prostate cancer

Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer

S J Freedland1, J Eastham2 and N Shore3

1. 1Departments of Surgery (Urology) and Pathology, Durham VA Medical Center and Duke Prostate Center, Duke University School of Medicine, Durham, NC, USA
2. 2Memorial Sloan-Kettering Cancer Center—Urology, New York, NY, USA
3. 3Atlantic Urology Clinics/Carolina Urologic Research Center, Myrtle Beach, SC, USA

Correspondence: Dr SJ Freedland, Departments of Surgery (Urology) and Pathology, Duke University School of Medicine, Box 2626 DUMC, 551 Research Drive, Room 475, Durham, NC 27710, USA. E-mail: steve.freedland@duke.edu

Received 28 April 2009; Revised 22 June 2009; Accepted 25 June 2009; Published online 1 September 2009.
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Abstract

Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and is increasingly used to treat asymptomatic patients with prostate-specific antigen recurrence after failed primary therapy. Although effective, ADT is associated with multiple adverse effects, many of which are related to the estrogen deficiency that occurs as a result of treatment. These include increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss. By providing clinicians with a greater awareness of the estrogen deficiency induced adverse effects from ADT, they can proactively intervene on the physical and psychological impact these effects have on patients.
Keywords:

adverse effects, androgen deprivation, estrogen, side effects, testosterone
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Introduction

In 2008, prostate cancer was estimated to account for 25% of all new cancer cases and 10% of all cancer deaths in men.1 Common treatment options for localized prostate cancer include active surveillance, radical prostatectomy, radiation therapy and cryosurgery.2 Some patients may experience an eventual increase in PSA or biochemical failure necessitating additional treatment.

Androgens and the functional status of androgen receptors are considered integral to both normal prostate development and prostate cancer progression;3 consequently, androgen deprivation therapy (ADT) is a common treatment for prostate cancer. Although ADT is the standard of care for symptomatic and metastatic disease,4 its use has expanded to include patients who show evidence of increased PSA recurrence or biochemical failure.5 Although the mortality rates for prostate cancer have been steadily decreasing since 1994 (whether a result of improved screening, diagnosis or therapy), the fact that the aging male population is increasing alongside a longer duration of survival is estimated to result in an increase in the number of men with prostate cancer by more than 50% over the next 20 years.6 Consequently, the number of patients receiving ADT is likely to see an increase.

Androgen deprivation therapy is typically performed through medical castration and, less frequently, surgical castration. Although there are several methods of medical castration (Table 1), it is most commonly achieved through the use of gonadotropin-releasing hormone (GnRH) agonists (for example, leuprolide, goserelin and triptorelin).7 GnRH is secreted by the hypothalamus and leads to the pulsatile release of follicle-stimulating hormone and luteinizing hormone by the pituitary gland. The release of follicle-stimulating hormone and luteinizing hormone promotes testosterone secretion by Leydig cells of the testes. High continuous exposure to GnRH, such as that which occurs through treatment with GnRH agonists, causes downregulation of receptors in the pituitary gland, leading to decreased pituitary hormone production and ultimately a decrease in the production of testosterone.8
Table 1 - Common methods of chemical androgen deprivation therapy.
Table 1 - Common methods of chemical androgen deprivation therapy - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the authorFull table

Although ADT is effective in treating prostate cancer, it is associated with adverse effects, some of which are due to a deficiency in testosterone levels (Figure 1). However, because estrogens are derived in men through the aromatization of testosterone, the reduction in testosterone due to ADT also decreases the levels of estrogen.9 This can lead to a number of estrogen deficiency induced side effects, including increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss (Figure 1). Although some of these estrogen related ADT side effects have been reviewed previously,10 it is important to revisit and update the issue given the projected increase in the number of patients with prostate cancer who are receiving ADT. By potentially improving treatment through increased awareness of these adverse effects and their mechanism of action, urologists can enhance overall patient care.
Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Androgen deprivation therapy: estrogen versus testosterone deficiency adverse effects.48, 49
Full figure and legend (135K)

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Estrogen deficiency induced adverse effects of ADT
Increased fracture risk

