discussed above, tiredness can also result from loss of muscle mass. Therefore it is important to monitor for the development of anemia with a simple blood test called a CBC. Normally men have a blood hematocrit of about 42% (the hematocrit is part of the CBC blood test). Treatment with TIP on the average reduces the hematocrit to around 36% which is usually well tolerated. About 10% of men develop a more severe degree of anemia with hematocrits less than 32%.8 This is significant for several reasons. First, if your doctor is unaware of this phenomenon he may conclude that you need evaluation with a bone marrow biopsy, a somewhat unpleasant and unnecessary procedure. Second, the anemia is easily correctable with low doses of hormone such as Procrit® or Aranesp®. This type of anemia does not respond to iron replacement.
Joint pains, particularly in the hands but sometimes in other joints, are fairly common with TIP. Actual joint swelling or visually arthritic changes are extremely uncommon if they occur at all. The pain may respond to glucosamine, MSM, Motrin®, Celebrex® and Aleve®. There is some soft evidence that chondroiten, another popular over the counter preparation for treatment of the joint, is not a good idea for men with prostate cancer. It is possible (but not proven) that chondroiten may accelerate the growth of prostate cancer.
Casodex® and flutamide can occasionally cause irritation of the liver. This is easily detected at an early stage with simple blood tests. When the problem occurs, whichever agent is being used must be stopped because the irritation" can progress to severe liver damage if allowed to proceed unchecked. The problem is easily reversible if the process is detected and the offending agent stopped in a timely fashion. Once the liver tests revert to normal we have had good luck by switching from one type of anti-androgen to the other. In other words, if the liver problem was incited by Casodex we have found that Eulexin is usually safe and vice versa.
Emotional changes as a result of hormonal treatment for cancer are not at all unexpected. How much of the emotional impact comes from medicines and how much is related to the overall situation (having cancer that requires treatment) is difficult to measure. Nevertheless men on TIP treatment do comment about being more closely in touch with their feelings and crying more easily. Some men find this effect of TIP unpleasant whereas others see it as a positive development. For men in the former situation low doses of common antidepressant medications (such as Zoloft®, Celexa® or Paxil®) easily reverse the unpleasant feelings.
Blood Pressure and Cholesterol Changes
We have observed both upward and downward movement of blood pressure and cholesterol after the initiation of TIP. Standard management with the addition or removal of blood pressure or cholesterol medications is effective in a manner similar to people who are not on TIP.
TIP affects many aspects of a man's life. Our general impression after many years of experience delivering this form of treatment is that it is tolerable if the side effects are expertly managed. Preventative measures such as weight lifting and diet make a huge difference in how men feel while they are on the treatment. Careful monitoring of blood tests, bone density is essential. The management of side effects like joint pains, hot flashes, reduced libido and impotence is imperfect but expert medical care by knowledgeable physicians and care givers can go accomplish much toward reducing the impact of these problems.
- Messing EM,et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol. 2006 Jun;7(6):472-9.
- Bolla M, et al. Duration of androgen suppression in the treatment of prostate cancer. The New England Journal of Medicine, June 2009.
- Moul JW, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. The Journal of Urology, March 2004
- Scholz M, Strum S. Re: Recovery of spontaneous erectile function after nerve-sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil: results of a prospective, randomized trial. J Urol. 1999 Jun;161(6):1914-5.
- Van Patten CL et al. Can a rehabilitative strength training program reverse muscle atrophy/weakness associated with androgen ablation therapy in prostate cancer patients? 2008 ASCO abstract 9642
- Dawson N et al. A randomized study comparing standard versus moderately high dose megestrol acetate for patients with advanced prostate carcinoma. Cancer Vol. 88 page 825, Feb 2000
- Kolvenbag GJ, et al Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer. Urology. 2001 Aug;58(2 Suppl 1):16-23.
- Strum S, et al: Anaemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol 79:933-941, 1997