Health and Prostate

After the initiation of androgen deprivation therapy (ADT), most patients with prostate cancer will show some evidence of clinical response; the magnitude and rapidity of that response remain the best predictors of its durability. Assuming that ADT effectively targets the androgen-sensitive population of prostate cancer cells, an incomplete or sluggish response is evidence of a significant androgen-refractory population. Early in the clinical use of prostate specific antigen (PSA) as a biomarker of prostate cancer, it was recognized that decline of PSA level could predict response. For example, patients who had more than an 80% drop of PSA level within 1 month of initiation of androgen deprivation therapy had significantly longer disease-free progression rate. Likewise, the nadir PSA predicted the progression-free interval, as did pretreatment testosterone levels. A rise in prostate specific antigen level, evidence of the emergence of androgen-refractory disease, preceded bone metastatic progression by several months, with a mean lead time of 7.3 months.

More recent studies of PSA response to ADT have confirmed and amplified those observations. The odds ratio for progression to androgen-refractory disease within 24 months of starting androgen deprivation therapy was almost 15 times higher for patients who did not achieve undetectable PSA. For each unit increase in Gleason score, the cumulative hazard of androgen-refractory progression was nearly 70%. In one cohort of Asian men, nadir prostate specific antigen was the most accurate predictor of disease progression and was independently prognostic of survival; achieving a PSA level of 1.1 ng/mL or less at 6 months after initiation of ADT was the most sensitive and specific predictor of progression at 2 years. Considering the kinetics of PSA rise before ADT compared with the rate of prostate specific antigen decline after ADT also predicted outcome, specifically prostate cancer–specific mortality. If the pre-ADT rise in PSA level was rapid and the decline after ADT was slow, the cancerspecific mortality was significantly worse than for those with slow rises of PSA level before ADT and rapid declines after androgen deprivation therapy.

Almost without exception, those no longer responding to ADT (androgen refractory) remain on ADT. Therefore, factors influencing survival in that disease state should be considered in this discussion. In most cases, available data are based on pretreatment or post-treatment responses to other systemic treatments. Consistently predictive variables (by both univariate and multivariate analysis) of survival in this state include performance status, serum lactate dehydrogenase concentration, serum alkaline phosphatase concentration, hemoglobin level, and prostate specific antigen response to secondary therapy. The survival of men treated on seven sequential chemotherapy protocols at one institution provided an early experience in developing predictive measures. A 50% decline in PSA level in response to chemotherapy was one of the most significant variables predicting survival. A nomogram based on a larger group of patients found the presence of visceral disease, Gleason score, performance status, baseline PSA level, serum lactate dehydrogenase and alkaline phosphatase concentrations, and hemoglobin level useful in modeling prognosis.

Response to androgen blockade

The magnitude and rapidity of the initial response to ADT are strong predictors of the durability of that response.

There are four therapeutic approaches for androgen axis blockade in current clinical use: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of luteinizing hormone–releasing hormone (LHRH) or luteinizing hormone (LH) release ( Table: Therapeutic Approaches to Androgen Deprivation Therapy ).

Table: Therapeutic Approaches to Androgen Deprivation Therapy[*]

DES, diethylstilbestrol; LH, luteinizing hormone; LHRH, luteinizing hormone–releasing hormone.

* Several agents have multiple mechanisms of action.

Ablation of Androgen Sources

Bilateral orchiectomy quickly reduces circulating testosterone levels to less than 50 ng/dL, which, on the basis of this procedure, is considered the castrate range. Within 24 hours of surgical castration, testosterone levels are reduced by more than 90%. The Veterans Administration Cooperative Urological Research Group (VACURG) conducted a series of large clinical trials, demonstrating the clinical effectiveness of surgical castration in reducing pain and performance status in men with advanced disease.