Estrogens have a fundamental role in regulating bone integrity in men. In general, estrogen deficiency appears to accelerate bone remodeling by prolonging the lifespan of osteoclasts,11 with converse effects on osteoblasts and osteocytes.12, 13 This disproportionate lifespan between osteoclasts and osteoblasts/osteocytes leads to greater bone resorption than formation and contributes to the development of osteoporosis and an increased fracture risk.12 Although many men experience both age-related hypogonadism14 and decreases in bone mineral density (BMD),15 the changes associated with ADT are far more severe. The result is reflected in a higher prevalence of fractures in men receiving ADT, who show an average rate of fractures of 5–8% per year of ADT therapy.10

Several recent large studies have established a strong association between ADT and increased fracture risk.16, 17, 18 One was a US study of the National Cancer Institute's Surveillance, Epidemiology, and End Results program and Medicare databases in a period from 1992 through 1997 that examined data from 50 613 men with prostate cancer, 31% of whom received ADT.16 In the 12–60 months after diagnosis, a significantly higher percentage of patients in the ADT group had a fracture (19.4%) compared with those who did not receive ADT (12.6%; P<0.001). This risk began early in the course of ADT administration and increased with the number of doses of GnRH agonist administered within the first year. Patients who received 1–4 doses were at a 7% higher risk (95% CI, -2 to 16%) and those who received greater than or equal to9 doses were at a 45% higher risk (95% CI, 36–56%). A comparable pattern was seen with fractures that required hospitalization: 5.2% of patients receiving ADT required hospitalization compared with 2.4% of patients who did not receive ADT (P<0.001).

Similar results were found in a population-based, epidemiologic, case–control study in Denmark of 15 716 men with fractures compared with 47 149 age-matched controls.17 Prostate cancer had been previously diagnosed in 2.5% of men in the fracture group (20% of whom received ADT) and 1.3% of men in the control group (15% of whom received ADT). Men with prostate cancer were at an increased risk for any fracture (odds ratio=1.8), particularly hip fracture (odds ratio=3.7). More importantly, ADT (once adjusted for prostate cancer, age and previous fracture) was also associated with an increased risk of any fracture with an odds ratio of 1.7 and hip fracture with an odds ratio of 1.9.

Finally, a Medicare claims-based cohort study of 11 661 eligible patients with nonmetastatic prostate cancer (3887 who received GnRH agonists and 7774 who did not) examined the effect of ADT therapy on specific fractures, including vertebral, hip and femur.18 On the basis of these results, there was a significant increase in the risk of fracture in men receiving ADT compared with control patients: specifically, there was increased risk of any fracture (21% higher risk; P<0.001), vertebral fracture (45% higher risk; P<0.001) and hip/femur fracture (30% higher risk; P=0.002).

Several recent studies have also established that ADT is associated with a significant decrease in BMD.19, 20 In an analysis of prospective 12-month data from 65 men, ADT using GnRH agonists resulted in a significant decrease in the mean BMD of the total hip by 1.9% at 12 months (P<0.001).19 Similar results were seen in another 12-month prospective study that examined four groups of men: those with prostate cancer receiving short-term ADT (<6 months), those maintained on long-term ADT (greater than or equal to6 months) or those not receiving ADT; and healthy men.20 Compared with the other groups, men receiving short-term ADT had significant reductions (P<0.05) in BMD at the total hip (-2.5%), trochanter (-2.4%), total radius (-2.6%), total body (-3.3%) and posteroanterior spine (-4.0%). After long-term use, men on ADT had an additional significant reduction in BMD only at the total radius (-2.0%, P<0.05).20

The increased risk of fracture associated with ADT is a significant health concern, as evidenced by the correlation of fractures with overall survival in men with prostate cancer.21 In 195 men with prostate cancer who were receiving long-term continuous ADT (24 of whom reported at least 1 fracture), there was a 39-month reduction in median overall survival after prostate cancer diagnosis for those with evidence of a fracture compared with those without a fracture (121 vs 160 months, P=0.04). Despite the presence of skeletal fractures as an independent risk factor for mortality, a recent study determined that only one-third of patients with ADT-treated prostate cancer were receiving proper screening, prevention or treatment for increased fracture risk.22 This analysis included 174 men with prostate cancer who had received ADT and determined whether they were receiving 'recommended' osteoporosis management including diagnostic dual-energy X-ray absorptiometry scans within the 2 years before the final ADT treatment or concurrent use of bisphosphonates, calcitonin, calcium or vitamin D while on ADT. Only 60 of the 174 patients (34%) had received the recommended dual-energy X-ray absorptiometry scans or pharmacologic treatment. The researchers suggested that the reasons were multifactorial but may include the lack of awareness in primary care providers of the increased fracture risk associated with ADT and the lack of a Food and Drug Administration approved treatment for ADT-induced bone loss.22
Hot flashes

