Androgen deprivation as a form of treatment for prostate cancer was first discovered by Huggins and Hodges in 1941; in 1966, this important discovery earned Huggins the Nobel Prize in medicine.[ 1] Androgen deprivation was initially achieved via orchiectomy, then later by using estrogen. However, patient acceptance of orchiectomy was poor, and problems with thromboembolic and cardiovascular events were associated with the early use of estrogen. Fortunately, in the mid-1980s the approval of lutenizing hormone-releasing hormone (LHRH) agonists by the US Food and Drug Administration (FDA) provided many prostate cancer patients with an alternative method for achieving androgen deprivation. In addition, researchers developed antiandrogen medications that block the androgen receptor. These medications have given rise to a multimillion dollar industry for the pharmaceutical companies; according to conservative estimates, approximately $230 million per year is spent on LHRH agonists.[2] Initially, the role of androgen deprivation was relegated to patients who had disease that was not curable by local measures such as radical prostatectomy or radiation, and to those who were not candidates for definitive local therapy due to other health problems. More recently, however, emerging data have suggested a progression and survival benefit with early hormone therapy in patients with metastatic prostate cancer.[3] Other data have shown an improvement in outcome after radiotherapy for higherstage tumors in patients who received concomitant hormone therapy.[4] Studies are now being conducted to determine whether the early use of hormone therapy for biochemical recurrence alone is advantageous. With these expanding indications, androgen deprivation therapy (ADT) is being used more commonly in men with prostate cancer. Indeed, a recent report by Cooperberg et al documented the dramatic rise in the use of ADT from 1989 to 2001.[5] Most dramatic was its increased use in combination with external-beam radiotherapy, with rates rising from 9.8% to 74.6% of such patients.[5] One common misconception about hormone therapy was that because it was not "chemotherapy" in the traditional sense, it did not produce as many side effects as other chemotherapeutic agents. Recent reports have begun to describe the comprehensive list of side effects associated with ADT. In this review, we describe the various side effects of ADT as well as some of the treatments for those side effects. Osteoporosis Osteoporosis after menopause has long been recognized as a serious health problem in women, and the controversy about hormone replacement therapy after menopause continues to be debated. However, osteoporosis in men has not received similar attention. At present, 33% of all hip fractures occur in men, and interestingly, men are more likely to die from complications due to hip fracture than women.[6] Recently, the attention given to "andropause" (the decline in testosterone seen in many aging males) has heightened the awareness of many physicians to the possibility of osteoporosis and its complications in men. This has led to an increased concern about the osteoporosis seen in men on ADT among physicians who treat men with prostate cancer. Despite the fact that androgen deprivation has been used to treat prostate cancer since the 1940s, it was not until 1989 that Stepan et al first reported the association between androgen deprivation and osteoporosis.[7] This study demonstrated that there was progressive loss of bone mineral content in the lumbar spine of men who had undergone orchiectomy as compared to eugonadal men. Osteoporosis as a complication of androgen deprivation is now well recognized, and a recent report demonstrated a 2.5 times increased risk of bone fracture in men who had undergone orchiectomy as compared to community fracture rates.[8] Strikingly, the cumulative incidence of fractures in patients followed for up to 10 years was 65%. Bone Mineral Content/Density
Evidence shows that LHRH agonist therapy results in significant changes in both bone mineral density and bone mineral content.[9] Stoch et al evaluated 60 men with prostate cancer. Of this group, 19 received LHRH agonist therapy, and 41 did not. Bone mineral density was measured by dualenergy x-ray absorptiometry, and bone mineral content, by markers of bone turnover such as urinary N-telopeptide, bone-specific alkaline phosphatase, and osteocalcin. The results revealed a statistically significant decrease in bone mineral density among patients on LHRH agonists compared to those who did not receive hormonal therapy. In addition, bone turnover was significantly increased in the LHRH agonist therapy group. These results confirm that the osteoporosis seen in these patients is due to the androgen deprivation itself rather than the prostate cancer, and that LHRH agonist therapy results in changes in bone similar to those associated with orchiectomy. Etiology Theories