Scrotal (Simple) Orchiectomy

A straightforward outpatient procedure, the simple scrotal orchiectomy can be performed under local anesthesia. At the level of the external ring, each spermatic cord is grasped and infiltrated with 10 mL of 1% lidocaine without epinephrine. This cord block can be performed before the formal skin preparation and draping. After infiltration of the skin overlying the median raphe with 1% lidocaine, a 6- to 8-cm incision is made directly over the median raphe. After the skin incision, electrocautery is used exclusively to transect the other tissue layers, reducing the risk of scrotal hematoma formation. The incision is directed into one hemiscrotum, where the tunica vaginalis is divided and the testicle delivered through the wound. The cord is mobilized above the testicle but below the level of the external ring. The cord structures are divided into two or three equal components, and the cord is ligated with nonabsorbable sutures. I favor double ligation of the proximal cord with two sutures, one of which is a suture ligature. The cord is transected relatively close to the ligatures to limit the amount of nonviable tissue distal to the ligature. Care is taken to examine for any bleeding as a scrotal hematoma after scrotal orchiectomy can be dramatically large. The identical procedure is performed on the contralateral side. The dartos is then reapproximated in the midline, closing each semiscrotal incision at the same time in one layer. The skin is closed with interrupted absorbable sutures. Drains are not used for clean scrotal wounds. Scrotal supports are used for the first several days after surgery, and ice is applied for symptomatic relief.

Subcapsular orchiectomy has been advocated as a technique of androgen deprivation therapy (ADT) that avoids the psychological consequences of an empty scrotum. Because this approach relies on the complete removal of all intratesticular tissue and Leydig cells, it is more dependent on technique to achieve ADT than a simple orchiectomy is. In a properly performed operation, however, the hormonal and cancer responses are indistinguishable from those of a simple, complete orchiectomy.

Antiandrogens

Cyproterone Acetate

The classic steroidal antiandrogen with direct androgen receptor–blocking effects, cyproterone acetate also rapidly lowers testosterone levels to 70% to 80% through its progestational central inhibition. An oral agent, the recommended dose is 100 mg, two to three times per day. Side effects are consistent with the hypogonadal state and include loss of libido, erectile dysfunction, and lassitude. Severe cardiovascular complications can occur in up to 10% of patients, limiting the use of cyproterone acetate. Gynecomastia occurs in less than 20% of men. Rare cases of fulminant hepatotoxicity have been reported. It has been used at doses of 50 to 100 mg/day for the treatment of hot flashes.

Nonsteroidal Antiandrogens

By blocking the testosterone feedback centrally, the nonsteroidal antiandrogens cause LH and testosterone levels to increase. Testosterone levels reach about 1.5 times the normal levels of hormonally intact men. This allows antiandrogen activity without inducing hypogonadism; potency, therefore, can be preserved. However, in clinical trials specifically examining erectile functioning and sexual activity in men receiving flutamide monotherapy, long-term preservation of those domains was only 20%, not much different from men undergoing surgical castration. The peripheral aromatization of increased testosterone to estradiol has been demonstrated after antiandrogen administration, leading to the widely recognized gynecomastia and mastodynia associated with these agents. Gastrointestinal toxicity, most notably diarrhea, is more common with flutamide than with the other nonsteroidal antiandrogens. Liver toxicity, ranging from reversible hepatitis to fulminant hepatic failure, is associated with all nonsteroidal antiandrogens, and periodic monitoring of liver function is required.

Antiandrogen Withdrawal Phenomenon

Patients treated with a combination of an antiandrogen and an luteinizing hormone–releasing hormone agonist can experience a decline in prostate specific antigen (PSA) level and even objective responses with the withdrawal of the antiandrogen from the combination. On the basis of this response, it appears that the antiandrogen is actually exerting agonistic activity on prostate cancer cells. This phenomenon, first described with flutamide has now been demonstrated with all antiandrogens, including cyproterone acetate as well as DES and progestational agents. Declines in prostate specific antigen level are seen within 4 weeks with flutamide withdrawal and within 6 weeks with bicalutamide and nilutamide withdrawal. Between 15% and 30% of patients may have declines in PSA level of more than 50% after antiandrogen withdrawal and have a median duration of 3.5 to 5 months. Objective, measurable tumor responses are observed less commonly. Overall survival has not been shown to be increased in those demonstrating the antiandrogen withdrawal phenomenon compared with those who have not. Clinical trial designs of novel agents must take this phenomenon into consideration, given the possible confounding effects. Prospective criteria to predict who will demonstrate this response have not been established, but it has been recognized that those with rapid PSA responses after androgen ablation have higher rates of antiandrogen withdrawal phenomenon.