Although not fully understood, estrogen withdrawal appears to have a prominent role in vasomotor symptoms, or hot flashes. Hot flash pathogenesis is thought to begin with estrogen withdrawal leading to a decrease in endorphin and catecholamine levels and an increase in hypothalamic norepinephrine and serotonin release.23 The increased norepinephrine and serotonin lower the body's thermoregulatory set point, and allow the heat loss mechanisms to result in hot flash symptoms with only subtle changes in body temperature.23

Hot flashes are common in men receiving ADT, with nearly 70% reporting this adverse effect during treatment.24, 25 Hot flashes are not limited to initial ADT, as they have been shown to persist throughout ADT and can continue for an extended period of time after the cessation of treatment.24 In one study of 63 patients receiving ADT, 43 (68%) reported experiencing hot flashes at some point during treatment.24 Furthermore, nearly 50% of these patients reported that they were still experiencing hot flashes 5 years after treatment and 40% continued to document them even 8 years after ADT cessation.24

The impact that hot flashes can have on patients is variable, ranging from mild in some to debilitating in others. For example, in the previously mentioned study,24 at a median of 7.6 years after treatment initiation, 28 patients were still experiencing hot flashes and were therefore queried regarding hot flash severity. Among these patients, 5 reported not being distressed at all by their hot flashes, 10 reported being seldom distressed, 8 reported being often distressed and 5 reported distress all the time.24

For those who are affected by hot flashes, they can be both a physical and psychological distress. The impact of hot flashes on patient quality of life was evidenced in a study of 55 men (58% of whom suffered from hot flashes) currently receiving ADT for prostate cancer by using the general and prostate cancer functional assessment of cancer therapy questionnaires (FACT-G and FACT-P, respectively).26 The FACT questionnaires (available at http://www.facit.org) consist of a series of questions with answers ranging from 'not at all' to 'very much' that address physical well-being (for example, I have a lack of energy); social/family well-being (for example, I feel close to my friends); emotional well-being (for example, I am satisfied with how I am coping with my illness); functional well-being (for example, I am able to enjoy life); and, in the case of FACT-P, additional prostate cancer concerns (for example, I am able to feel like a man).27, 28 Patients who experienced hot flashes scored significantly higher (denoting a greater impact of hot flashes) on total FACT-G score (P=0.029); total FACT-P score (P=0.030); and physical well-being (P<0.001), social/family well-being (P=0.033), and prostate cancer-specific (P=0.041) subscales compared with patients who did not have hot flashes.26

A more recent analysis examined the effect of hot flashes on cancer-related distress in 68 men with prostate cancer during the first 3 months of ADT through the use of the Impact of Event Scale (IES).29 The IES measures distress related to an event with particular regard to intrusive (for example, unwanted thoughts and feelings) or avoidant (for example, behavior that allows people to avoid particular thoughts or feelings) responses.29, 30 Results showed that men who did not have hot flashes had a significant decrease in total cancer-related stress over the 3 months (P=0.01), whereas those with hot flashes showed no change. Furthermore, on the basis of a hierarchical regression analysis, hot flash score (severity times frequency) was determined to be a significant predictor for greater increases in intrusion and total cancer-related distress (Pless than or equal to0.02).
Gynecomastia

Gynecomastia is characterized by excessive growth of the male mammary glands and appears to be caused by a change in the estrogen to testosterone ratio and the resulting effects on the hypothalamic–pituitary–gonadal axis.7 The specific reason for the change in ratio varies depending on the choice of treatment. Although GnRH agonists eliminate gonadal androgens, adrenal androgens are still produced and their aromatization to estrogen can cause an increased estrogen-to-testosterone ratio.31 Antiandrogens, however, block the effect of androgens in the body, which leads to a reduction in feedback to the hypothalamus and pituitary gland, thus resulting in increased testosterone release and aromatization to estrogen.7 Regardless of the specific etiology, the outcome of the change in the estrogen-to-testosterone ratio is the same—breast enlargement frequently accompanied by pain or tenderness.