The etiology of osteoporosis due to ADT is currently not well understood. It appears that the condition is caused by the absence of circulating testosterone. Support for this theory comes from data showing that patients on nonsteroidal antiandrogen monotherapy had lower levels of urinary N-telopeptide and serum osteocalcin than men treated with LHRH agonists.[ 10] Androgens have been shown to mediate osteoblast proliferation and differentiation and increase bone matrix production and osteocalcin secretion.[ 11] In addition, testosterone has been shown to stimulate growth factors such as transforming growth factor- beta and insulin-like growth factor-1, which may be important in osteoblast proliferation.[11] Data suggest, however, that what is truly important is the peripheral conversion of testosterone to estrogen and the positive effects of estrogen on bones. This theory is supported by a case report from Smith et al, who described a male patient with significant osteoporosis despite normal testosterone levels but a mutation in the estrogen-receptor gene.[12] Estradiol(Drug information on estradiol) levels have been shown to be significantly reduced in men receiving LHRH agonist therapy, lending further support to the importance of estrogen in preventing osteoporosis.[ 13] Scherr et al further confirmed the significant role of estrogen in preventing osteoporosis by demonstrating that men on LHRH agonists who also received 1 mg/d of diethylstilbestrol(Drug information on diethylstilbestrol) (Stilphostrol) had decreased bone turnover, as measured by urinary N-telopeptide levels.[14] Prevention of Osteoporosis
Intermittent androgen therapy has been evaluated as a possible means of preventing osteoporosis. In a study by Higano et al, the effects of intermittent androgen ablation on bone mineral density, as measured by dualenergy x-ray absorptiometry, were examined.[15] Patients were treated for 9 months with LHRH agonist therapy and then followed off therapy. Androgen deprivation was reinitiated when prostate-specific antigen (PSA) levels began to rise. Bone mineral density was measured at the end of each treatment cycle and was found to be significantly decreased, suggesting that measurable changes in bone density occur after as little as 9 months of androgen deprivation. At 1 year, the loss of bone mineral density is approximately 3% to 5%, with less bone loss over subsequent years.[16] Because osteoporosis is a well-recognized adverse effect of ADT, measures to prevent its development should be discussed with the patient at the initiation of ADT. Many of these preventive measures are the same as those recommended to postmenopausal women, including smoking cessation, moderation of alcohol(Drug information on alcohol) and caffeine(Drug information on caffeine) consumption, vitamin D and calcium supplementation, and regular weight-bearing or resistance exercise. Seeman et al demonstrated that smoking and excessive alcohol consumption were independent risk factors for osteoporosis in men, thus underscoring the need for these modifications in lifestyle.[17] Interestingly, obesity had a protective effect, presumably due to the increased peripheral conversion of testosterone to estrogen. Some reports have shown a significant deficiency in vitamin D and calcium among men with prostate cancer.[18,19] Therefore, current recommendations are to maintain calcium intake at 1,200 to 1,500 mg/d and to supplement vitamin D with 400 IU/d.[18,19]

• Bisphosphonates-More effective medical options for the prevention and treatment of osteoporosis are now available, and bisphosphonates constitute one such option. These agents inhibit osteoclasts, thereby decreasing the resorption of bone. Currently, alendronate (Fosamax), pamidronate(Drug information on pamidronate) (Aredia), and zoledronic acid (Zometa) are the three bisphosphonates used in clinical practice. Alendronate recently became the first agent to be approved by the FDA for the treatment of male osteoporosis and offers the advantage of oral administration. One of the first studies to address the use of bisphosphonates for the prevention of osteoporosis in prostate cancer patients was conducted by Orwoll et al.[20] In this study, a mean increase in the bone mineral density of the lumbar spine and femoral neck was observed among those receiving alendronate.[20] However, none of the study participants was receiving ADT, and thus the efficacy of this drug in preventing or improving osteoporosis in men on ADT is unknown. Patients who are to be started on alendronate should be informed that the medication must be taken on an empty stomach with the patient sitting in an upright position for at least 30 minutes. Moreover, there is a risk of gastrointestinal side effects such as epigastric pain, severe esophagitis, and gastroesophageal ulceration.[21] Pamidronate and zoledronic acid(Drug information on zoledronic acid) are currently only available in an intravenous formulation. In a study by Smith et al, 47 men with prostate cancer and no evidence of bone metastases were randomized to receive either LHRH agonist therapy alone or LHRH agonist therapy plus pamidronate.