Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2007-2595
The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2042-2049
Copyright © 2008 by The Endocrine Society
Androgen Deprivation Therapy in Prostate Cancer and Metabolic Risk for Atherosclerosis
Sadeka Shahani,
Milena Braga-Basaria and
Shehzad Basaria
Department of Internal Medicine (S.S.), Harbor Hospital of Baltimore, Baltimore, Maryland 21225; Consultant Endocrinologist (M.B.-B.), Baltimore, Maryland 21209; and Division of Endocrinology and Metabolism and Oncology (S.B.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21224
Address all correspondence and requests for reprints to: Shehzad Basaria, M.D., Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Suite 4300, Baltimore, Maryland 21224. E-mail: sbasari1{at}jhmi.edu.
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Abstract
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Context: Prostate cancer (PCa) is the most common cancer in men. Androgen-deprivation therapy (ADT) is generally employed in the treatment of locally advanced and metastatic PCa. Although its use as an adjuvant therapy has resulted in improved survival in some patients, ADT has negative consequences. Complications like osteoporosis, sexual dysfunction, gynecomastia, and adverse body composition are well known. Recently, metabolic complications like insulin resistance, diabetes, dyslipidemia, and metabolic syndrome have emerged, which may be responsible for the increased cardiovascular mortality in this population.
Evidence Acquisition: A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa populations evaluating the association between testosterone and metabolism were also reviewed and briefly mentioned where relevant.
Evidence Synthesis: Prospective studies evaluating early (3–6 months) metabolic changes of ADT show development of hyperinsulinemia; however, glucose levels remain normal. Cross-sectional studies of men undergoing long-term (
12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. Furthermore, men undergoing ADT also experience higher cardiovascular mortality.
Conclusion: Long-term prospective studies of ADT are needed to determine the timing of onset of these metabolic complications and to investigate the mechanism behind them. In the meantime, we recommend baseline and serial screening for fasting glucose, lipids, and other cardiovascular risk factors in men receiving ADT. Glucose tolerance tests and cardiac evaluation may be required in selected cases.
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Introduction
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Prostate cancer (PCa) is the most common malignancy in men. Statistics suggest that its incidence is on the rise, primarily due to increased screening with prostate-specific antigen (PSA). In 2007, approximately 219,000 new cases of PCa were diagnosed in the United States with an estimated death rate of 27,000 (second only to lung cancer) (1). In 1941, Huggins et al. (2) described the androgen dependence of PCa by showing that castration decreases its growth. Six decades later, androgen-deprivation therapy (ADT) has become a common treatment, and approximately 600,000 men in the United States alone are receiving it (3). The modalities of ADT include surgery (orchiectomy) or medical therapy (GnRH agonists or antagonists), with most patients choosing the latter. In some cases, androgen receptor antagonists are used in conjunction with GnRH analogs to block the action of androgens of adrenal origin, known as combined androgen blockade. ADT has been the cornerstone in the treatment of advanced and metastatic PCa. In the latter, ADT has been shown to significantly improve morbidity, such as quality of life and bone pain (4). Recent data suggest that adjuvant use of ADT in men with locally advanced PCa has resulted in a decrease in recurrence rate and an improvement in survival (5). A recent metaanalysis also found ADT to be effective for palliation in men with advanced PCa and improving survival in high-risk cases in combination with radiation therapy (6). Although the use of ADT in this group of men is justified, recently there has been an increasing trend of employing ADT even in patients with early-stage (localized) PCa (which has a favorable prognosis) and in those who experience biochemical recurrence (rising PSA after initial remission), even though no survival advantage has been shown in such patients (7). Recent data suggest that the use of ADT has significantly increased from 3.7% in 1991 to 31% in 1999 (8). Interestingly, this increased use was even seen in men over 80 yr old who had localized disease. Because the prognosis for early-stage PCa is already favorable, the use of ADT in such patients may have a negative impact on their overall health and quality of life.
The aim of ADT is to achieve serum testosterone levels as low as possible, with current guidelines recommending levels less than 50 ng/dl (9) (normal range in young men, 300-1000 ng/dl). Male hypogonadism (of any etiology) is associated with numerous adverse effects. These include decreased libido, impotence, decreased lean body mass and muscle strength, increased fat mass, decreased quality of life, and osteoporosis (10). Although these complications of hypogonadism are well established, newer complications have recently surfaced. Population studies have shown that a serum testosterone level that is below the normal range is an independent risk factor for diabetes and metabolic syndrome in men (11, 12). These findings are significant considering the fact that men undergoing ADT have castrate levels of testosterone that may put them at a higher risk of developing these metabolic complications.