The incidence of gynecomastia varies widely based on the selected method of ADT. As shown in a recent review, antiandrogen monotherapy was associated with an incidence range of 30–79%, estrogens 40–77%, orchiectomy 1–14% and GnRH agonists 1–16%.32 Unfortunately, little is known regarding the physiological impact that gynecomastia has on men treated with ADT. However, as reported in a recent review of the social context for gynecomastia, for many men it can be psychologically distressing, even to the point of requiring psychological support or intervention.33
Lipid changes

Recent observational data from a Medicare enrollees database suggest that treatment with GnRH agonists is associated with an increased risk of coronary heart disease, acute myocardial infarction and sudden cardiac death.34 Specifically, this study examined 73 196 men with prostate cancer aged 66 years or older, 43% of whom received ADT (36.3% with GnRH agonists and 6.9% through orchiectomy). Treatment with GnRH agonists was associated with an adjusted hazard ratio of 1.16 (95% CI, 1.10–1.21; P<0.001) for coronary heart disease, 1.11 (95% CI, 1.01–1.21; P=0.03) for myocardial infarction and 1.16 (95% CI, 1.05–1.27; P=0.004) for sudden cardiac death. These associations may be due to metabolic changes related to ADT (primarily GnRH agonists), including increases in body weight and fat mass, decreases in lean body mass, decreased insulin sensitivity and changes in serum lipid levels.35 However, only changes in serum lipid levels appear to be associated with estrogen deficiency (through estrogen–receptor-mediated changes in hepatic apoprotein gene expression36) and will, therefore, be the focus of this section.

In general, ADT is associated with notable effects on total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides.37, 38 Specifically, a cross-sectional study evaluated serum lipid levels in 44 men: 16 men with prostate cancer who received ADT for at least 12 months, 14 age-matched men with nonmetastatic prostate cancer who did not receive ADT and had rising PSA levels, and 14 age-matched healthy men with normal PSA.37 After adjustment for body mass index, men receiving ADT had higher levels of total cholesterol compared with both the healthy controls (P=0.02) and men who did not receive ADT (P=0.06), and significantly higher low-density lipoprotein (P=0.04) and non-HDL cholesterol (P=0.03) compared with the control group.37 Similar changes in lipid levels within individual patients were seen in 32 asymptomatic men with nonmetastatic prostate cancer who were receiving GnRH agonists.38 After 48 weeks, significant increases from baseline were noted in total cholesterol by 9.0% (P<0.001), HDL cholesterol by 11.3% (P<0.001), low-density lipoprotein cholesterol by 7.3% (P=0.05) and triglycerides by 26.5% (P=0.01).38

Although observational data suggest that ADT is associated with increased risk of heart disease,34 a recent randomized clinical study contradicts the assertion, finding a lack of increased risk of cardiovascular mortality.39 Data from this study of 945 men found that after 9 years the cardiovascular mortality rate for men receiving adjuvant treatment with the GnRH agonist goserelin after primary radiotherapy was 8.4% compared with 11.4% for those who did not receive adjuvant goserelin (P=0.17). The difference between the epidemiologic and clinical data suggests that further studies are needed to clearly ascertain the effect of ADT on cardiovascular mortality.

