TY - JOUR
AU1 - Thompson, Carrie A.
AU2 - Shanafelt, Tait D.
AU3 - Loprinzi, Charles L.
AB - Abstract Learning Objectives After completing this course, the reader will be able to: Explain the side effects of hormonal ablation therapy for prostate cancer. Provide a list of potential non-hormonal therapies for treatment of vasomotor symptoms. Appreciate the impact of hormonal ablation therapy on bone mineral density. Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com Andropause, or the age-related decline in serum testosterone, has become a popular topic in the medical literature over the past several years. Andropause includes a constellation of symptoms related to lack of androgens, including diminished libido, decreased generalized feeling of well-being, osteoporosis, and a host of other symptoms. The andropause syndrome is very prominent in men undergoing hormonal ablation therapy for prostate cancer. Most significant in this population are the side effects of hot flashes, anemia, gynecomastia, depression, cognitive decline, sarcopenia, a decreased overall quality of life, sexual dysfunction, and osteoporosis with subsequent bone fractures. The concept of andropause in prostate cancer patients is poorly represented in the literature. In this article, we review the current literature on the symptoms, signs, and possible therapies available to men who cannot take replacement testosterone. Prostatic neoplasms, Antineoplastic agents, hormonal, Androgens, Hot flashes, Osteoporosis, Impotence, Quality of life Andropause Andropause is defined as an age-related decline in serum testosterone levels in older men to below the normal range in young men, which is associated with a clinical syndrome consistent with androgen deficiency. The syndrome may include decreased muscle strength and/or endurance, decreased pubic and axillary hair, reduced physical function, diminished libido, fatigue, depressed mood, decreased generalized well-being, hot flashes, osteoporosis/osteopenia, and anemia [1]. In men, four hormones significantly decrease with age: testosterone, estradiol, dehydroepiandrosterone (DHEA)/ DHEA sulfate (DHEA-S), and growth hormone (GH) [2]. A longitudinal study showed that mean total testosterone levels decreased by 30% between the ages of 25 and 75 and mean free-testosterone levels decreased by as much as 50% [3]. This decline in testosterone is secondary to a decrease in the number of testicular Leydig cells, a decrease in testicular perfusion, and changes in the hypothalamic-pituitary axis [4]. Serum estradiol also decreases in aging men, likely due to a decrease in available testosterone to be aromatized to estradiol [5]. Serum levels of the adrenal androgens, DHEA and DHEA-S, decline most dramatically as men age; however, the clinical significance of this change is unclear [6]. Lastly, the GH/insulin-like growth factor 1 (IGF-1) axis also declines with age [7]. Andropause is being recognized increasingly in the geriatric, endocrinology, and primary care literature as a syndrome of aging men. Office screening tools, such as the Androgen Deficiency in Aging Males (ADAM) questionnaire, have been developed to determine which older men should have testosterone testing performed [8]. If the ADAM questionnaire is positive, bioavailable or free testosterone is low, and, if there are no specific contraindications, it has been recommended that men should be treated with replacement testosterone therapy [9]. Other trials have explored the benefit of GH replacement. A 1990 study showed that replacement of GH in aged men for 6 months improved lean body mass and decreased body fat [10], but a more recent study, looking at replacement of both GH and sex steroids, demonstrated unacceptable adverse effects, including the development of diabetes mellitus [11]. The benefits and side effects of simply replacing ‘deficient’ hormones are unclear, however, as was recently demonstrated by the results of the Women's Health Initiative study [12]. Prospective, longitudinal studies of the safety and efficacy of androgen replacement and GH replacement are, thus, needed to guide practice. Andropause and Prostate Cancer Prostate cancer accounts for 30% of new cancer cases in men, with 189,000 new such diagnoses expected in the year 2002 [13]. With the advent of prostate-specific antigen (PSA) testing in 1986, the incidence of prostate cancer in the U.S. rose sharply, and the mean age at diagnosis decreased [14]. Given the ease of checking PSA level, the number of patients with ‘biochemical recurrence’ of prostate cancer following radical prostatectomy or radiation therapy is increasing. Although the data are controversial regarding the timing of hormonal ablation therapy, it is clear that hundreds of thousands of men are treated with medical or surgical castration each year in the U.S. [15]. Huggins and Hodges demonstrated the effects of androgen hormones on the prostate gland in the early 1940s, and hormonal ablation has been utilized in the treatment of advanced prostate cancer since that time [16–18]. There are several available methods to achieve androgen deprivation, including bilateral orchiectomy, estrogen therapy, and luteinizing hormone-releasing hormone (LHRH) agonists/antagonists. Additional agents can be used to achieve complete androgen ablation by blocking adrenal androgen production. This is also referred to as complete androgen deprivation (CAD). The benefit of this approach over androgen ablation with surgical castration or LHRH agonists/ antagonists alone is unproven [19]. The constellation of andropause symptoms can be greatly enhanced in patients treated with medical or surgical castration for prostate cancer. Most significant in this population are the side effects of hot flashes, osteoporosis with subsequent bone fractures, sexual dysfunction, anemia, gynecomastia, cognitive decline, sarcopenia, depression, and a decreased overall quality of life (QOL). This article reviews the current literature on the symptoms, signs, and possible therapies available to men who cannot take replacement testosterone. Vasomotor Symptoms