It has been postulated that mutations in the androgen receptor may underlie this phenomenon, allowing the antiandrogen to behave like an activator of the androgen receptor. The widely used prostate cancer cell line LNCaP expresses an androgen receptor with a specific point mutation that causes cell proliferation in the presence of hydroxyflutamide; the identical mutation was found in human tumor samples from patients who had remarkable declines in prostate specific antigen level after antiandrogen withdrawal. Similar point mutations in the androgen receptor have been described for bicalutamide to act as an agonist; the structural basis of this mutation, resolved by x-ray crystallography, demonstrates the ability of bicalutamide to bind to the mutant androgen receptor in a fashion similar to dihydrotestosterone (DHT) to the wild-type androgen receptor.

Flutamide

A nonsteroidal antiandrogen, flutamide was the first “pure” antiandrogen. Because of the short half-life (6 hours) of the active metabolite, 2-hydroxyflutamide, this oral agent requires a three-times-a-day dosing schedule, 250 mg per dose. Elimination of hydroxyflutamide is by renal excretion. Unlike with the steroidal antiandrogens, there are no associated side effects of fluid retention or thromboembolism. In a randomized, double-blind study comparing flutamide with DES (3 mg/day) in metastatic prostate cancer, overall survival was significantly shorter with flutamide (28.5 months) than with DES (43.2 months).

Bicalutamide

A nonsteroidal antiandrogen with a long serum half-life (6 days), bicalutamide has a once-per-day dosing schedule and therefore is likely to have better compliance. It is the most potent of the nonsteroidal antiandrogens and the best tolerated. The pharmacokinetics of bicalutamide are not affected by age, renal insufficiency, or moderate hepatic impairment. The R isomer of bicalutamide has about a 30-fold higher binding affinity to the androgen receptor compared with the S isomer and functionally processes the antiandrogen activity. Like the other antiandrogens, bicalutamide is associated with maintenance of serum testosterone levels; in the majority of patients, these remain within the normal range.

Bicalutamide as monotherapy has been most extensively studied, and like the inferiority of flutamide monotherapy to DES, bicalutamide monotherapy at a dose of 50 mg/day was inferior to castration in survival of men with metastatic disease. At higher dose of 150 mg/day, however, bicalutamide monotherapy appears to have efficacy equivalent to that of medical or surgical castration in men with metastatic or locally advanced disease. In these large phase III studies, bicalutamide monotherapy (150 mg/day) had significantly better quality of life in the domains of sexual interest and physical capacity. There was, however, a high rate of gynecomastia (66.2%) and breast pain (72.8%). Of more concern, in men with low-risk, localized prostate cancer, bicalutamide was associated with significantly worse overall survival compared with those on watchful waiting.

Nilutamide

The plasma half-life of nilutamide is 56 hours, and elimination is by hepatic clearance employing the cytochrome P-450 system. Because steady-state plasma levels are achieved in 14 days on once-per-day dosing, dosing recommendations are a single 300-mg daily dose for the first month of treatment followed by a single 150-mg daily dose. About one quarter of men receiving nilutamide therapy will note a delayed adaptation to darkness after exposure to bright illumination. In approximately 1% of patients, nilutamide is also associated with interstitial pneumonitis, which can progress to pulmonary fibrosis. The early effects are usually reversible with cessation of nilutamide. In a small study, there was a suggestion of a role for nilutamide as an effective secondary hormonal agent.

Inhibition of LHRH

LHRH Agonists

The LHRH agonists exploit the desensitization of luteinizing hormone–releasing hormone receptors in the anterior pituitary after chronic exposure to LHRH, thereby shutting down the production of LH and, ultimately, testosterone. The clinical utility of the current LHRH agonists is based on the creation of analogs of native LHRH by amino acid substitutions, particularly position 6 in the peptide, increasing their potency and half-lives ( Table: Structure of LHRH and Therapeutic Analogs ). Pharmacologic depot preparations and osmotic pump devices allow dosing to extend from 28 days to 1 year, respectively ( Table: LHRH Agonists Approved for the Treatment of Prostate Cancer ). In a review of 24 trials involving more than 6600 patients, survival after therapy with an LHRH agonist was equivalent to that of orchiectomy.

