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Published-Ahead-of-Print June 20, 2008, DOI:10.2164/jandrol.108.005454
Journal of Andrology, Vol. 29, No. 5, September/October 2008
Copyright © American Society of Andrology
DOI: 10.2164/jandrol.108.005454

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Review

Androgen Deprivation Therapy, Insulin Resistance, and Cardiovascular Mortality: An Inconvenient Truth

SHEHZAD BASARIA

From the Division of Endocrinology and Metabolism and the Division of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Correspondence to: Dr Shehzad Basaria, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 5200 Eastern Ave, Suite 4300, Baltimore, MD 21224 (e-mail: sbasari1{at}jhmi.edu).
Received for publication April 1, 2008; accepted for publication June 5, 2008.

Abstract

Prostate cancer (PCa) is the most common cancer in men. Androgen deprivation therapy (ADT) is used 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. Recent studies have also found metabolic complications in these men. Studies show that short-term ADT (3–6 months) results in development of hyperinsulinemia without causing hyperglycemia. Studies of men undergoing long-term (≥12 months) ADT reveal higher prevalence of diabetes and metabolic syndrome compared with controls. In addition, men undergoing ADT also experience higher cardiovascular mortality. Long-term prospective studies of ADT are needed to determine the timing of onset of these complications and to employ strategies to prevent them. In the meantime, baseline and serial screening for fasting glucose and other cardiac risk factors in men receiving ADT is prudent. In selected cases, glucose tolerance testing and cardiac evaluation may be required.

     Key words: Prostate, androgen deprivation, cardiovascular mortality, insulin resistance, metabolic syndrome


Prostate cancer (PCa) is the most common malignancy in men. In 2007 alone, approximately 219 000 new cases of PCa were expected in the United States with an estimated death rate of 27 000 (Jemal et al, 2007). The androgen dependence of PCa was initially shown by Huggins and Hodges in 1941 (Huggins et al, 1941); they won a Nobel Prize for this work in 1967. Half a century later, androgen deprivation therapy (ADT) has become a common treatment in the management of men with PCa. Recent estimates suggest that of 2 million men in the US with PCa, approximately 600 000 are receiving ADT (Smith, 2007). The majority of patients use medical ADT (gonadotropin-releasing hormone [GnRH] agonists). In some cases, androgen receptor antagonists are used in conjunction with GnRH analogues to block the action of adrenal androgens. ADT has become part and parcel in the treatment of advanced and metastatic PCa. In metastatic disease, ADT has been shown to improve cancer-related morbidities such as quality of life and bone pain (Chodak et al, 2002). Recent data also suggest that adjuvant use of ADT in men with locally advanced PCa has improved survival (Messing et al, 1999). It has also improved survival in high-risk cases in combination with radiation therapy (Sharifi et al, 2005). Although the use of ADT is justifiable in these patient populations, ADT is now being used even in men with early-stage PCa (which has a good prognosis) and in men who experience biochemical recurrence (despite lack of a survival advantage) (Chodak, 1998). To complicate things further, the use of ADT has increased by 27% in less than a decade, and it is used even in elderly men with localized disease (Shahinian et al, 2005). Hence, ADT in such patients may have a high risk/benefit ratio.

Male hypogonadism is associated with decreased libido, impotence, decreased lean body mass (LBM) and muscle strength, increased fat mass, decreased quality of life, and osteoporosis (Basaria and Dobs, 2001). These are also well-established complications of ADT (Figure 1). Recently, newer complications have surfaced. Population studies have shown that serum testosterone level that is below the normal range is an independent risk factor for diabetes and metabolic syndrome in men (Haffner et al, 1996; Muller et al, 2005). The goal during ADT is to achieve serum testosterone levels <50 ng/dL (Bubley et al, 1999). This is important because men undergoing ADT may be at an even higher risk of developing these metabolic complications. Recent studies show that cardiovascular disease has become one of the most common causes of mortality in men with PCa (Satariano et al, 1998; Lu-Yao et al, 2004). It could be hypothesized that employment of ADT may trigger development of metabolic complications, which in turn may accelerate atherosclerosis, leading to increased cardiovascular disease. Therefore, it is important for caregivers and patients to be aware of these adverse effects.