Vasomotor symptoms, or hot flashes, are frequent side effects of hormonal ablation and can be distressing to the patient. Following orchiectomy, hot flashes are reported in 58%–76% of patients [20]. The incidence is similar for men treated with medical castration, with 80% of men reporting hot flash symptoms while receiving neoadjuvant hormonal ablation therapy prior to prostatectomy [21]. In a retrospective study, Karling et al. reported that 68% of men had hot flashes during treatment with medical or surgical castration, and that symptoms generally did not subside with time on treatment, with 48% of men experiencing symptoms at 5 years and 40% of men continuing to experience symptoms at 8 years [22]. The pathophysiology of hot flashes is complicated and not yet well understood. It is thought that thermoregulatory centers in the hypothalamus control the vasomotor symptoms involved with hot flashes and that these are regulated by neurotransmitters, including norepinephrine, estrogen, testosterone, serotonin, and endorphins [23]. Changes in the levels of the neurotransmitters and hormones, including testosterone, can cause dysregulation of the thermoregulatory centers. The efficacies of multiple nonhormonal agents to relieve hot flash symptoms have been studied in both women with breast cancer and in men with prostate cancer. Experience from randomized, placebo-controlled studies has taught us that hot flash frequency and hot flash scores (frequency multiplied by severity) decrease by 20%–30% with placebo alone. Therefore, anecdotal data reporting a new agent effectively treating hot flashes must take into consideration the large placebo effect [24]. Clonidine was one of the first nonhormonal drugs proposed to reduce hot flashes. It is a centrally active alpha agonist that decreases vascular reactivity and has been used to treat opioid, nicotine, and alcohol withdrawal. A small pilot study suggested that clonidine was efficacious in reducing hot flashes in men after orchiectomy [25]; however, a randomized, double-blind, crossover trial in prostate cancer survivors showed no statistically significant benefit for clonidine when compared with placebo [26]. Trials of clonidine in women with hot flashes have suggested a modest reduction in hot flashes accompanied by significant side effects [25]. Cyproterone acetate, an antiandrogen that inhibits gonadotropin release, was shown to be effective in the treatment of postorchiectomy hot flashes in a double-blind, crossover trial [27]. However, this drug is not available in the U.S. It is well known that estrogen withdrawal causes hot flashes in women, and therefore, estrogen replacement therapy is a mainstay of treatment for postmenopausal hot flashes in women. Low-dose diethylstilbestrol (DES) was associated with improved symptoms in 75%–90% of men in several small, prospective, nonrandomized studies; however, painful gynecomastia was a common side effect. No cardiovascular or thromboembolic events were recorded in those studies [28, 29]. Atala et al. gave 1 mg of DES to men with hot flashes following orchiectomy in a double-blind, crossover study. Eighty-six percent of those men reported a complete resolution of symptoms while on DES, while the remaining 14% reported a significant reduction in symptoms. There was a 21% moderate reduction in symptoms while on placebo. Side effects included gynecomastia and breast tenderness [30]. In a pilot study, Gerber et al. gave transdermal estrogen to men with hot flashes after hormonal therapy for prostate cancer. Eighty-three percent of those men reported an improvement in symptoms, but side effects were comparable with what would be expected with oral DES, including a 17% incidence of breast swelling and a 42% incidence of nipple tenderness [31]. Although not reported in those studies, estrogen has been associated with untoward cardiovascular effects and thromboembolic events; therefore, caution must be used when prescribing estrogen therapy to men with prostate cancer [32]. Investigators at the Mayo Clinic demonstrated the effectiveness of megestrol acetate, a synthetic progesterone, in treating hot flashes in a double-blind, randomized, placebo-controlled crossover study. In that trial, men who were medically or surgically castrated and women with a history of breast cancer were enrolled. Patients treated with megestrol acetate reported an 85% reduction in hot flashes, compared with a 21% reduction in patients treated with placebo. Data also showed that it took 2–3 weeks of receiving the drug to get the maximum reduction in hot flashes. There was also a residual effect of megestrol acetate, with the symptomatic relief lasting for several weeks posttherapy [33]. The patients in that study were followed after the initial study to determine long-term side effects. Of the initial enrollees, 55% of men continued to take megestrol acetate to control hot flashes at 3 years of follow-up [34]. Several investigators have reported patients’ PSA levels declining after withdrawal of megestrol acetate, hypothesizing that, in some cases, megestrol acetate may be detrimental [35–37]. More recently, antidepressant agents have shown promise for the treatment of hot flashes with few side effects. Venlafaxine inhibits both serotonin reuptake and norepinephrine reuptake. A pilot study of low-dose (25 mg) venlafaxine appeared to reduce hot flash scores by more than half in men with substantial hot flashes on androgen-deprivation therapy [38]. The same investigators showed a significant improvement in hot flashes with venlafaxine (60%) compared with placebo (27%) in women with breast cancer. Side effects included mouth dryness, decreased appetite, nausea, and constipation. The optimal dose with the least side effects in that study was 37.5 mg daily for a week, then titrating up to 75 mg daily if necessary [39]. Other selective serotonin reuptake inhibitor (SSRI)-type antidepressants have also been tested. A double-blind, randomized crossover study of fluoxetine in women with breast cancer demonstrated a 50% reduction in hot flash scores for women taking fluoxetine