[18] Patients who received 60 mg of IV pamidronate every 12 weeks did not show a loss in bone mineral density, in contrast to those who did not receive pamidronate. Zoledronic acid is the most potent of the three bisphosphonates, demonstrating up to 850 times the potency of pamidronate in animal studies. At a dose of 4 mg IV every 3 weeks, it has been shown to decrease skeletal- related events (including fractures) in men with hormone-refractory prostate cancer and bone metastases.[22] It has also demonstrated efficacy in decreasing pain due to bone metastases and their complications.[22] A recently reported prospective randomized controlled trial of zoledronic acid at 4 mg IV was shown to prevent bone loss in men on LHRH agonists for nonmetastatic prostate cancer.[23] Therefore, in those men with evidence of osteoporosis on dual-energy x-ray absorptiometry scan, zoledronic acid may improve bone mineral density. Side effects of bisphosphonates include fever, anemia, constipation, hypophosphatemia, and reactions at the injection site.[24,25] Decreased renal function manifested by elevated creatinine levels was observed in initial trials of zoledronic acid.[25] This effect appears to be associated only with the 8-mg dose, shorter infusion times, and smaller infusion volumes, although most physicians continue to monitor creatinine levels in patients receiving zoledronic acid on any schedule.

Screening Considerations
No standardized recommendations for osteoporosis screening in men exist. In addition, no clear definition of osteoporosis in men has been described, as men have higher peak bone mass and larger bones than women.[ 26] Risk factors such as activity level, patient age, tobacco use, alcohol consumption, and the presence of hypogonadism should be considered when deciding when to screen men for osteoporosis. Given the data from Higano et al, which suggest that bone mineral density can be decreased after as few as 9 months of therapy, a dual-energy x-ray absorptiometry scan within the first year is probably indicated. Although no trials have addressed the benefit of screening for osteoporosis in men on ADT, Ross et al recommended a dual-energy x-ray absorptiometry scan at the initiation of ADT and at 1 year posttherapy.[16] Further screening is based on the results of previous scans, with more frequent evaluation recommended for those nearing osteoporosis. Hot Flashes When counseling a man about ADT, we may look to the patient's female partner to confirm the side effects of the therapy. In particular, postmenopausal women can often accurately portray one of the more common side effects-hot flashes. Up to 80% of patients on LHRH agonists will experience hot flashes.[27,28] The degree to which these hot flashes disrupt their lives varies, but up to 27% of those surveyed in one study found this side effect to be the most bothersome of all.[28-30] Hot flashes are typically described as an intense sensation of warmth in the face and upper portion of the body. They may be associated with nausea and sweating and may even occur during sleep. They vary in duration from several seconds to up to 1 hour but most commonly occur for less than 5 minutes. Triggers for hot flashes include heat, stress, changes in body position, or ingestion of hot liquids, although many patients cannot identify any inciting factors.[31] Hot flashes may spontaneously resolve, but many patients continue to experience them as long as they are receiving ADT. Hot flashes are thought to result from an alteration in the feedback mechanism to the hypothalamus due to the lack of testosterone. An increase in catecholamine secretion in response to decreased endogenous peptide secretion stimulates the nearby thermoregulatory center of the hypothalamus, resulting in the perception of increased heat.[31,32] Treatment
Many of the treatments employed for hot flashes in men on ADT are similar to those used to treat postmenopausal women. They include progestins, estrogen, phenobarbital(Drug information on phenobarbital), megestrol acetate, antidepressants, clonidine(Drug information on clonidine), acupuncture, soy, and vitamin E(Drug information on vitamin e).[33-40]

• Diethylstilbestrol-An estrogen, diethylstilbestrol has been used successfully to treat hot flashes in men on ADT.[31,33] Doses as low as 0.3 mg have been shown to be effective and have not been associated with the cardiovascular complications seen with the higher doses of diethylstilbestrol used in the past.[33] The advantages of this therapy are its low cost and the prevention of osteoporosis; drawbacks are the potential side effect of tender gynecomastia and difficulty in obtaining the medication. Currently, only approximately 15 pharmacies in the United States carry diethylstilbestrol. However, most pharmacies that do compounding can produce it at little cost.