Figure 1
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  		Figure 1. Known adverse effects of androgen deprivation therapy. Color figure available online at www.andrologyjournal.org.

 

ADT and Body Composition

Because the metabolic complications of ADT may be a result of alterations in body composition during therapy, a brief review of changes in body composition in these men is justified. Male hypogonadism is associated with a decline in lean body mass and an increase in fat mass, which is reversed with testosterone replacement (Basaria et al, 2001). Numerous studies have confirmed that men undergoing ADT have unfavorable body composition. A cross-sectional study showed that men undergoing long-term ADT (mean, 45 months) have increased fat mass in the trunk and extremities compared to eugonadal men with PCa not undergoing ADT (status-post prostatectomy and/or radiation therapy) and age-matched eugonadal controls (Basaria et al, 2002). A 3-month longitudinal study of ADT in 22 men with newly diagnosed PCa showed a significant increase in fat mass and reduction in LBM (Smith et al, 2001). A long-term prospective study of 40 men followed for 48 weeks showed that average body mass index (BMI) increased by 2.4%, fat mass increased by 9.4%, and LBM decreased by 2.7% (Smith et al, 2002). The abdominal girth also increased by 3.9%, mainly because of an increase in subcutaneous fat. Recent 1-year prospective data from 65 men undergoing GnRH agonist treatment showed that LBM decreased by 2.0% and fat mass increased by 6.6% (P < 0.001 for each comparison; Lee et al, 2005). Another case-control study of men receiving ADT for 1–5 years showed that men with PCa had significantly higher body weight and percentage body fat than normal controls (Chen et al, 2002).


Figure 2
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  		Figure 2. Possible mechanisms underlying metabolic dysregulation in male hypogonadism. Color figure available online at www.andrologyjournal.org.

 
In summary, ADT results in an unfavorable body composition. The increase in adiposity during ADT correlates with increasing insulin levels (Smith et al, 2001) and may be the inciting event leading to metabolic dysregulation, possibly via elaboration of adipokines and inflammatory cytokines (Figure 2). Furthermore, a decrease in muscle mass may also result in decreased glucose uptake by the muscle fibers. The resulting insulin resistance and diabetes may predispose these men to increased cardiovascular disease.

Metabolic Complications of ADT

     Insulin Resistance and Hyperglycemia— Recently, insulin resistance and type 2 diabetes have emerged as one of the complications of male hypogonadism. Population studies have shown that hypotestosteronemia predicts the development of insulin resistance, type 2 diabetes, and metabolic syndrome in men (Haffner et al, 1994; Laaksonen et al, 2004; Muller et al, 2005). Furthermore, serum testosterone levels have a direct relationship with insulin sensitivity (Pitteloud et al, 2005). These findings are supported by interventional studies showing an improvement in insulin sensitivity with testosterone replacement in hypogonadal obese men (Marin et al, 1992). Because men on ADT have serum testosterone levels <50 ng/dL, this may predispose them to a higher risk of developing metabolic dysregulation. These metabolic complications may lead to accelerated atherosclerosis, which in turn may lead to the increased cardiovascular complications seen in these men.


Figure 3
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  		Figure 3. Hyperinsulinemia developing within 3 months of androgen deprivation therapy.

 
     Metabolic changes after short-term (3–6 months) ADT. Most of the studies evaluating metabolic changes after short-term ADT have been prospective. A study of 22 hormone-naïve men with newly diagnosed PCa receiving ADT showed a significant increase in serum insulin from baseline; however, there was no change in fasting glucose (Smith et al, 2001). This hyperinsulinemia correlated with an increase in fat mass. Another 3-month prospective study showed a 63% increase in fasting insulin levels without any changes in fasting glucose (Figure 3) (Dockery et al, 2003). Use of combined androgen blockade has shown similar results. A recent 3-month prospective study using leuprolide and bicalutamide showed a 26% increase in insulin levels, indicating development of insulin resistance with increasing adiposity (fat mass increasing by 43%; Smith et al, 2006). Again, no significant change in fasting glucose was seen; however, a statistically significant increase in glycosylated hemoglobin was observed (though this increase was within the normal range), possibly reflecting postprandial hyperglycemia. The results of these short-term studies suggest that insulin resistance develops within a few months of starting ADT; however, the resulting hyperinsulinemia is adequate to maintain euglycemia.

