What are some of the side effects of hormonal therapy and how are they treated

LHRH analogues and antagonists have side effects that may affect your quality of life over the short and long term (Table 9). Some of the side effects related to these medications, such as hot flashes, erectile dysfunction, anemia, and osteoporosis, can be treated. Erectile dysfunction occurs in about 80% of men taking LHRH analogues and antagonists and is associated with decreased libido (sexual desire). The widely prescribed drug silde-nafil (Viagra) as well as the other oral therapies for erectile dysfunction, vardenafil (Levitra) and tadalafil (Cialis) are effective in most of these men if they had normal erectile function before starting hormone therapy. Unfortunately, there is no medication to restore libido.

Osteoporosis

The reduction in the amount of bone mass, leading to fractures after minimal trauma.

A recent Gallup survey of American men revealed that most men believe that osteoporosis is "a woman's disease." Osteoporosis is loss of bone density, and it leads to weakened bones that break more easily. Yet this disease can affect men, particularly men taking hormone therapy for prostate cancer. It is anticipated that there will be approximately 2,000 osteoporosis-induced fractures in men with advanced prostate cancer.

How can you tell if you have osteoporosis? The best way to check the bone mineral density is the dual-energy x-ray absorptiometry (DEXA) scan, the same study used to evaluate for osteoporosis in women. It is noninvasive, precise, and a quick test involving minimal radiation exposure. The test measures the bone mineral density, which is compared with values obtained from normal, young, adult control subjects.

Several factors contribute to loss of bone mineral density, but decreased sex hormone production has the most significant impact on bone mineral density. Low testosterone levels affect bone mineral density in men almost the same as low estrogen levels in women. The use of androgen deprivation therapy, whether it is via orchiec-tomy or LHRH analogue or LHRH antagonist with or without antiandrogen, causes decreased bone mineral density. There is an average loss of 4% per year for the first 2 years on hormone therapy and 2% per year after year 4, which is similar to the loss in women after removal of the ovaries or natural menopause. This loss of bone mineral density in men taking hormone therapy occurs for at least ten years and probably accounts for the increased incidence of fractures: 5 to 13.5% of men taking hormone therapy have fractures compared to 1% in men with prostate cancer who are not receiving hormone therapy.

Lifestyle modifications that may help decrease the risks of bone complications in men on hormonal therapy include smoking cessation, decreased alcohol intake, performing weight bearing and arm exercises, and taking supplements of 1200 mg of calcium and 400 to 800 international units of vitamin D daily. Calcium rich diets include dairy products, salmon, spinach, and tofu.

When should men on hormone therapy be evaluated for osteoporosis? There are no good guidelines to help determine how frequently DEXA scans should be obtained in men with prostate cancer who are taking hormone therapy. It may be helpful to obtain a baseline DEXA scan before starting hormone therapy and then obtain periodic DEXA scans thereafter. There are things that can be done to prevent or treat osteoporosis. Several studies have shown that an increase in bone mineral density loss occurs in men who have had an orchiectomy compared to men who are receiving LHRH analogues. The reason for this is not clear, but this result suggests that other

It may be helpful to obtain a baseline DEXA scan before starting hormone therapy and then obtain periodic DEXA scans thereafter.

chemicals are produced by the testes that may be important in maintaining bone density. Further studies may help identify these chemicals. Certain factors can put one at increased risk for osteoporosis, including sedentary lifestyle, decreased sun exposure, glucocorticoid therapy, excess caffeine intake, decreased dietary calcium and vitamin D intake or exposure, increased salt intake, aluminum-containing antacid consumption, alcohol abuse, and smoking.

Changes in lifestyle can help prevent osteoporosis. Various medications have been used in women with osteoporosis, but no treatments have been approved by the United States Food and Drug Administration (FDA) for men taking hormone therapy.

A group of medications commonly used in women with osteoporosis are the biphosphonates, which prevent bone breakdown. Three different biphosphonates, ale-dronate (Fosamax), neridronate (Nerexia), and zole-dronate (Zometa) have been used to prevent osteoporosis in androgen-deficient men with prostate cancer. Zole-dronate has been shown to increase bone density in men on hormonal therapy. Intermittent administration of either intravenous pamidronate or zoledronic acid prevents treatment-related bone loss in men with prostate cancer. In a clinical study, zoledronic acid (4 mg intravenous every 3 months) prevented bone loss and actually increased bone marrow density, during androgen-depri-vation therapy for prostate cancer. Side effects of intravenous biphosphonates include an influenza-like illness (14-15%), hot flashes (23-58%), fatigue (10-38%), arthralgias (13-22%) and fever (10-11.5%). Osteonecrosis of the jaw (ONJ) has been reported in cancer patients receiving complex treatment regimens, including radiation therapy, chemotherapy, and/or corticosteroids, along with an intravenous biphosphonate. ONJ has been reported more frequently in patients with cancer types other than prostate cancer. Cancer patients undergoing invasive dental procedures (i.e. tooth extraction) are at greater risk of developing ONJ.

Another way of decreasing the risk of osteoporosis is the use of intermittent hormone therapy. With this form of therapy, you are on and off the hormones for set periods of time. The idea of intermittent hormone therapy is that the prostate cancer cells that survive while you are on hormone therapy (hormone insensitive) become hormone sensitive again when they are exposed to androgens. Possible advantages of intermittent androgen suppression include preservation of androgen sensitivity of the tumor, possible prolonged survival, improved quality of life because of recovery of libido and potency and improved sense of well-being, decrease in treatment costs, increased sensitivity of the prostate cancer to chemotherapy, and the fact that it can be used to treat all stages of prostate cancer. Intermittent hormone therapy appears to affect bone mineral density loss at six years.