• Megestrol Acetate-This progestin is a commonly used medication that has been shown to reduce hot flashes by up to 85%.[41] The side effects of megestrol(Drug information on megestrol) can include chills, weight gain, and carpal tunnel-type pain, although most patients tolerate the medication with few such problems.[ 41] One concern associated with its use for hot flashes in men on ADT came from a case report by Sartor et al, which showed an increase in PSA level among patients on megestrol.[ 40] However, to our knowledge, this is the only published report of such an occurrence.
• Cyproterone Acetate-This synthetic derivative of hydroxyprogesterone is a steroidal antiandrogen that has been used in Europe (it is not an approved medication in the United States) as monotherapy for prostate cancer.[42] It has been shown to produce fewer side effects in terms of hot flashes, but its efficacy as monotherapy is dubious. Furthermore, it does not appear to decrease the incidence of osteoporosis and is associated with adverse effects on lipid profiles and increased cardiovascular risk.[42] Cervenakov et al reported the use of cyproterone to relieve hot flashes in men on complete androgen blockade.[ 43] In this study, 50 mg of cyproterone(Drug information on cyproterone) twice daily or a 300-mg intramuscular depot injection given every 2 weeks was effective in decreasing hot flashes in approximately 80.6% of the patients studied.
• Medroxyprogesterone Acetate- Another progestin, medroxyprogesterone(Drug information on medroxyprogesterone) acetate (Depo-Provera), has been reported to be effective in relieving the hot flashes associated with ADT. Ellsworth et al demonstrated an 82% complete response rate and a 12% partial response rate, with only 6% of patients reporting no response.[ 35] Patients were treated with a 400-mg intramuscular depot injection at the time ADT therapy was initiated. Interestingly, several patients who stopped therapy due to the resolution of hot flashes had no recurrence of symptoms. The medication was well tolerated, with side effects mainly limited to sexual dysfunction.
• Other Agents-Clonidine was initially thought to have some efficacy in the treatment of hot flashes. However, more rigorous placebocontrolled studies have failed to demonstrate the efficacy of this medication.[44] Other centrally acting agents such as the antidepressants have been reported to decrease the incidence of hot flashes.[45,46] In particular, the serotonin-reuptake inhibitor venlafaxine hydrochloride (Effexor) has demonstrated efficacy in treating hot flashes associated with ADT. In placebo- controlled studies, this drug was shown to decrease the incidence of hot flashes by up to 50%. Breast cancer patients received doses of 75 mg; however, lower doses of 12.5 mg have been reported to be effective in men.[45-47] Side effects include dry mouth and constipation, but overall, the medication is well tolerated. In addition, venlafaxine offers the added benefit of treating depression, which is commonly present in cancer patients.

Complementary and Alternative Treatments
The fastest growing segment of the health-care market in recent years has been complementary and alternative medicine. Prostate cancer management is certainly affected by such treatments, and some of these methods have been used to treat the side effects associated with ADT. Acupuncture is one such therapy, and its efficacy was examined by Hammar et al.[36] In this study of seven men, acupuncture was performed twice weekly for 2 weeks, then once a week for 10 weeks. All patients reported a decrease in hot flashes, with an average decrease of 70% after 10 weeks.

