COMPLICATIONS OF HORMONAL TREATMENT OF PROSTATE CANCER       Introduction The number of prostate cancer survivors in the United States is estimated at 2 million, and approximately one-third of these men are currently receiving ADT (androgen deprivation therapy, i.e. lowering testosterone with Lupron or Zoladex). In addition to a role in the adjuvant treatment of early, localized prostate cancer, ADT represents the primary treatment for recurrent prostate cancer. Once ADT is initiated for recurrent prostate cancer, therapy typically continues until the time of death, a period that may extend over many years. A singularly effective therapy in treating prostate cancer, ADT is increasingly recognized to have undesirable physiologic effects that may result in important long-term adverse consequences. Awareness of the potential adverse effects of ADT and the overall risk/benefit ratio is important in determining the suitability of treatment in individual patients.  ADT may be accomplished by either surgical or chemical castration. GnRH (gonadotropin-releasing hormone) agonists are the most commonly used agents for this purpose and effectively result in hypogonadism with reduction in serum testosterone levels of >95% and in estrogen levels of >80%. The adverse effects of ADT are due to hypogonadism and include vasomotor flushing, loss of libido, decreased bone density, increased fat mass, and decreased muscle mass.106 Additionally, long-term ADT is associated with an increased risk of diabetes and cardiovascular disease.     Vasomotor Flushing Most men treated with ADT will experience vasomotor flushing, or hot flashes, which may have substantial impact on quality of life in some men. Hot flashes are described as unpredictable episodes of intense warmth in the upper part of the body and face, accompanied at times by diaphoresis. A number of "natural remedies" have been touted to treat hot flashes, including acupuncture, black cohosh, flax seed, or soy products, but none is demonstrated to help in other than anecdotal instances. Transdermal estrogen and megestrol acetate have been shown to reduce hot flashes, but with adverse consequences, including breast swelling and nipple tenderness with estrogens and weight gain with megestrol. Selective serotonin uptake inhibitors are effective in women with breast cancer and menopausal hot flashes; although no randomized trials have been carried out in men, venlafaxine and paroxetine appear to be occasionally effective in small studies of men with hot flashes.     Anemia Androgens promote erythropoiesis by increasing erythopoietin production and by direct activation of erythrocyte progenitors. GnRH agonists significantly decrease hemoglobin concentrations in men with prostate cancer. The median decrease in hemoglobin concentrations is about 1 g/dL but sufficient to cause anemia in most men. Treatment-related anemia is usually mild and not associated with symptoms. It is characteristically normochromic and normocytic. Erythropoietin increases hemoglobin concentrations in men receiving GnRH agonists for prostate cancer, although treatment for anemia in this setting is rarely necessary.     Fatigue Fatigue is a common and important adverse effect of ADT. Approximately two-thirds of men report increases in fatigue after treatment with a GnRH agonist. Changes in body composition, particularly decreased lean body mass, may contribute to treatment-related fatigue. Anemia may also contribute to treatment-related fatigue.     Gynecomastia and Mastodynia Gynecomastia is defined as benign proliferation of the glandular subareolar breast tissue. Mastodynia refers to breast/nipple tenderness. The incidence of gynecomastia and/or mastodynia varies with the type and duration of ADT. About 10% to 15% of men develop gynecomastia after bilateral orchiectomies or treatment with a GnRH agonist. In contrast, the majority of men receiving monotherapy with an antiandrogen develop gynecomastia. Prophylactic breast irradiation appears the most effective strategy to prevent or mitigate gynecomastia; treatment after development of gynecomastia may improve pain but does not improve enlargement. Tamoxifen is the most effective medical therapy for gynecomastia and/or mastodynia. Breast reduction surgery may benefit the occasional man with severe breast symptoms that are refractory to medical treatment.     Osteoporosis and Fractures Several prospective studies have demonstrated that ADT results in immediate and sustained decrease in bone mineral density (BMD) in men with prostate cancer.The decrease in BMD continues at an average rate of 2% to 3% per year during treatment, and the risk of fracture and development of osteoporosis therefore appears to increase steadily with duration of therapy. The mechanism of BMD decline may relate to an increase in bone turnover due to ADT. Bone turnover markers measured in serum and urine demonstrate increased activity of both osteoblasts and osteoclasts and reach a plateau after 6 months of ADT. Changes in sensitivity of bone to parathyroid hormone might also contribute to increased osteoclast activation and decreased BMD. Osteoporosis is common in men, with an estimated prevalence of more than 2 million men in the United States. Hypogonadism may be the most common cause of acquired osteoporosis in men and together with alcohol abuse and chronic glucocorticoid therapy accounts for one-half of all cases of male osteoporosis. The decreased BMD and increased risk of osteoporosis engendered by ADT in men with prostate cancer is now firmly linked to an increased fracture risk. In one claims-based analysis, for example, men with prostate cancer who were receiving GnRH agonists were 1.4 times as likely to develop fractures as men with prostate cancer who had not received GnRH agonists.     