compared with a 36% reduction for those treated with placebo (p = 0.02) [40]. Investigators at Georgetown University Medical Center performed a pilot study of paroxetine in women with hot flashes and reported a 75% reduction in hot flash scores with associated improvements in depression, sleep, anxiety, and QOL scores. There was no placebo comparison group in that study, so those investigators developed a follow-up placebo-controlled trial with this agent [41]. Lastly, there is anecdotal data that sertraline also improves hot flashes in men with prostate cancer on hormone ablation therapy [42]. Multiple additional randomized, controlled trials are under way to determine the roles of the newer antidepressants in treating hot flashes. Gabapentin, a gamma-aminobutyric acid analog used to treat a variety of neurologic disorders including epilepsy and neuropathic pain, has been reported, in case studies, to provide control of hot flash symptoms in several men with prostate cancer on hormonal ablation therapy [43, 44]. It has also been shown to be effective in women with hot flashes at doses titrating from 300 to 600 to 900 mg/day, with a 70% decrease in hot flash score in a pilot study. A pronounced effect was even noted in women concurrently taking venlafaxine [45]. The exact mechanism of action is unclear, but some hypothesize that gabapentin may reduce noradrenergic hyperactivity [44]. Based on these initial reports, randomized controlled trials of gabapentin in the treatment of hot flashes have been initiated. Few trials have examined alternative medicine therapies for the treatment of hot flashes in men. Hammar et al. performed a small pilot study of acupuncture, which was neither randomized nor placebo controlled. The men in that study reported a 70% reduction in hot flashes at 10 weeks, compared with baseline, and a 50% reduction at 3 months. It was hypothesized that such an effect may be due to an increase in hypothalamic β-endorphin activity [46]. Further controlled study evaluation is necessary before accepting this treatment for hot flashes. Data from intermittent androgen-deprivation studies show improvement or resolution of hot flashes during the off-therapy cycle. Higano et al. reported a 100% improvement in hot flashes for the men in their study when off therapy, although the improvement was not quantified [47]. An abstract regarding quality of life while on intermittent androgen-deprivation therapy reported that 66% of men who had hot flashes experienced a complete resolution of symptoms, and 33% of men reported a decrease in hot flashes during the off-therapy cycles [48]. Osteoporosis Osteoporotic fractures in men are a serious health problem. In most studies, men have a higher mortality rate after a hip fracture than women, with 1-year mortality rates ranging from 12%–35% [49]. An Australian study reported significant morbidity, with 50% of patients requiring institutionalized care following hospitalization and only 30% of patients getting back to baseline functional status after 1 year [50]. Osteoporotic fractures are a heavy burden to the health care system, accounting for $13.8 billion in health care expenditures in the U.S. during 1995 [51]. It is well known that sex steroids influence bone metabolism, but the mechanism is not completely understood. Both estrogen and androgen receptors are present in bone [52]. A complex relationship exists between sex hormones and other hormones, including IGF-1 and 25-OH vitamin D [53]. Until the 1990s, it was thought that androgens alone modulated skeletal health in men. Then, in 1994, Smith et al. reported a young male with a homozygous estrogen-receptor gene mutation, causing estrogen resistance, with normal testosterone levels and osteoporosis [54]. Several case reports followed of men with aromatase deficiency and osteopenia that were successfully treated with estrogen therapy [55–57]. A large cohort study, the Rancho Bernardo Study, reported that, of all sex hormones, estrogen was most strongly associated with bone mineral density (BMD) in both men and women, although testosterone was also associated with BMD [58]. By blocking testosterone and estrogen in elderly men via leuprolide injection and selectively replacing testosterone, estrogen, both, or neither, researchers found that estrogen played a significant role in bone resorption, and testosterone had a smaller role that was not significantly significant [59]. The relationship between sex steroids and bone growth/turnover is an ongoing active area of research. There are several retrospective studies that reported the incidence of osteoporotic fractures following androgen ablation for prostate cancer. Daniell compared 59 men who underwent orchiectomy with a control group of men with prostate cancer who had not undergone orchiectomy. Fourteen percent of the men with orchiectomy had had at least one osteoporotic fracture compared with 1% of the control group (p < 0.001). Osteoporotic fractures were more common than other types of fractures, including pathological fractures from bone metastasis [60]. In another study, Townsend et al. retrospectively telephone interviewed 224 patients treated with LHRH agonists for prostate cancer. Five percent of those patients reported fractures secondary to osteoporosis [61]. Oefelein et al. retrospectively performed chart reviews and interviewed 181 patients with prostate cancer treated with various forms of androgen deprivation, and found that the proportion of patients who survived without osteoporotic fractures was 96% at 5 years, but only 80% at 10 years. They identified African-American race and greater body mass index as significant factors that provided protection from fractures. Lastly, a significant association was found between the length of androgen suppression and risk of fracture [62]. Similarly, Hatano et al. found a 6% incidence of fractures in 218 patients with prostate cancer treated with gonadotropin releasing hormone (GnRH) agonists. Those patients with fractures had significantly longer treatment periods and lower bone densities than did the patients without fractures [63]. Multiple prospective studies have examined the relationship between androgen ablation for prostate cancer and BMD. Collectively, those studies suggest that orchiectomy, or treatment with a GnRH agonist, results in a 5%–10% decrease in BMD per year, and that this correlates with higher levels of markers of bone resorption [64–69]. Interestingly, several prospective studies noted that men with prostate cancer had low BMDs prior to hormonal ablation therapy [66, 70]. Smith et al. did a cross-sectional study of prostate cancer patients without bone metastases who had no hormonal treatment and found that 34% of them had osteopenia by dual energy x-ray absorptiometry scan of the hip and spine and that 63% of them had osteoporosis by quantitative computed tomography of the lumbar spine. Further analysis showed that 20% of those men had hypogonadism, 17% were vitamin D deficient, and 59% had less than the recommended daily allowance of calcium intake [71]. Preliminary data from intermittent androgen-blockade therapy shows a significant decrease in BMD during the first 9 months of therapy, which appears to either stabilize or reverse during the off-therapy period [72]. Kiratli et al. observed similar losses in BMD in men treated with intermittent hormonal therapy and those treated with continuous hormonal therapy up to the first 4 years of therapy; but those on intermittent therapy had significantly less bone loss at year 6 [64]. Further studies are necessary to prove if intermittent androgen blockade decreases the prevalence of osteoporosis in men treated with hormone therapy. Given the clinical significance of osteoporotic fractures in men, it is prudent to treat andropause-induced osteoporosis. Testosterone supplementation in otherwise healthy hypogonadal men significantly increased BMD by 15%–25% [73]. Testosterone replacement, however, is obviously contraindicated in men with prostate cancer. Recent studies with bisphosphonates and estrogen have provided some guidelines for treatment. Bisphosphonates have been studied in healthy men with primary osteoporosis. Alendronate was proven to be safe and efficacious in a 2-year double blind trial, with a 7.1% increase in BMD at the lumbar spine, a 2.5% increase at the femoral neck, and a 2.0% increase for the total body (p < 0.001). Vertebral fractures were less frequent in the treatment group than in the placebo group (0.8% versus 7.1%, p = 0.02). There was no statistical difference in nonvertebral fractures [74]. Ringe et al. observed similar results in an open-label alendronate study over a 2-year period [75]. More recently, studies have proven the efficacy of bisphosphonates in preventing or decreasing bone loss secondary to androgen ablation therapy for prostate cancer. Smith et al. randomized two groups of men with advanced or recurrent prostate cancer without bone metastases to either leuprolide or leuprolide and pamidronate, and showed no significant change in BMD from baseline to 48 weeks in the pamidronate treatment group. In contrast, the placebo group had a significant decrease in BMD at the lumbar spine (3.3%), trochanter (2.1%), and total hip (1.8%) [76]. Diamond et al. published data regarding men with metastatic prostate cancer treated with CAD therapy and bisphosphonates. In one study, matched groups on CAD received either a single 90-mg i.v. dose of pamidronate or i.v. saline. An increase in BMD 6 months later was evident in the treatment group, in contrast with the placebo group in which BMD losses were observed [77]. Diamond et al. also demonstrated that 6 months of cyclic etidronate and calcium therapy reversed the bone loss that occurred after 6 months of CAD [70]. The BMD measurements were secondary outcome measures in those studies and, although it is assumed that this translates into the clinical benefit of fracture reduction, this has not yet been proven in a randomized clinical trial designed to study this issue. In addition, those studies did not all routinely use both calcium and vitamin D as standard therapy, thus raising the question of whether that approach would be equally efficacious and less toxic. Ongoing trials are addressing the use of bisphosphonates as prophylactic therapy in men undergoing androgen ablation therapy. Estrogen therapy was previously the standard of care for treatment of metastatic prostate cancer but has fallen out of favor due to severe cardiovascular side effects [32]. When it was still standard, Eriksson et al. gave estrogen therapy with the goal of medical castration to a group of prostate cancer patients and compared them with a group of patients treated with orchiectomy. BMD significantly decreased in the patients who underwent orchiectomy but did not change in the estrogen group. Treatment was tolerated well in both groups [78]. More recent studies revisited estrogen therapy, given the better understanding of the importance of estrogens in bone metabolism. Taxel et al. randomized 25 men, who were either on established LHRH agonist therapy for prostate cancer or initiating LHRH agonist therapy, to receive either placebo or 1 mg/day of micronized estrogen. Markers of bone turnover, urinary crosslinked N- and C- telopeptides of type I collagen, significantly decreased from baseline after 9 weeks of estrogen therapy in both groups. As expected, the decline was greater in the group that had been treated with LHRH agonists for a longer period of time than in the patients initiating treatment (38% versus 25% for N-telopeptide and 41% versus 9% for C-telopeptide, respectively). BMD was measured only at baseline [79]. It is recommended that all men treated with hormone ablation prophylactically receive calcium supplements of 1,200–1,500 mg/day (total daily dose including dietary intake) and vitamin D supplements of 400 IU/day. Lifestyle modification, including smoking cessation, no more than moderate alcohol intake, and weight-bearing exercise should be recommended [80]. Screening for osteoporosis with BMD is recommended prior to treatment with androgen deprivation, again at 1 year, and then at appropriate intervals thereafter, which