At a time when the link between male hypogonadism and diabetes is emerging, studies show that cardiovascular disease has recently become one of the most common cause of mortality in men with PCa (13, 14). Hence, it is conceivable that the use of ADT (and resulting profound hypogonadism) may trigger the development of metabolic complications, which in turn may accelerate the atherosclerotic process and lead to increased cardiovascular disease. Therefore, it is important for the caregivers and patients to be aware of these adverse effects.
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Search Strategy
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A MEDLINE search was conducted for articles published over the last 20 yr based on the key words androgen deprivation therapy AND insulin resistance, hyperglycemia, diabetes, dyslipidemia, metabolic syndrome, and cardiovascular disease. Relevant studies in non-PCa male populations evaluating the association between testosterone and glucose/lipid metabolism were also reviewed and briefly mentioned in the paper where relevant.
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ADT-Related Changes in Body Composition
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Because the alterations in body composition during ADT may be responsible (wholly or partly) for these metabolic complications, we will first review the changes in the body composition seen in men undergoing ADT. Male hypogonadism (of any etiology) results in a decline in lean body mass (LBM) and an increase in fat mass, which is reversed with testosterone replacement (15). Both cross-sectional and longitudinal studies have confirmed that men undergoing ADT have unfavorable body composition. A cross-sectional study showed that men undergoing long-term ADT (12–101 months) have increased fat mass in the trunk and all extremities [measured by dual-energy x-ray absorptiometry (DEXA)] compared with eugonadal men with PCa not undergoing ADT (treated with prostatectomy and/or radiation therapy) and age-matched eugonadal controls (16). A short-term longitudinal study in 22 newly diagnosed men with PCa showed a significant increase in fat mass (+1.7 kg) and a significant reduction (+1.7 kg) in LBM after 3 months of ADT (17). These findings were confirmed by a long-term prospective study in which 40 men were followed for 48 wk on ADT (18). Both the average body weight and body mass index (BMI) increased by 2.4% (P = 0.005), and fat mass on DEXA increased by 9.4%, whereas LBM decreased by 2.7%. The cross-sectional area of the abdomen also increased by 3.9%. Interestingly, this increase was mainly due to an increase in sc rather than visceral fat. Another case control study examined the prevalence and magnitude of obesity and fat mass in a group of 62 men with PCa receiving ADT for 1–5 yr (19). Healthy men (n = 47) with a PSA of less than 4.0 ng/ml were recruited as controls. The study showed that men with PCa had significantly higher body weight (86.5 vs. 80.6 kg) and percent body fat (30 vs. 26%) than controls. Recent prospective data from 65 men undergoing GnRH agonist treatment showed that LBM decreased by 2.0%, whereas fat mass increased by 6.6% at 12 months (P < 0.001 for each comparison) (20). Table 1
summarizes body composition changes in men receiving ADT.
These studies demonstrate that ADT results in an unfavorable body composition. The increase in fat mass on ADT correlates positively with rising insulin levels (17). Hence, this increasing adiposity may be the primary event leading to these metabolic complications (possibly via elaboration of adipokines and inflammatory cytokines). Similarly, it is possible that a decrease in muscle mass may result in decreased glucose uptake by the muscle. These changes may ultimately lead to insulin resistance and diabetes in this population, hence predisposing them to cardiovascular disease.
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Metabolic Complications of ADT (Tables 2 and 3)
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Insulin resistance and hyperglycemia
In recent years, it has become evident that one of the complications of male hypogonadism is insulin resistance and type 2 diabetes. Epidemiological studies have shown that low testosterone levels predict the development of insulin resistance, type 2 diabetes, and metabolic syndrome in men (12, 21, 22). Studies have also confirmed a direct relationship between serum testosterone and insulin sensitivity (23). These findings are further supported by interventional studies showing an improvement in insulin sensitivity with testosterone replacement in hypogonadal obese men (24). Because men undergoing ADT have castrate levels of androgens, this may put them at a higher risk of developing these complications. This issue demands attention because mortality due to cardiovascular disease in these men is as common as PCa-related deaths (14). Hence, it is conceivable that metabolic dysregulation due to ADT accelerates atherosclerosis and results in increased cardiovascular complications.