What is clear, however, is that estrogen deficiency associated with ADT has a significant impact on serum lipid levels, as evidenced above. While increased triglycerides and cholesterol are independent risk factors for cardiovascular disease, they also contribute to metabolic syndrome, as defined by the National Cholesterol Education Program's Adult Treatment Panel III criteria of greater than or equal to3 of the following criteria for men: waist circumference >102 cm, triglycerides greater than or equal to150 mg per 100 ml, HDL cholesterol <40 mg per 100 ml, blood pressure greater than or equal to130/greater than or equal to85 mm Hg and fasting glucose greater than or equal to110 mg per 100 ml.40 In fact, a recent study of 58 men (20 with prostate cancer who received ADT for greater than or equal to12 months, 18 with prostate cancer who did not receive ADT and had increasing PSA levels and 20 age-matched healthy men with normal PSA) found that significantly more men who received ADT (55%; overall P=0.03) met the Adult Treatment Panel III's criteria for metabolic syndrome compared with those who did not receive ADT (22%) and healthy men (20%).41 However, several of the effects associated with ADT differ from this definition of metabolic syndrome (for example, ADT is associated with an increase in 'good' HDL cholesterol), suggesting that although there are similarities and lipid changes should be monitored as a cardiovascular disease risk factor, the ADT-associated changes are different from the classic metabolic syndrome.35
Memory loss

Although evidence suggests that ADT is associated with memory loss,42, 43 it remains unclear whether this is due to an estrogen or testosterone deficiency as both estrogen and testosterone receptors are found in the portions of the brain that control two of the major forms of memory (working memory and verbal long-term memory).42 However, a study examining the contribution of conversion of testosterone to estradiol on cognitive processing in healthy older men showed that improvement in verbal memory depended on aromatization of testosterone to estradiol.44

Similar analyses have been carried out on men with prostate cancer receiving ADT. In one study, the impact of the ADT-induced decline in estrogen on cognition was examined over a period of 1 year in 23 men with prostate cancer, all of whom were receiving ADT.43 Cognition was assessed using a standardized, cognitive test battery that measured verbal, visuomotor and memory performance, along with cognitive processing from various domains of attention.43 Significant cognitive declines (compared with baseline) in association with reduced estradiol levels were identified at 6 months (albeit insignificant at 12 months) in visual memory of figures (P=0.022), recognition speed of numbers (P=0.030) and verbal fluency (P=0.019). Furthermore, the magnitude of the impact was associated with the degree in estrogen decline, for example, the highest impairment occurred in patients with the greatest decline in estrogen.43

Another study examined the impact of not only ADT on cognition, but also of subsequent estrogen replacement in men with prostate cancer.42 Eighteen men with prostate cancer who completed ADT were given replacement estrogen and compared with 18 age-matched men currently receiving ADT and 17 healthy controls. Intelligence levels were measured using the Wechsler Adult Intelligence Scale-Revised Vocabulary subtest. At baseline, all patients receiving ADT scored significantly worse than healthy patients in immediate and delayed verbal memory (Pless than or equal to0.01). However, in subsequent testing, patients who received estrogen showed a significant improvement in both immediate and delayed verbal memory compared with their baseline scores (Pless than or equal to0.01); there was no change in the other two groups.

Although these studies suggest that estrogen deficiency related to ADT may affect areas of cognition such as visual memory of figures and recognition speed of numbers, similar studies have suggested a role for testosterone deficiency as well, including influence on visuomotor slowing, working memory and recognition of letters.45 As such, it appears that both estrogen and testosterone deficiency may have a role in ADT-related memory loss; however, further study is needed.
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Summary and conclusions

Because of the increase in PSA testing, prostate cancer is being diagnosed earlier in the course of the disease and patients are receiving ADT both earlier in treatment and for longer duration.46 Many clinicians, however, may not be aware of the adverse effects associated with estrogen deficiency that results from ADT, including increased fracture risk, hot flashes, gynecomastia, adverse lipid changes and memory loss. Not only do these adverse effects create physical and psychological distress, but as is the case with increased fracture and lipid changes, they can also greatly impact patients' overall health and have a significant impact on survival. Although treatment options exist for many of the individual adverse effects, none are Food and Drug Administration approved for ADT-induced adverse effects, and there is currently no single treatment option that can manage multiple adverse effects.
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Conflict of interest

Stephen J Freedland worked as a consultant and/or was present on the advisory board and speakers' bureau for AstraZeneca, Amgen and GTx Inc. James Eastham has no conflict of interest to declare. Neal Shore worked as the consultant/investigator for Amgen, GTx Inc., Pfizer, sanofi-aventis, Dendreon, Novartis, Ferring, Endo Pharmaceuticals, GP Pharm.
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