may be every 2 years. If the patient develops osteoporosis, treatment is recommended, although further studies with bisphosphonates and estrogens in both preventative and treatment settings are necessary [81]. Anemia An association between low androgen levels and anemia was noted as far back as 1948. Hamilton then published data on several hundred institutionalized castrated men, demonstrating decreases in erythrocyte count, hematocrit, and hemoglobin by an average of 9%, 6%, and 7%, 40 days after castration, respectively [82]. It has been demonstrated in both animals and humans that androgens stimulate erythropoiesis by enhancing the renal production of erythropoietin [83]. Androgens have also been shown to directly act on bone marrow stem cells, enhancing the differentiation of uncommitted cells to the erythroid lineage [84]. In fact, prior to the availability of recombinant human erythropoietin (rHuEpo), androgens were used to treat the anemia of chronic renal failure and bone marrow failure [85]. More recent studies have corroborated Hamilton's early data. Fonseca et al., at the Mayo Clinic, compared pre- with postoperative hemoglobin levels in men with normal renal function undergoing bilateral orchiectomies. All 64 men had normal preoperative hemoglobin levels, but then had a statistically significant mean drop of 1–2 g/dl hemoglobin at follow-up, with no other identified cause of anemia [86]. Other methods of hormone ablation appear to have similar effects. One study of men with benign prostatic hyperplasia, who were treated with an LHRH agonist for 6 months had a significant decrease in hemoglobin levels over pretreatment levels, which returned to normal with the removal of the androgen blockade. The LHRH agonist, nafarelin acetate, did not show any in vitro inhibition of erythroid and myeloid progenitor cells of the patients, suggesting that the anemia was not a direct effect of the drug, but rather an indirect effect related to androgen ablation [87]. CAB appears to have a greater hematological effect than either LHRH agonists/antagonists or antiandrogens alone. Strum et al. reported on their experience with 133 patients treated with CAB, who had a statistically significant fall in hemoglobin, reaching a mean nadir of -2.5 g/dl at 5.6 months. Thirteen percent of those patients became symptomatic and were treated successfully with subcutaneous rHuEpo [88]. Asbell et al. reported on a multicenter study that demonstrated the development of anemia in 141 patients undergoing CAB 2 months prior to pelvic radiotherapy. Their conclusion was that the anemia was attributable to CAB therapy, as the drop in hemoglobin was much more pronounced than that which is usually seen with radiation therapy to the prostate [89]. Since the early 1990s, treatment with rHuEpo for solid tumor cancer patients with treatment-induced symptomatic anemia has become the standard of care [90]. However, very few studies specifically evaluating patients with prostate cancer exist. Beshara et al. gave subcutaneous rHuEpo (150 U/kg, with dose escalation if needed) three times weekly for 12 weeks to nine patients with anemia and hormone-refractory prostate cancer. Basal hemoglobin concentrations were 7.0–11.6 g/dl. Although only one of the patients completed the full 12 weeks, they were able to demonstrate a partial response (median increase in hemoglobin of 1.7 g/dl) in three patients and a full response (median increase of 2.0 g/dl) in four patients [91]. A Swedish group demonstrated that hormone-refractory prostate cancer patients with anemia who were treated with rHuEpo three times weekly for 12 weeks had improved QOL and physical functioning and less symptoms of fatigue [92]. Studies are under way to determine the efficacy and influence on QOL of once-weekly rHuEpo compared with the standard three-times-a-week dosing schedule [93]. Sarcopenia Sarcopenia is the loss of muscle mass and strength that occurs with normal aging. It is thought that sarcopenia plays a major role in impaired functional performance, increased physical disability, and an increased risk for falls in the elderly population [94]. This can lead to a loss of independence, an inability to care for one's self, and ultimately, nursing home placement. It has been suggested that sarcopenia is accelerated in men treated with hormonal ablation therapy for prostate cancer. The pathophysiology of sarcopenia is multifactorial and complex. It appears that the decrease in anabolic hormones (testosterone, GH, and estrogen), a concomitant increase in cytokines (interleukin [IL]-1β, tumor necrosis factor alpha, and IL-6), as well as nutritional factors and atherosclerosis all contribute to the resulting loss of muscle mass [95]. Baumgartner et al. performed a cross-sectional analysis of healthy elderly adults to determine the best predictor of skeletal muscle mass [94]. Free serum testosterone was the strongest predictor in men, with physical activity, IGF-1 level, and cardiovascular disease less important factors. Multiple studies have shown that replacement of testosterone in hypogonadal men improves muscle mass, perhaps by stimulating muscle protein synthesis [96]. A double-blinded, placebo-controlled study of testosterone replacement in healthy men over the age of 65 demonstrated a significant increase in lean mass and a decrease in fat mass for those given testosterone replacement therapy, although no difference in strength was seen. The treatment group did report a subjective increase in physical function [97]. At this time, however, routine testosterone replacement is not recommended in aging men due to the lack of a clear-cut overall clinical benefit that outweighs the potential toxicities of this therapy [98]. There is one formal study on sarcopenia in relationship to hormone ablation therapy for metastatic prostate cancer. Stone et al. took a group of 62 men undergoing LHRH antagonist and cyproterone treatment for prostate cancer and assessed their subjective fatigue and voluntary muscle strength at baseline and 3 months later. There was a significant increase in subjective fatigue