Health and Prostate

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Osteoporosis

The increased number of men being prescribed androgen ablation therapy much earlier in the course of their disease allows the chronic manifestations of the hypogonadal state to emerge. Widespread androgen ablation therapy applied to an increasingly aging population, already predisposed to loss of bone mineral density, has created an epidemic of osteopenia and osteoporosis. Fragile bones increase the risk of skeletal fracture. More than half of men meet the bone mineral density criteria for osteopenia or osteoporosis — defined as more than 2.5 standard deviations below an age-specific reference mean — before the initiation of androgen deprivation therapy (ADT). The longer a man receives ADT, the greater the risk of fracture. After 5 years of androgen deprivation therapy, 19.4% of men experienced fractures compared with 12.6% of controls; with more than 15 years, cumulative incidence of fractures was 40% compared with 19% of non-castrate controls. It has been estimated that 4 years of ADT will place the average man in the osteopenia range. Rarely discussed even 10 years ago, skeletal health is now becoming a major concern of patients and their physicians.

Treatment of osteoporosis begins with recognition. Bone mineral density of the hip, as measured by dual energy x-ray absorptiometry, should be considered for all men anticipated to be prescribed long-term androgen deprivation therapy. Smoking cessation, weight-bearing exercise, and vitamin D and calcium can help improve bone mineral density. Prevention of osteoporosis in men receiving ADT has been demonstrated in controlled studies with the bisphosphonate pamidronate; bone mineral density actually increased in men receiving ADT with the considerably more potent bisphosphonate zoledronic acid. Bisphosphonate therapy should be considered in any man with evidence of osteopenia or osteoporosis. Transdermal estradiol also increases bone mineral density in men with prostate cancer. Not surprisingly, serum testosterone and estradiol levels were much lower in men receiving luteinizing hormone–releasing hormone (LHRH) agonists compared with those receiving a nonsteroidal antiandrogen; interestingly, markers of bone turnover were significantly higher in men receiving LHRH agonists compared with those receiving a nonsteroidal antiandrogen, suggesting that nonsteroidal antiandrogens may help maintain bone mineral density.

Hot Flashes

For more than 100 years, hot flashes (also called hot flushes, vasomotor symptoms) have been recognized as a side effect of androgen ablation; in 1896, Cabot mentioned “uncomfortable flushes of heat, similar to those experienced by women at the time of menopause” in men undergoing castration for prostatic enlargement. Described as a subjective feeling of warmth in the upper torso and head followed by objective perspiration, hot flashes are not life-threatening but are among the most common side effects of androgen ablation, affecting between half and 80% of patients. Occurring spontaneously and precipitated by changes in body position, ingestion of hot liquids, or changes in environmental temperature, the exact etiology of hot flashes remains undefined. The proposed mechanisms include increases in hypothalamic adrenergic concentrations, alterations in β-endorphins, and involvement of calcitonin generelated peptides acting on the thermoregulatory center in the hypothalamus. Hot flashes generally decrease in both frequency and intensity over time but can persist in some men.

Treatment of hot flashes should be reserved for those who find them bothersome. Just as hot flashes are a consequence of alterations in the hormonal milieu, the mainstay of treatment has been based on efforts to influence that milieu. In a double-blind, placebo-controlled, cross-over study, the progestational agent megestrol acetate (20 mg, twice per day) significantly reduced the frequency of hot flashes. The dose can be reduced to 5 mg twice daily, which may help reduce the appetitestimulating effect of this agent. The efficacy of cyproterone acetate is based on its progestational effects. Dosing should start at 50 mg/day and be titrated to 300 mg/day. Estrogenic compounds, such as low-dose DES and transdermal estradiol, appear to be the most effective treatment, with up to 90% partial or complete resolution of symptoms. With estrogen compounds, however, the cure may be worse than the disease; painful gynecomastia and thromboembolic effects have limited the utility of this approach. Clonidine, a centrally acting α agonist that decreases vascular reactivity, has been used with mixed results; in a placebocontrolled study, transdermal clonidine did not significantly decrease hot flashes. Antidepressant agents, particularly the selective serotonin reuptake inhibitor venlafaxine (12.5 mg, twice daily), have reduced hot flashes in more than 50% of men.

Sexual Dysfunction (Erectile Dysfunction and Loss of Libido)

The effects of ADT on sexual function are profound, as first described by Huggins: “Sexual desire and penile erections were absent in all cases following castration”. Loss of sexual functioning is not inevitable, however; up to 20% of men receiving ADT are able to maintain some sexual activity. Specifically, between 10% and 17% of men undergoing androgen deprivation therapy can maintain an erection adequate for intercourse. Libido is more severely compromised, with approximately 5% of men maintaining a high level of sexual interest with ADT. Sexual desire is inversely related to the duration of androgen deprivation. Loss of penile volume, penile length, nocturnal penile tumescence, and, for those undergoing medical ADT, testicular volume are common.