Table: Structure of LHRH and Therapeutic Analogs

LHRH, luteinizing hormone–releasing hormone.

Table: LHRH Agonists Approved for the Treatment of Prostate Cancer

LHRH, luteinizing hormone–releasing hormone.

The initial exposure to more potent agonists of LHRH results in a flare of LH and testosterone levels. This phenomenon is seen with all available LHRH preparations and can result in a severe, life-threatening exacerbation of symptoms. The flare, associated with up to a 10-fold increase in luteinizing hormone, may last 10 to 20 days. Fortunately, the co-administration of an antiandrogen functionally blocks the increased levels of testosterone. Although it had been argued that the administration of the antiandrogen should precede the administration of the LHRH agonist by a week, others have found no differences in prostate specific antigen levels with the simultaneous administration of both agents. Given the predictable length of the flare phenomenon, co-administration of antiandrogens is required for only 21 to 28 days.

LHRH Antagonists

The LHRH antagonists bind immediately and competitively to the LHRH receptors in the pituitary, reducing LH concentrations by 84% within 24 hours of administration. The direct antagonistic activity eliminates the LH and testosterone flare, which is a major therapeutic advantage of these agents; there is no need for antiandrogen co-administration. Hormonally naive patients with impending spinal cord compression or severe bone pain for whom surgical castration is not appropriate may uniquely benefit from this class of agents; clinical response has been observed with the LHRH antagonist cetrorelix.

In clinical trials of the luteinizing hormone–releasing hormone antagonist abarelix, testosterone levels dropped quickly, with 34.5%, 60.5%, and 98.1% of men chemically castrate at 2, 4, and 28 days, respectively. Compared with an LHRH agonist and an antiandrogen, abarelix monotherapy was equally effective in achieving castrate levels of testosterone. Ninety percent of men with symptomatic prostate cancer treated in an open-label fashion had improvements in pain or disease-related problems.

Many of the first- and second-generation antagonists induced significant histamine-mediated side effects, complications not as often observed in third- and fourth-generation agents. Nevertheless, severe allergic reactions can occur, even after previously uneventful treatment. Abarelix is approved in the United States for the treatment of advanced prostate cancer in patients who cannot take other hormonal therapies and have refused surgical castration. Given the rare but serious allergic reactions, patients must be monitored for at least 30 minutes after administration.

FSH levels are only partially suppressed by LHRH agonists, and FSH levels are significantly elevated after surgical castration, given the loss of inhibitory feedback. LHRH antagonists reduce both LH and FSH levels. In an androgen-insensitive prostate cancer xenograft model, cetrorelix significantly reduced tumor growth, suggesting that other factors stimulate tumor growth. In men with disease progression after surgical castration, treatment with abarelix reduced FSH levels by nearly 90% but did not meet criteria for PSA response.

Inhibition of Androgen Synthesis

Aminoglutethimide

Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone, an early step in steroidogenesis. Given its inhibition of a very proximal step in adrenal function, aminoglutethimide blocks production of aldosterone and cortisol. As the medical version of a total adrenalectomy, the use of this agent requires replacement of cortisone and fludrocortisone. Side effects include anorexia, nausea, rash, lethargy, vertigo, hypothyroidism, and nystagmus. Clinical responses have been observed in a subset of patients with androgen-refractory prostate cancer treated with aminoglutethimide plus cortisone. In the PSA era, 37% of patients had more than a 50% decline in PSA level with treatment by aminoglutethimide (1000 mg/day) and hydrocortisone acetate (40 mg/day), with median response times lasting 9 months.