measurements after 3 months and a small but significant increase in hand grip fatiguability. There was also a significant decrease in mid-arm muscle circumference with no change in body mass index, suggesting that there was a decrease in muscle bulk but no weight change [99]. Exercise appears to be the best treatment to combat sarcopenia [95]. Multiple studies have demonstrated an improvement in muscle mass with exercise programs, particularly resistance training, in the elderly. No formal studies of exercise with prostate cancer patients have been performed. A small phase II study demonstrated a 37% improvement in muscle strength with vitamin D replacement in patients with metastatic prostate cancer. All patients had been treated with hormonal therapy [100]. Larger clinical trials are necessary before it is known if this association is true; however, calcium and vitamin D supplementation is recommended for these patients to prevent osteoporosis. The potential consequences of sarcopenia in prostate cancer patients are devastating (loss of independence, falls, gait difficulties, nursing home placement, etc.); therefore, staying active with an exercise program should be recommended to all men taking hormone ablation therapy. Resistance training appears to offer the most benefit. A healthy diet and, perhaps, vitamin D supplementation are also indicated. Gynecomastia Gynecomastia can be an embarrassing and sometimes painful side effect for men with andropause, causing some prostate cancer patients to discontinue androgen blocking treatments. It occurs secondary to the increase in estrogen-to-androgen ratio often seen after treatment with androgen ablation therapy. Gynecomastia usually starts within the first year of hormonal treatment and is initially reversible. After gynecomastia is present for about 1 year, however, hyalinization and fibrosis occur, which are irreversible [101]. In a review of drug studies by Hedlund, it was reported that treatment with estrogen had the highest incidence of gynecomastia, at 40%–80%. Antiandrogens, including flutamide, bicalutamide, and nilutamide, were next, with a 40%–70% incidence, followed by GnRH analogs and combined androgen deprivation, both with incidences of 13% [102]. Therefore, gynecomastia is not nearly as common a problem now as it was in the era of estrogen therapy for prostate cancer. Treatment and preventative options for gynecomastia include radiation, surgery, and, possibly, medical therapy. Radiation therapy has been used for gynecomastia in men treated for prostate cancer since the early 1960s. Alfthan and Molsti irradiated one breast in male patients prior to estrogen therapy for prostate cancer. Subsequent histological examination of the nonirradiated and irradiated breasts showed fewer ducts, less hyperplasia of the glandular epithelium, and less stromal collagen in the irradiated breasts [103]. A review of 262 patients who underwent prophylactic radiation therapy of their breasts prior to estrogen treatment showed an 89% efficacy rate. Efficacy was defined as no or minimal breast changes after estrogen therapy [104]. However, once gynecomastia is established, it does not appear to regress with radiation treatment, although radiation treatment may reverse breast tenderness [105]. Surgical treatment is another option. In 1962, Amelar reported that a simple subareolar mastectomy could be performed at the time of orchiectomy, which effectively prevented gynecomastia [106]. Mastectomy was compared with prophylactic irradiation and was reported to have comparable results, although 12 of the 78 patients who underwent prophylactic surgery still developed gynecomastia after estrogen therapy [98]. Depression It is well established that, as men age and testosterone levels decrease, the prevalence of depression increases. There are a number of studies examining the association between depression and androgens. Bahrke et al.'s large review of the literature in 1990 came to the conclusion that “the evidence at present is limited and much additional research will be necessary for a complete understanding of this relationship” [107]. Several studies examined testosterone levels in depressed men, compared with matched controls, and found no significant difference [108, 109]. Sih et al. randomized and blinded hypogonadal men to either testosterone replacement or placebo for 12 months and found no difference on the Yesavage Geriatric Depression Scale [110]. Conversely, there are studies that reported lower levels of testosterone in depressed men compared with controls [111, 112]. Investigators have also shown improvements in mood, as measured by patient self-reporting, after testosterone treatment in hypogonadal men [113, 114]. Seidman and Rabkin replaced testosterone in five hypogonadal men with SSRI-refractory depression and found improved Hamilton Depression Inventory scores after treatment. Depression relapsed after crossover to placebo [115]. Only one case report in the literature addressed the issue of depression after androgen ablation for prostate cancer. Rosenblatt and Mellow reported on three patients who developed severe depression after starting either a GnRH agonist or a GnRH agonist and an antiandrogen. Depression was refractory to medical treatment and improved only after discontinuation of the androgen blockade. Nonetheless, those patients had multiple other possible etiologies of depression, including new cancer diagnoses, histories of alcohol abuse, and many other comorbidities [116]. The conflicting data make it difficult to assess the relationship between androgen levels and depression. Prostate cancer patients on androgen-deprivation therapy often have confounding factors, including the diagnosis of either recurrent or metastatic cancer, possible pain, and other medical comorbidities. At the present time, it is reasonable to screen men with prostate cancer for depression and, if positive, treat appropriately. Further randomized, controlled studies on the safety and efficacy of testosterone augmentation for refractory depression in hypogonadal men without prostate