Hot Flushes/Flashes

Hot flashes occur in men receiving hormone therapy for the treatment of high-stage prostate cancer and in patients receiving neoadjuvant hormone therapy (hormone therapy administered before definitive treatment, e.g., radical prostatectomy or interstitial seeds to shrink the prostate cancer).

Approximately three-quarters (75%) of the men being treated with hormone therapy for prostate cancer report bothersome hot flashes that begin 1 to 12 months after starting hormone therapy and often persist for years. The hot flashes may vary in intensity and can last from a few seconds to an hour.

The cause of hot flashes and sweating (vasomotor symptoms) associated with hormone therapy (shots or orchiectomy) is not well known. The symptoms are similar to those that women experience while going through menopause, yet they are not typically experienced by men, whose testosterone level slowly declines with aging. The symptoms appear to be related to the sudden large decrease in the testosterone level and the effects that testosterone has on blood vessels. There are no identifiable factors that put one individual at higher risk for hot flashes than another.

There are many ways to treat hot flashes associated with hormone therapy, and different men respond to different treatments (Table 10). Some options include clonidine (a blood pressure medication), the hormone megestrol acetate (Megace), medroxyprogesterone acetate (Provera), estrogen patches, low-dose estrogen (DES), and medroxyprogesterone acetate (Depo-Provera). Oral estrogen has been effective in getting rid of the hot flashes; however, estrogen use carries the risk of heart problems, strokes, and blood clots. Low-dose megestrol acetate (Megace) has been used effectively to treat hot flashes and works in about 85% of people. However, it has been associated in rare cases with an increase in PSA that decreased with stopping the Megace and must be used cautiously. Another chemical, cyproterone acetate, has been used to treat hot flashes, but it is associated with cardiac side effects, is expensive, and is not approved for this use by the FDA. The hormone Provera, given orally or intramuscularly, has been effective in treating hot flashes, but it also may have

Table 10 Drugs Commonly Used in Treating Hot Flashes

Drug

Dosage

Possible Side Effects

Megestrol acetate (Megace)

20 mg BID

Chills, appetite stimulation, weight gain

Clonidine (Catapres)

0.1-mg patch each week

Hypotension, skin reaction

Medroxyprogesterone Acetate (Provera or Depo-Provera)

400 mg IM or 25 mg PO BID

Cardiovascular side effects

Venlafaxine

12.5 mg PO BID

Depression, nausea, loss of appetite

Cyproterone acetate

50 mg PO TID

Rarely, tumor may grow; cardiovascular side effects

Diethylstilbestrol (DES)

1 mg PO QD

Cardiovascular side effects, difficult to obtain, blood clots

Abbreviations: BID, twice a day; TID, three times a day; IM, intramuscularly; PO, orally; QD, every day.

Ellsworth, P. 100 Questions and Answers About Prostate Cancer, 2e. Jones and Bartlett Publishers, LLC, 2009.

Abbreviations: BID, twice a day; TID, three times a day; IM, intramuscularly; PO, orally; QD, every day.

Ellsworth, P. 100 Questions and Answers About Prostate Cancer, 2e. Jones and Bartlett Publishers, LLC, 2009.

some cardiovascular side effects. Clonidine patches have been helpful in decreasing the incidence and severity of hot flashes with natural or surgically-induced (hysterectomy and removal of the ovaries) menopause, but they do not appear to be as effective in men. Eating a serving of soy daily in addition to 800 IU of vitamin E in one study was shown to decrease the number and the severity of hot flashes to 50% (see Question 9). You should not take this amount of vitamin E without consulting your doctor first. Lastly, antidepressants such as gabapentin and venlafaxine have been shown to be useful in treating hot flashes. Limiting caffeine intake and avoiding strenuous exercise and very warm temperatures are also helpful in controlling hot flashes.

Breast Swelling and Tenderness (Gynecomastia)

Antiandrogens may cause swelling and tenderness in the breast area (gynecomastia). This can affect one or both breasts and can range from mild sensitivity to ongoing pain. About one-half of men taking antiandro-gens will develop breast swelling and between 25% and 75% will note some breast tenderness. Gynecomastia is not as common in men who have had an orchiectomy or in those who are on combination therapy (an LHRH agonist or antagonist and an anti-androgen). A single dose of radiation to the breasts can decrease the risk of developing gynecomastia but is only effective if the radiation is given the first month of the hormone therapy. If gynecomastia has already developed then radiation treatment is not helpful. Tamoxifen, a medication that is used to treat breast cancer, can help in treating gynecomastia in men taking antiandrogens. It can't be used in those men who are taking estrogens (DES) to treat prostate cancer as the tamoxifen stops the estrogens from working properly. Tamoxifen may help treat gynecomastia that has already developed in men after starting antiandrogens. Another option for the treatment of gynecomastia is surgical removal of the breast tissue. However, this has the risk of damage to the nipple and loss of feeling.

Hormone therapy can also cause weight gain and muscle loss. Exercise and diet regimens can help with these problems. Hormone therapy can also cause tiredness and lethargy, memory problems, and moodiness. The lethargy and tiredness may improve over time, but regular exercise can give men more energy and help them cope.

Anemia (lowering of the red blood cell count) may occur in men who are on hormone therapy. For men with advanced prostate cancer, use of an LHRH

agonist/antagonist without the antiandrogen may be beneficial in limiting the anemia that is caused by complete androgen blockade (antiandrogen plus LHRH agonist or antagonist). Erythropoietin, iron preparations, and vitamin supplementation may be helpful in improving the anemia.

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