     Metabolic changes after long-term (≥12 months) ADT. The findings that metabolic changes are seen as early as 3 months after initiation of ADT opened the door to study of the severity of metabolic changes in men on long-term ADT, particularly to see if these subjects decompensate metabolically, resulting in hyperglycemia. A recent cross-sectional study attempted to answer this question. Fifty-three 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) (Basaria et al, 2006). None of the men had known history of diabetes mellitus, nor were any taking 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 analogue, and 3 had undergone orchiectomy. In 14 of these men, the indication for ADT was biochemical recurrence ({uparrow}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. Both non-ADT and control groups were eugonadal with total testosterone >280 ng/dL. The non-ADT group was enrolled to control for any effect of PCa itself on metabolic parameters, and the control group was enrolled to control for metabolic dysregulation that may occur as a result of normal aging. After adjusting for age and BMI, subjects in the ADT group had significant hyperinsulinemia and insulin resistance (measured according to the Homeostasis Model Assessment for Insulin Resistance [HOMAIR]), compared with other groups (Figure 4). However, the key finding of the study was a significantly higher prevalence of fasting hyperglycemia in the ADT group. The mean glucose level in the ADT group was 131 ± 7.43 mg/dL, compared to 103 ± 7.42 mg/dL and 99 ± 7.58 mg/dL in the non-ADT and control groups, respectively (Figure 4). Importantly, 44% of men in the ADT group had a fasting glucose level >126 mg/dL (a criterion for the diagnosis of diabetes mellitus) compared to 12% and 11% in the non-ADT and control groups, respectively. Men on ADT also had hyperleptinemia, reflecting increased fat mass. This study showed that longer duration of ADT could result in hyperglycemia and frank diabetes.


Figure 4
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  		Figure 4. Hyperinsulinemia (A), hyperglycemia (B), insulin resistance (C), and hyperleptinemia (D) in men undergoing long-term androgen deprivation therapy (adapted from Basaria et al, 2006). Color figure available online at www.andrologyjournal.org.

 
A recent population-based study found that men undergoing ADT with GnRH agonists had a higher risk of incident diabetes, coronary artery disease, myocardial infarction, and sudden death (Keating et al, 2006). Orchiectomy was associated only with a higher risk of diabetes. The increased risk of cardiovascular events with GnRH analogues could be partly because of pure drug effect, because they have been shown to possess arrhythmogenic potential (Garnick et al, 2004). Another retrospective study using a claims-based database showed that men on ADT were 36% more likely to develop incident diabetes compared to non-ADT men, with many men developing it within the first year (Lage et al, 2007).

These studies indicate that insulin resistance develops within a few months of starting ADT, but the resulting hyperinsulinemia maintains glucose levels in the normal range. Eventually, this compensatory mechanism fails during prolonged treatment, resulting in hyperglycemia (Figure 5). Studies are being planned to understand the mechanism of insulin resistance in these men. Based on the fact that male hypogonadism is an inflammatory state, adipokines and inflammatory cytokines may be playing a role (Cutolo et al, 2004).


Figure 5
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  		Figure 5. Proposed insulin and glucose dynamics during short- and long-term androgen deprivation therapy. Solid line suggests beta cell failure. Dashed line suggests continuing hyperinsulinemia. Color figure available online at www.andrologyjournal.org.