cancer are necessary. Cognitive Decline Cognitive decline has been noted in women who have been treated with LHRH antagonists, but this has not been well studied in men. A case report of an Australian patient with mild-moderate Alzheimer's dementia describes a loss of cognitive function after initiating treatment for metastatic prostate cancer with flutamide and leuprorelin. The patient was followed serially with Mini-Mental State Examinations (MMSEs) as well as the Cambridge Examination for Mental Disorders of the Elderly (CAMCOG-R) cognitive scale over a 24-week period. A significant decrease in cognitive function was seen, with his MMSE score dropping from 17/30 to 8/30, and his CAMCOG-R score dropping from 46/105 to 28/105. This correlated with a decrease in testosterone. No other changes in health status occurred during that time period; therefore, it was hypothesized that the hormone ablation therapy accelerated that patient's cognitive decline [117]. There is one published small, randomized, controlled study that evaluated the effect of LHRH antagonists on cognitive function. Green et al. randomized 82 men with metastatic prostate cancer to either leuprorelin, goserelin, cyproterone acetate (an antiandrogen), or monitoring. Baseline cognitive function was assessed with multiple tests of neurocognitive ability and followed at 1 week and 6 months. Results show that about half the patients in all three treatment groups had decreases in test scores across multiple tasks, indicating a decline in complex information processing. No significant decreases in function were noted in the control arm. No patient withdrew from treatment due to concerns about cognitive ability. Based on these early results, further studies are under way, including one in men treated with bilateral orchiectomy [118]. Quality of Life The quality of life of men with andropause, best recognized in prostate cancer patients, has become an important topic in the literature recently, with good reason. Prostate cancer is one of the most common cancers in the U.S. and, given its long natural history, patients live for many years after diagnosis. Hormonal treatments are used for metastatic disease, asymptomatic lymph node metastases, biochemical recurrence, and for patients with localized disease who are poor operative candidates. Health-related (HR) QOL studies have been helpful in shedding light on the effects of androgen deprivation therapy that are difficult to quantify, including sense of well-being, mental health, perception of physical health, and specific side effects, including urinary symptoms, sexual function, and fatigue [119]. Litwin et al. compared HRQOL evaluations in a group of men with metastatic prostate cancer treated with either bilateral orchiectomy or combined androgen blockade (leuprolide and flutamide), pre- and post-therapy, with follow-ups out to 24 months. They found no difference between the two groups, and all patients had significant improvements in overall QOL from baseline to the 12-month follow-up time, with the greatest improvements being in social function, role-emotional, and social well-being. There was a trend toward worse sexual function after treatment, but it was not statistically significant. Both groups had poor sexual function at baseline, but their low ‘bother’ scores indicated that it did not negatively impact their quality of life [120]. da Silva et al. studied a similar group of European patients with metastatic prostate cancer who completed HRQOL questionnaires prior to, and during, treatment. Patients had ranked their sexual function, urinary function, pain, fatigue, and social roles low pretherapy. There was a statistically significant improvement in pain and urological symptoms after treatment, but no difference in the other symptoms. Interestingly, those researchers found that there was a discrepancy between physicians' perceptions of QOL and patients' reports, illustrating the importance of patient-physician communication [121]. The Prostate Cancer Outcomes Study compared quality of life between two groups of men receiving monotherapy with either LHRH agonists or orchiectomy. Participants completed an HRQOL questionnaire at 6- and 12-month intervals posttreatment. Both groups reported decreased sexual function, including decreased sexual interest, frequency, and impotence, when retrospectively compared with pretreatment levels, but there was no significant difference between the two groups. Patients on LHRH therapy were more likely to worry about prostate cancer and report overall poorer health than the orchiectomy patients [122]. Moinpour et al. found, in a double-blinded study, that patients treated with orchiectomy and flutamide (CAB), when compared with orchiectomy and placebo, had significantly worse qualities of life, apparently related to problems with diarrhea, a decrease in physical function, fatigue, mental health, and pain. These symptoms tended to improve in both groups over the course of 6 months, but more so in the placebo group [123]. Not surprisingly, Albertsen et al. found that patients with metastatic prostate cancer who were not responding to CAB had significantly worse QOL than those on the same therapy who were responding. Interestingly, they found no difference between patients in remission and a matched male population without prostate cancer [124]. The controversial topic of hormonal treatment versus observation in men with advanced prostate cancer has been examined in terms of quality of life. An early study by Herr et al. compared two groups of men with metastatic prostate cancer that were either observed or treated with hormonal ablation. The treated group had worse sexual interest, sexual enjoyment, and erectile function at 6 months. However, the baseline characteristics of the two groups were not matched [125]. Later, Herr and O'Sullivan evaluated quality-of-life parameters in a group of asymptomatic patients with rising PSA levels after local therapy as well as those with asymptomatic locally advanced prostate cancer who chose either androgen-deprivation therapy or watchful