Early metabolic changes of ADT
A few studies have evaluated glucose homeostasis in this patient population. A prospective study of 22 hormone-naive men with recently diagnosed PCa undergoing ADT showed a significant increase in serum insulin from a baseline level of 11.8 mU/liter to 19.3 mU/liter at 3 months; however, there was no significant change in plasma glucose levels (Fig. 1) (17). This hyperinsulinemia correlated with an increase in fat mass of 1.7 kg. This study, however, did not have a control group. This report was followed by another 3-month prospective study that showed a 63% increase in fasting insulin levels without any changes in fasting glucose (25). Although this study included seven non-ADT PCa men and eight normal controls, their metabolic parameters and testosterone levels were not reported. Use of combined androgen blockade has shown similar results. A recent 3-month prospective study using combined androgen blockade with leuprolide and bicalutamide showed a 43% increase in fat mass and a 26% increase in insulin levels from baseline, again indicating development of insulin resistance with increasing adiposity (26). Although there was no significant change in fasting glucose levels, a statistically significant increase in glycosylated hemoglobin was seen (though this increase was within the normal range from 5.46–5.62%). These observations suggest that insulin resistance develops within a few months of initiating ADT; however, this compensatory hyperinsulinemia prevents the development of diabetes.
Late metabolic changes of ADT
Based on the information available from the studies evaluating early metabolic changes, it was important to determine the severity of metabolic dysregulation in men undergoing long-term ADT, particularly to evaluate whether hyperglycemia develops in these patients. A recent cross-sectional study attempted to answer these questions. A total of 53 men were evaluated, 18 with PCa undergoing ADT for at least 12 months (ADT group), 17 age-matched eugonadal men with nonmetastatic PCa who had undergone prostatectomy and/or radiotherapy and were not androgen-deprived (non-ADT group), and 18 age-matched eugonadal controls (control group) (27). None of the men had known history of diabetes mellitus nor were they on any antidiabetic medications. The mean duration of ADT was 45 months (range 12–101 months). In the ADT group, 15 men were undergoing treatment with GnRH analog, whereas three had undergone orchiectomy. In 14 of these men, the indication for ADT was biochemical recurrence (increased PSA). Patients in the non-ADT group were enrolled at the time when they were experiencing biochemical recurrence (to match with the ADT group); however, they had not yet received ADT. The non-ADT group was enrolled to account for any influence that the disease (PCa) may have on these metabolic parameters, and the control group was enrolled to control for any metabolic changes that may occur with aging. Both non-ADT and control groups were eugonadal with total testosterone more than 280 ng/dl. After adjusting for age and BMI, men in the ADT group had significantly higher insulin levels and insulin resistance, measured as homeostasis model assessment for insulin resistance (HOMA-IR), compared with the other two groups (Fig. 2). However, the key finding of the study was the prevalence of fasting hyperglycemia in the ADT group. The mean glucose level in the ADT group was 131 ± 7.43 mg/dl compared with 103 ± 7.42 mg/dl and 99 ± 7.58 mg/dl in the non-ADT and control groups, respectively (Fig. 2). Importantly, 44% of men in the ADT group had a fasting glucose level of more than 126 mg/dl (a criterion for the diagnosis of diabetes mellitus) compared with 12 and 11% in the non-ADT and control groups, respectively (Fig. 3). Men on ADT also had higher serum levels of leptin, reflecting increased fat mass. Because the data were adjusted for age and BMI, it appears that hypogonadism could be directly responsible for at least some of these metabolic changes. Hence, it appears that longer duration of ADT could result in hyperglycemia and frank diabetes.
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FIG. 2. Higher prevalence of insulin resistance and hyperglycemia in men undergoing long-term ADT compared with age- and disease-matched controls (adapted from Ref. 27 ).
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A recent observational study of a population-based cohort found that men undergoing ADT with GnRH agonists had a higher risk of incident diabetes (11%), coronary artery disease (25%), myocardial infarction, and sudden death (28). Interestingly, orchiectomy was associated only with a higher risk of diabetes. In some men, this risk was evident within 4 months of starting ADT. These findings suggest that although both medical and surgical modalities of ADT result in increased metabolic burden, GnRH analogs are also associated with cardiovascular events. This increased risk could be, at least partly, due to the pharmacological properties of GnRH analogs because a preliminary report has suggested that GnRH analogs may possess an arrhythmogenic potential (29). This difference between the two modalities of ADT should be explored in future studies.