Treatment for loss of libido is extremely difficult if not impossible for those receiving androgen deprivation therapy. Likewise, medical treatments, such as oral phosphodiesterase type 5 inhibitors, or local treatments, such as intracavernosal injections of alprostadil, can still be effective in selected patients, but patients may decide not to use them during the long term. If there is any fairness in the negative effects of ADT on sexual function, it is the decline in both libido and erectile functioning; despite no erections or desire, the majority of patients have little or no problem with their lack of sexual functioning.

Cognitive Function

In both men and women, the hypogonadal state is associated with declines in cognitive functioning. Testosterone supplementation improves verbal fluency; other controlled studies have found no effect of such supplementation on memory. In a small study, men with prostate cancer randomized to androgen deprivation therapy performed worse in cognitive studies compared with men with prostate cancer under surveillance; the declines were associated with tasks requiring complex information processing. Compared with tests for other cognitive domains, tests for spatial ability uniquely declined in men receiving intermittent hormone therapy. In men receiving neoadjuvant ADT before radiotherapy, cognitive functioning declined. Unfortunately, the studies examining the effects of androgen deprivation therapy on cognitive functioning have been small and underpowered.

Not surprisingly, given the many side effects of ADT, quality of life worsens, specifically in men receiving flutamide in addition to castration, compared with placebo, in the domain of emotional functioning. A short course of androgen deprivation therapy (36 weeks) increased depression and anxiety scores on formal neuropsychological evaluations; major depressive disorder was prevalent in 12.8% of men receiving ADT, 8 times greater than the national rate and 32 times the rate of men older than 65 years. Finally, psychological distress accounted for approximately one third of declines in fatigue severity scale in men undergoing androgen deprivation therapy.

Changes in Body Habitus

A loss of muscle mass and increase in percentage of fat body mass are common in men undergoing androgen deprivation therapy. After 1 year of ADT, the mean overall weight increases 1.8% to 3.8%, which translates into about 5 pounds for a 200-pound man. One study found weight increased a median of 6 kg (13.2 lb), with a range of 3 to 15 kg (6.6 to 33 lb). Since lean body mass usually decreases by the same magnitude, the weight gain is largely due to an increase in fat mass. The average increase in fat mass ranges from 9.4% to 23.8%. As noted by Huggins, androgen deprivation therapy is associated with an increase in appetite, and low testosterone level is associated with increased insulin level and abdominal girth.

The Cancer Prevention Studies I and II (1959-1972 and 1982-1996, respectively) were large population-based studies of obesity and the risk of cancer mortality. In both studies, the risk of death from prostate cancer in obese men was 34% (Study I) and 36% (Study II) compared with men of normal weight. Furthermore, men older than 65 years who engaged in vigorous exercise more than 3 hours per week had a 70% reduction in prostate cancer–specific death. The body composition changes associated with androgen deprivation therapy may portend a worse prognosis for men with prostate cancer. Regular vigorous exercise may help patients limit the accumulation of fat and even prevent prostate cancer progression.

Gynecomastia

Depending on the agents used in ADT, alterations in breast tissue are common. Gynecomastia, an increase in breast tissue, and mastodynia, or breast tenderness, may occur together or independently. Estrogenic compounds, such as diethylstilbestrol (DES), induce gynecomastia in 40% of patients. Likewise, the peripheral conversion of testosterone to estradiol associated with the antiandrogens induces gynecomastia at high rates; 66.3% of men taking 150 mg of bicalutamide developed gynecomastia and 72.7% developed mastodynia.

Prophylactic radiation therapy (10 Gy) has been used to prevent or to reduce painful gynecomastia as a result of DES or antiandrogen therapy. Radiation has no benefit once gynecomastia has begun. Liposuction and subcutaneous mastectomy have been used to treat established gynecomastia. The selective estrogen receptor modulator tamoxifen has been used to treat mastodynia.

Anemia

The anemia associated with ADT is normochromic, normocytic, and it is common; 90% of men receiving combined androgen blockade experienced declines in hemoglobin concentration of at least 10%. Although anemia can be further complicated by tumor growth in the marrow space, compromising hematopoiesis, even men with nonmetastatic prostate cancer experience anemia with androgen deprivation therapy. Unfortunately, anemia (defined as hemoglobin level below 12 g/dL) is associated with a shorter survival in those anemic before initiation of ADT. Declines in hemoglobin concentration begin within 1 month of androgen deprivation therapy initiation and continue for 24 months. Compensatory mechanisms limit the symptomatic effects of anemia to a small subset (13%) of men.

The etiology of anemia is thought to be secondary to lack of testosterone stimulation of erythroid precursors and a decrease in erythropoietin production. In an animal model, however, erythropoietin levels increased after androgen deprivation therapy. Whatever the etiology, clinically, patients respond to recombinant human erythropoietin. The anemia is reversible after ADT is stopped, but it may take up to a year.

Key points: complications of androgen ablation

The side effects of androgen deprivation therapy (ADT) include osteoporosis, hot flashes, sexual dysfunction, cognitive function alterations, changes in body habitus, gynecomastia, and anemia. These side effects can be progressive but are responsive to other treatments.

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