• Soy Products-The use of soy products for the treatment of hot flashes in both men and women has grown in popularity, even achieving commercial success among postmenopausal women. The basis for this success is hypothesized to be soy's phytoestrogenic properties. Two components of soy-genistein and diadzein- are believed to be particularly responsible for decreasing hot flashes,[ 38] but the substance may also provide benefits such as reducing cholesterol and modestly reducing PSA levels. The source from which soy is obtained is important when recommending this form of treatment to patients. Foodstuffs such as soy milk, and some soy powders do not result in large amounts of bioavailable soy, and soy sauce has essentially no bioavailable soy. Soybeans are typically the best source of soy and can often be found in the frozen food section of most grocery stores.
• Vitamin E-Vitamin E has also been shown to be effective in reducing hot flashes. Barton et al conducted a placebo-controlled study of vitamin E in women with breast cancer who were suffering from hot flashes and found that their symptoms decreased by 30%.[39] However, up to 22% of patients in the placebo group also experienced a decrease in symptoms. Given recent attention to the beneficial effects of vitamin E and soy in prostate cancer patients, there is probably little downside to using these therapies with or without other treatments for hot flashes. Many of these therapies tend to be initiated by the patient, but when initiated by the physician, patient acceptance is typically very good.

Anemia Fatigue is a common complaint of patients on ADT. Often, no objective cause for the fatigue can be determined, but anemia is one side effect that may contribute to the problem. The anemia seen in patients on ADT is usually normocytic and normochromic. The condition is thought to be due to the lack of testosterone and 5-beta-dihydrotestosterone stimulation of erythroid precursors as well as a decrease in erythropoietin(Drug information on erythropoietin) production.[48] Strum et al examined the incidence and severity of anemia in patients on complete androgen blockade.[48] In this study, the investigators found that up to 90% of patients experienced at least a 10% decline in hemoglobin levels, and in 13%, hemoglobin declined by 25% or more. Importantly, a decrease in hemoglobin was noted as quickly as 1 month after the initiation of ADT, but the nadir hemoglobin level was not reached until after 5.6 months of therapy. Symptoms directly related to anemia occurred in 13% of patients. Anemia was worse in patients on complete androgen blockade than in those on LHRH agonist therapy alone, and when an antiandrogen was added to the regimen of a patient on LHRH agonist therapy, a further drop in hemoglobin was seen. No statistically significant difference was seen in terms of percent decrease based on patient age; however, because older patients tended to have lower baseline hemoglobin levels, the change in hemoglobin may be more significant in these patients. The authors found that typically the anemia was easily corrected with the subcutaneous administration of recombinant human erythropoietin. Previous reports suggested that the anemia seen with ADT reversed fairly rapidly with the discontinuation of therapy. In this study, however, resolution of anemia in patients receiving long-term ADT often took more than 1 year. Antiandrogen monotherapy also appears to be associated with anemia, although the mechanism of this effect is not clear. Strum et al recommended following hemoglobin levels every 2 to 3 months in patients on ADT, and more closely in those who complain of anemia-related symptoms such as chest pain, shortness of breath with exertion, or syncope.[48] Changes in Body Mass and Lipid Profiles Patients often complain of weight gain during ADT. The etiology of this effect may be related to several factors, such as an increase in sedentary activity secondary to fatigue, a change in appetite, or the decrease in serum testosterone levels. Serum testosterone concentrations have been shown to correlate positively with increased muscle mass and negatively with increased body fat.[49] Higano et al examined the effect of combined androgen blockade on weight, and found a median increase of 6 kg (~13 lb).[50] In a study by Smith et al, weight and body mass index were increased by 2.4% after only 48 weeks of therapy.[51] Strikingly, this increase in weight appeared to be due to an 11% increase in fat body mass, whereas lean body mass decreased by 2.4%. Because this study was performed in patients with no evidence of metastatic prostate cancer, the changes in body composition are attributed to the effects of ADT. Also documented in this study was a 9% increase in total cholesterol and a 26.5 % increase in serum triglycerides. Although no link has been documented between an increase in cardiovascular complications and ADT (other than with high doses of diethylstilbestrol), the change in body composition and lipid profiles is worrisome and deserves further study.