From the review of the above studies, one can conclude that insulin resistance develops within a few months of initiation of ADT, but the resulting hyperinsulinemia maintains euglycemia. However, eventually, this compensatory mechanism fails during prolonged treatment, resulting in hyperglycemia. Currently, neither the mechanism nor the site (liver or muscle) of insulin resistance is known. Because male hypogonadism is considered to be a proinflammatory state (30), it is possible that increased levels of adipocytokines (e.g. resistin, IL-6, and TNF-
) may be playing a role in insulin resistance (31).
Metabolic syndrome
In the past decade, a great deal of literature has emerged on the association of metabolic syndrome with various cardiovascular endpoints. According to the Adult Treatment Panel III criteria (32), a male is considered to have metabolic syndrome if he has three of the following five criteria: fasting plasma glucose level higher than110 mg/dl, serum triglyceride level of 150 mg/dl or higher, serum high-density lipoprotein (HDL) level lower than 40 mg/dl, waist circumference more than 102 cm, and blood pressure 130/85 mm Hg or higher. Subjects on antihypertensives and lipid-lowering medications are also classified as positive for the respective criterion. Recently, male hypogonadism has emerged as an independent risk factor for metabolic syndrome. Cross-sectional studies have shown that men with low testosterone levels have a higher prevalence of metabolic syndrome after adjusting for confounders (12). Similarly, longitudinal studies indicate that lower testosterone levels in men independently predict the development of metabolic syndrome (22).
Recently, a cross-sectional study evaluated the prevalence of metabolic syndrome in men with PCa undergoing long-term ADT compared with age- and disease-matched controls (33). In that study, 58 men were evaluated, including 20 patients undergoing ADT for at least 12 months (ADT group), 18 age-matched eugonadal men not receiving ADT (non-ADT group), and 20 age-matched healthy eugonadal men with normal PSA (control group). Interestingly, more than half (55%) of the men in the ADT group had metabolic syndrome compared with 22 and 20% in the non-ADT and control groups, respectively (Fig. 4). Hyperglycemia and abdominal obesity were the major determinants of metabolic syndrome.
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FIG. 4. Prevalence of metabolic syndrome and its components in men undergoing long-term ADT (adapted from Ref. 33 ).
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These observations suggest that profound hypogonadism due to ADT imparts increased metabolic burden. Long-term prospective studies are needed to determine the time of onset of various metabolic alterations in these men. These studies should be followed by interventional studies to treat insulin resistance and components of metabolic syndrome in this patient population.
Dyslipidemia
Hyperlipidemia is a known risk factor for cardiovascular disease. Recent epidemiological research suggests that low serum testosterone levels in men are associated with an adverse lipid profile, especially elevated total cholesterol, LDL cholesterol, and triglycerides (34). Furthermore, interventional studies have shown that testosterone replacement in hypogonadal men results in an improvement in lipid profile (35).
The effect of ADT on lipid profile has been evaluated in both cross-sectional and prospective trials. Initially, Moorjani et al. (36) reported the effect of different methods of androgen deprivation on plasma lipoproteins that included estrogen use, orchiectomy, and combination treatment with LHRH agonist and flutamide. The lipoprotein profile resulting from combination treatment was more beneficial than estrogen or orchiectomy alone. Patients receiving estrogen developed significant hypertriglyceridemia along with elevation in high-density lipoprotein (HDL) cholesterol (including apolipoprotein A-I and A-II concentration), whereas LDL cholesterol was significantly lower. No change was seen in very-low-density lipoprotein (VLDL) cholesterol. Orchiectomized patients developed higher plasma apolipoprotein B levels without any changes in triglyceride, VLDL, LDL, or HDL cholesterol. Combined treatment with LHRH agonist and flutamide showed less adverse effect on lipid profile. Plasma apolipoprotein B did not increase significantly, whereas HDL cholesterol and apolipoprotein AI concentration increased. A recent cross-sectional study showed that men on long-term ADT had significantly higher fasting level of total and LDL cholesterol compared with the control group (37). Prospective studies have revealed similar information. A study of 16 men showed a significant increase in total and HDL cholesterol after 3 months, whereas no changes were seen in LDL and triglycerides (25). A longer prospective study of 40 men undergoing ADT for 48 wk showed increases in total cholesterol of 9%, LDL cholesterol of 7.3%, and triglycerides of 26.5% (18). However, HDL cholesterol also increased by 11.3%. These findings are not universal because one prospective study did not show any change in lipids after 3 months of ADT (17).
In summary, ADT in men with PCa leads to an increase in total cholesterol, LDL cholesterol, and triglycerides. Because HDL cholesterol also increased in some studies, the contribution of these lipid changes on the overall cardiovascular risk is currently unclear. Evaluation of subclasses of LDL and HDL particles may shed some further light in evaluating this risk.