Ketoconazole

An orally active, broad-spectrum azole antifungal agent, ketoconazole interferes with two cytochrome P-450–dependent pathways: inhibition of 14-methylation in the conversion of lanosterol to cholesterol and blockade of 17,20-desmolase, affecting the conversion of C21 to C19 steroids. On the basis of the observation that some patients taking the drug developed gynecomastia, investigations of its effects on steroid synthesis demonstrated loss of adrenal steroid synthesis and testosterone synthesis by Leydig cells. The effects were rapid, with testosterone levels dropping to the castrate level within 4 hours of administration in some cases; the effects were also immediately reversible, indicating that dosing must be continuous to maintain low testosterone levels (400 mg every 8 hours).

Early experience with ketoconazole in the treatment of prostate cancer showed this agent to be tolerable, durable, and effective and palliative for those whose first-line androgen ablation therapy had failed. Although it is effective in rapidly bringing testosterone levels into the castrate range, with continuous treatment with ketoconazole in the otherwise hormonally intact individual (no other surgical or chemical ADT), testosterone levels begin to rise and can reach low-normal ranges within 5 months of therapy. Therefore, ketoconazole is currently used for men with androgen-refractory prostate cancer, often as the first or second agent in so-called secondary hormonal manipulation. In addition to gynecomastia (caused by alterations in testosterone-to-estradiol ratios), ketoconazole is associated with lethargy, weakness, hepatic dysfunction, visual disturbance, and nausea. Because of the adrenal suppression, ketoconazole is usually given with hydrocortisone (20 mg, twice per day).

Mechanisms of androgen axis blockade

There are four general forms of androgen deprivation therapy: ablation of androgen sources, inhibition of androgen synthesis, antiandrogens, and inhibition of LHRH or LH.

Bilateral orchiectomy reduces testosterone by 90% within 24 hours of surgery.

Nonsteroidal antiandrogens cause LH and testosterone levels to increase.

Serious liver toxicity is a possible side effect of all antiandrogens.

Antiandrogens can act agonistic on some tumors; antiandrogen withdrawal results in decline of PSA level in 15% to 30% of patients.

Bicalutamide 150-mg monotherapy appears to have efficacy equivalent to that of medical or surgical castration for locally advanced or metastatic prostate cancer.

All LHRH agonists induce a testosterone increase on initial exposure. Co-administration of an antiandrogen functionally blocks the effects of testosterone.

Testosterone is the major circulating androgen, with 90% produced by the testes. More than half of testosterone is bound to sex-binding globulin and 40% is bound to albumin. Only 3% of testosterone remains unbound, and this is the functionally active form of the hormone. After passive diffusion through the cell membrane into the cytoplasm, testosterone undergoes conversion to dihydrotestosterone (DHT) through the action of the enzyme 5α-reductase. Although the relative potencies of testosterone and DHT are similar (as defined by the ability to cause half-maximal response in a prostate regrowth model), if the conversion of testosterone to dihydrotestosterone is blocked by the 5α-reductase inhibitor finasteride, 13-fold more testosterone is required for the same effect. Both testosterone and DHT exert their biologic effects by binding to the androgen receptor in the cytoplasm, promoting the association of androgen receptor co-regulators. The complex then translocates to the nucleus and binds to androgen response elements in the promoter regions of target genes.

Molecular biology of androgen axis

Androgen deprivation is one of the most effective therapies against any solid tumor; unfortunately, with time, almost all prostate cancers will become androgen refractory.

All current forms of ADT function by either lowering levels of circulating androgens or blocking the binding of androgen to the androgen receptor.

Almost all androgen-refractory prostate cancer remains sensitive to androgen; therefore, ADT should continue in hormone-refractory disease.

Androgens produced by the adrenal gland, androstenedione and dehydroepiandrosterone, are stimulated by adrenocorticotropic hormone (ACTH) released by the pituitary gland in response to corticotropin-releasing factor. Adrenal androgens do negatively feed back on ACTH secretion; cortisol acts as the feedback signal. Adrenal androgens are relatively weak compared with testosterone and DHT and are almost entirely bound to albumin ( Table: Major Circulating Androgens ). Adrenal androgens remain normal in men who have undergone orchiectomy, and adrenal androgens are insufficient to maintain prostatic epithelium in such men.

Table: Major Circulating Androgens

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.