Management of Treatment-related Osteoporosis Daily supplementation of calcium and vitamin D is recommended by the National Institute of Health at doses of 1200 to 1500 milligrams/day and 400 IU/day, respectively. Supplementation with calcium and vitamin D modestly decreases fracture incidence in men and women over age 65 years. However, this is not sufficient to prevent bone loss in men treated with ADT. The increased risks of osteoporosis and fractures in men with prostate cancer receiving ADT have led to randomized controlled trials aimed at preventing or ameliorating these risks. Bisphosphonates, including pamidronate and zoledronic acid (ZA), are effective at preventing ADT-related BMD loss. In a study that treated 106 men receiving ADT for nonmetastatic prostate cancer with ZA versus placebo, ZA administered at 4 mg every 12 weeks significantly increased BMD in the hip and lumbar spine by 3.9% and 7.3%, respectively.129 In another randomized study, a single infusion of ZA resulted in significantly increased BMD in the hip and spine after 1 year.138 The differences in BMD between the men treated with ZA versus placebo were similar in the 2 studies, suggesting that annual infusion of ZA might be sufficient to prevent treatment-related loss of BMD.  Three ongoing randomized controlled trials are assessing the impact of medical therapy with denosumab, toremifene, or ZA on fracture prevention:  Denosumab is a monoclonal antibody that blocks the activity of receptor activator of NF-B ligand (RANKL), a protein that stimulates osteoclast activity. A Phase III trial of 1,468 men receiving ADT for nonmetastatic prostate cancer is assigning men to either denosumab or placebo administered every 6 months. The primary objectives are evaluation of fracture risk and BMD. Toremifene is a selective estrogen-receptor modulator that has been shown to increase BMD and reduce vasomotor flushing in men receiving ADT. A Phase III trial of 1,392 men receiving ADT for nonmetastatic prostate cancer is assigning men to daily toremifene or placebo.The primary objectives are evaluation of fracture risk, BMD, lipid levels, and hot flashes. As described previously, ZA is proven to prevent treatment-related BMD loss. Further, in hormone-refractory metastatic prostate cancer, ZA reduces the risk of bone complications, including fractures. A Phase III cooperative group study of 1,272 men with early-stage prostate cancer is assigning men treated with GnRH agonists in combination with radiation to either ZA or placebo every 3 months. The primary objectives are evaluation of fracture risk and BMD. Currently, we recommend routine use of supplemental calcium and vitamin D in all men treated with ADT. Men undergoing long-term ADT for nonmetastatic prostate cancer should have assessment of fracture risk by history, laboratory testing, and measurement of BMD. For men at greatest fracture risk, selective use of drug therapy should be considered.     Obesity ADT is accompanied by prompt and often marked changes in body composition. Quantitative analysis of men beginning GnRH-agonist therapy has shown an increase in fat mass of 9.4% to 11% in 1 year, with a concurrent decrease in lean body mass of 2.7% to 3.8%. The increase in fat mass is observed in subcutaneous rather than intra-abdominal fat. Two other studies in men with nonmetastatic prostate cancer found an increase in mean fat mass of 8.5% or 4.3% within 3 months of starting ADT, suggesting that this effect may be important even for men treated with short courses of ADT. Because of the association between increased weight, fat mass, and insulin resistance, further studies have assessed the relationship between ADT and insulin resistance.      Lipid Alterations and Insulin Resistance Treatment-related changes in body composition are accompanied by adverse metabolic effects. GnRH agonists increase serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides.In a prospective 12-month study, for example, GnRH agonists increased serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides by 9.0%, 7.3%, and 26.5%, respectively. GnRH agonists increase fasting plasma insulin level, a surrogate for insulin resistance.In a prospective study of nondiabetic men with prostate cancer initiating GnRH-agonist therapy, fasting plasma insulin levels increased by 26%, and the whole-body insulin sensitivity index decreased by 11%. The term "metabolic syndrome" refers to a clustering of specific cardiovascular disease risk factors whose pathophysiology appears related to insulin resistance. The National Cholesterol Education Program's Adult Treatment Panel (ATP III) and World Health Organization have defined the metabolic syndrome using distinct but related criteria. A recent cross-sectional study reported a higher prevalence of the metabolic syndrome (as defined by the ATP III) in 18 men receiving a GnRH agonist than in age-matched control groups of untreated men with prostate cancer and men without prostate cancer. Men receiving GnRH-agonist therapy had greater prevalence of increased abdominal girth, elevated triglycerides, and elevated fasting plasma glucose—consistent with results of prospective studies of GnRH-agonist treatment. In contrast with the metabolic syndrome, however, prospective studies have shown that GnRH agonists preferentially increase subcutaneous rather than visceral abdominal fat and increase rather than decrease high-density lipoprotein cholesterol.149 In addition, GnRH agonists increase serum adiponectin levels in men with prostate cancer, whereas the metabolic syndrome is associated with low adiponectin levels. Taken together, these observations suggest that GnRH agonists cause a pattern of metabolic changes that is distinct from the classically defined metabolic syndrome.     Cardiovascular Disease and Diabetes Diabetes and cardiovascular disease are leading causes of death in men. The adverse treatment-related changes in weight, body composition, lipids, and insulin sensitivity raise the possibility that ADT may increase the risk of these medical conditions. To evaluate the relationship between ADT and risk for incident diabetes and cardiovascular disease, Keating and colleagues conducted a large population-based study using the SEER-Medicare database. This landmark study included 73,196 men diagnosed with local or locoregional prostate cancer between 1992 and 1999 with follow up through 2001. Of the total population, one-third of men were treated with ADT during the study period. The analysis was adjusted for both patient and tumor characteristics. After adjusting for a variety of covariates, ADT with a GnRH agonist was associated with a significantly greater risk of incident diabetes (adjusted hazard ratio 1.42, P <.001), coronary heart disease (adjusted hazard ratio 1.16, P <.001), and admission for myocardial infarction (adjusted hazard ratio 1.1142, P <.03). A subsequent study using SEER-Medicare data confirmed the link between ADT and incident cardiovascular disease.