 
     Metabolic Syndrome— Metabolic syndrome is a known risk factor for cardiovascular disease (Eckel et al, 2005). According to the Adult Treatment Panel III guidelines (Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, 2001), a man is considered to have metabolic syndrome if he meets 3 of the following 5 criteria: fasting plasma glucose level >110 mg/dL, serum triglyceride level ≥150 mg/dL, serum high-density lipoprotein level <40 mg/dL, waist circumference >102 cm, and blood pressure ≥130/85 mmHg. Subjects on antihypertensive and antilipid medications are also considered positive for the respective criteria. Recently, male hypogonadism has surfaced as an independent risk factor for metabolic syndrome. Cross-sectional studies have shown that men with hypotestosteronemia have a higher prevalence of metabolic syndrome (Muller et al, 2005). Longitudinal studies also show that lower androgen levels in men independently predict the development of metabolic syndrome (Laaksonen et al, 2004).

A cross-sectional study recently evaluated the prevalence of metabolic syndrome in men with PCa undergoing long-term ADT compared with age- and disease-matched controls (Braga-Basaria et al, 2006). Fifty-eight men were recruited, including 20 patients undergoing ADT for at least 1 year (ADT group), 18 age-matched eugonadal men not receiving ADT (non-ADT group), and 20 age-matched healthy eugonadal controls with normal PSA (control group). The results showed that 55% of the men in the ADT group had metabolic syndrome, compared to 22% and 20% in the non-ADT and control groups, respectively. Hyperglycemia and abdominal obesity were the major determinants of metabolic syndrome.

These observations suggest that profound male hypogonadism leads to significant metabolic derangements. Longer prospective studies are needed to determine the timing of onset of these metabolic alterations. These studies should be followed by interventional studies to treat insulin resistance and other features of metabolic syndrome.

ADT and Cardiovascular Mortality

Men with PCa have higher cardiovascular mortality. A decade ago, the first report was published showing that the second most common cause of death (after PCa-specific mortality) in men with PCa was cardiovascular disease (Satariano et al, 1998). Six years later, Lu-Yao et al showed that cardiovascular mortality in these men has equaled PCa-specific mortality (Lu-Yao et al, 2004). These reports, however, did not look at the difference in cardiovascular mortality rates between men on ADT vs men not on ADT. Finally, a recent report showed that men receiving ADT have a 25% higher risk of incident coronary artery disease compared to non-ADT men (Keating et al, 2006). Another population-based study also showed that men on ADT for at least 1 year had a 20% higher risk of cardiovascular morbidity compared to non-ADT subjects, with many men incurring this risk within the first year of treatment (Saigal et al, 2007). Pooled data from 3 randomized trials showed that older men (≥65 years) receiving ADT for only 6 months experience shorter times to fatal myocardial infarction compared to age-matched non-ADT men and younger men (<65 years) (D'Amico et al, 2007). These reports are further supported by results of recent analysis from the CAPSURE database showing that men receiving ADT were 2.6 times more likely to have cardiovascular mortality than non-ADT controls (Tsai et al, 2007). In this study, the increased risk was seen even in younger (<65 yrs) men.

Conclusion

Recent evidence suggests that the use of ADT is associated with complications such as insulin resistance, diabetes, and metabolic syndrome. These metabolic alterations may be responsible for the increased cardiovascular mortality in these men. Evidence suggests that short-term ADT (3–6 months) leads to the development of insulin resistance without causing hyperglycemia. However, long-term ADT (≥12 months) is associated with hyperglycemia, frank diabetes, and metabolic syndrome. Physicians should have detailed discussions regarding these complications with all their patients before initiating ADT, especially with men who have early-stage PCa and those with biochemical recurrence, because they are most likely to have a higher risk/benefit ratio. For the time being, we recommend that physicians screen all their patients, those already receiving or planning to receive ADT, for diabetes by checking fasting glucose and HbA1c (at baseline and then every 3 months). Counseling for diet and exercise should be given to all subjects. Men who have impaired fasting glucose at baseline should undergo an oral glucose tolerance test (because it may unmask underlying diabetes). Men with impaired glucose tolerance and/or diabetes should be referred for endocrine consultation. Men with existing coronary artery disease may benefit from cardiology consultation prior to initiation of ADT. Prospective studies are needed in hormone-naïve men with newly diagnosed PCa that will follow them long-term to determine the timing of onset of these complications, to identify the phenotype of men more likely to develop metabolic dysregulation, and to evaluate the role of diet, exercise, and insulin sensitizers in them.


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