waiting. HRQOL surveys were completed at baseline, 6 months, and 12 months. There were no differences between groups at baseline, but patients opting for androgen-deprivation therapy subsequently had significantly worse physical function, fatigue, psychological distress, sexual problems, and overall QOL than those who had no hormonal therapy [126]. Green et al. compared HRQOL in men with nonlocalized prostate cancer randomized to either observation or hormonal ablation. Men treated with hormones reported significantly worse changes in sexual function and decreases in social roles and subjective cognitive function, but increases in physical and urinary function [127]. Recent studies of the impact of intermittent androgen blockade on quality of life have shown improvement when men are in their off-therapy cycle. Goldenberg et al. reported an overall sense of well-being when off therapy in the patients they studied [128]. Bales et al. studied men with a QOL questionnaire; 37.5% of those men reported improvements in overall sense of well-being and 42% had higher energy levels when off treatment [48]. Results from the HRQOL studies are, thus, mixed. In summary, it seems that most men with advanced prostate cancer do have sexual dysfunction, regardless of whether they have been treated with hormonal ablation; however, it is not necessarily a bother to them. Androgen deprivation therapy negatively affects generalized QOL in many studies. Low QOL at baseline can improve over time. This phenomenon may be related to the initial shock of receiving the diagnosis of metastatic cancer. da Silva et al. found that physicians' perceptions of quality of life were not necessarily the same as patients' perceptions. Therefore, it is important that patients are educated about various treatment options and their preferences are taken into consideration when prescribing hormonal treatment for prostate cancer. Sexual Dysfunction As reviewed in the above section, sexual dysfunction is a major side effect of hormonal ablation therapy for prostate cancer. Sexual dysfunction is also a frequent problem in older men who do not have prostate cancer but are going through andropause. The Massachusetts Male Aging Study reported a prevalence of moderate-to-complete impotence of 34.8% in men aged 40–70 [129]. A large national cohort study of men aged 18–59 reported a 31% overall sexual dysfunction prevalence, and noted that the oldest group of men, aged 50–59, were three times more likely to report erection problems and low sexual desires [130]. The role of testosterone in sexual function is complex and not yet fully understood. Nocturnal penile tumescence and spontaneous morning erections are hormone dependent [131], but erection in response to visual erotic stimuli does not appear to be androgen dependent [132]. Libido is dependent on hormonal influences [113, 133]. Therefore, it appears that testosterone has both central and peripheral actions in the control of sexual function. Testosterone-replacement therapy in hypogonadal, impotent men is the treatment of choice for erectile dysfunction [134]. Trials have been successful in restoring sexual attitudes and performance with testosterone supplementation in hypogonadal men [135–137]. Unfortunately, treatment of prostate cancer with hormonal ablation tends to decrease sexual function. In an early study by Bergman et al., men who underwent orchiectomy were more likely to be incapable of intercourse or erections than men treated with radiotherapy or estrogen therapy [138]. Klotz et al. reported that, of the 12 patients who were sexually active prior to initiation of DES therapy (out of 20 total), two remained potent on therapy [139]. Other investigators have shown decreased sexual desire, arousal, and frequency of spontaneous early morning erections and greater difficulty in attaining and maintaining erections after starting GnRH analogs for prostate cancer [140]. An objective measurement of nocturnal penile tumescence prior to LHRH agonist therapy and 4 and 12 weeks after treatment showed a statistically significant decrease in frequency, magnitude, duration, and rigidity of nocturnal erections. The men in that study also reported decreased sexual desire, interest, and frequency of intercourse [141]. There are no treatments that have been studied specifically for erectile dysfunction secondary to hormonal ablation therapy for prostate cancer. Because androgen-deprivation therapy causes a severe decrease in libido, medications are often not effective. However, sildenafil [142], intraurethral alprostadil (MUSE) [143], intrapenile injections of vasoactive drugs [144], and vacuum-assist erection devices have been shown to be safe and effective in other causes of erectile dysfunction and, therefore, they may potentially be useful in men on androgen-deprivation therapy. Intermittent androgen suppression also has been shown to restore potency during the off-therapy periods [119, 131]. Conclusions Prostate cancer is the most common cancer in men in the U.S. Many of these men are treated with hormonal ablation therapy for metastatic disease or rising PSA levels. Similar to the syndrome of natural andropause, side effects of hormonal ablation include vasomotor symptoms, osteoporosis, anemia, gynecomastia, depression, sexual dysfunction, and overall decrease in quality of life. In men who are hypogonadal secondary to aging, testosterone replacement appears to alleviate many of these symptoms; however, more studies on safety are necessary before this can be recommended for widespread use. Testosterone replacement is contraindicated in men with prostate cancer; therefore, nonhormonal therapies are necessary to treat symptoms in those patients. 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TI - Andropause: Symptom Management for Prostate Cancer Patients Treated With Hormonal Ablation
JF - The Oncologist
DO - 10.1634/theoncologist.8-5-474
DA - 2003-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/andropause-symptom-management-for-prostate-cancer-patients-treated-HkDS1wpSVV
SP - 474
EP - 487
VL - 8
IS - 5
DP - DeepDyve
ER -