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ADT and Cardiovascular Mortality
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It has been recognized for almost a decade that men with PCa have higher cardiovascular mortality. It was Satariano et al. (13) who first reported that the second most common cause of death in men with PCa was cardiovascular disease (after PCa-specific mortality). A few years later, another report showed that the proportion of deaths due to cardiovascular disease had equaled those related to PCa itself (14). However, these studies did not evaluate the difference in mortality between patients on ADT vs. non-ADT men. Keating et al. (28) recently reported that men undergoing ADT have 25% higher risk of incident coronary artery disease compared with non-ADT men. A recent population-based study of approximately 23,000 men showed that men undergoing ADT for at least 12 months had a 20% higher risk of cardiovascular morbidity (after controlling for multiple confounders) compared with subjects who did not receive ADT (38). Furthermore, many men started incurring this risk within the first year of treatment. Another report looked at the pooled data from three randomized PCa trials and showed that men 65 yr or older receiving ADT for as short as 6 months experienced shorter times to fatal myocardial infarction compared with age-matched men not receiving ADT and younger men (<65 yr) (39). Lastly, a recent report found that men receiving ADT were 2.6 times more likely to have cardiovascular mortality than non-ADT controls after adjusting for age and other cardiovascular risk factors (40). Importantly, this increased risk was seen in both younger (<65 yr) and older (>65 yr) men.
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Follow-Up Strategy
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These above-mentioned findings suggest that men already receiving or planning to start ADT may benefit from screening for various cardiovascular risk factors. This especially applies to older men (>65 yr) who may be at a higher risk than their younger counterparts. Men with personal or family history of cardiovascular disease may even benefit from cardiology consultation before starting ADT. These men should be advised lifestyle modification (diet, exercise, smoking cessation, etc.) and treatment of any existing conditions like diabetes, hyperlipidemia, and hypertension. Treatment of hypertension is important in these men because ADT has been shown to increase vascular stiffness (17, 25). The preventive role of aspirin, statins, and insulin sensitizers should be studied in this population. A strategy to monitor for diabetes is summarized in Fig. 5.
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FIG. 5. Strategy to monitor for diabetes in men receiving ADT. IGT, Impaired glucose tolerance; OGTT, oral glucose tolerance test.
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Conclusion
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Although ADT is beneficial in a subset of patients with PCa, the range of its complications is expanding (Fig. 6). Metabolic complications such as insulin resistance, diabetes, and metabolic syndrome have recently surfaced and may be responsible for the increased cardiovascular mortality seen in these men. The physicians should consider this risk before initiating ADT, especially in men with early-stage PCa or with biochemical recurrence because the risk/benefit ratio may be high in them. Although the studies are limited, it appears that short-term ADT (3–6 months) leads to the development of insulin resistance without resulting in hyperglycemia. However, long-term ADT (12 months or longer) is associated with hyperglycemia and frank diabetes. Furthermore, metabolic syndrome is present in more than half of such men. Because these men have increased fat mass, it is possible that adipocytokines may be responsible in the pathogenesis of insulin resistance. However, it should be appreciated that the studies evaluating late complications of ADT are cross-sectional and do not establish causality. Prospective studies are needed in men with newly diagnosed PCa (who are hormone naive) and follow them long-term to determine the timing of onset of these metabolic complications and to identify the phenotype of men who are more at risk to develop them. Furthermore, prevention of these metabolic complications with diet, exercise, and insulin sensitizers needs to be studied. Prospective studies are under way to answer some of these questions.
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Footnotes
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Disclosure Statement: The authors have nothing to declare.
First Published Online March 18, 2008
Abbreviations: ADT, Androgen deprivation therapy; BMI, body mass index; DEXA, dual-energy x-ray absorptiometry; HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment for insulin resistance; LBM, lean body mass; LDL, low-density lipoprotein; PCa, prostate cancer; PSA, prostate-specific antigen; VLDL, very-low-density lipoprotein.
Received November 26, 2007.
Accepted March 10, 2008.
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Lower serum testosterone is independently associated with insulin resistance in non-diabetic older men: the Health In Men Study
Eur. J. Endocrinol.,
October 1, 2009;
161(4):
591 - 598.
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A. M. Traish, F. Saad, R. J. Feeley, and A. Guay
The Dark Side of Testosterone Deficiency: III. Cardiovascular Disease
J Androl,
September 1, 2009;
30(5):
477 - 494.
[Abstract]
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Abstract
Introduction
