Metabolic and cardiovascular effects of androgen deprivation therapy
Payam Hakimian, Division of Urology, Maimonides Medical Center, 4802 10th Avenue, Brooklyn, New York, NY 11219, USA.
Prostate cancer is the most common gender-specific malignancy in men in the USA. Androgen-deprivation therapy (ADT) is commonly used in the treatment of metastatic or recurrent prostate cancer. The use of ADT is increasing with the advocacy of adjuvant and neoadjuvant ADT for treating asymptomatic patients with locally advanced prostate cancer. Although the use of ADT has resulted in improved survival in men with advanced prostate cancer, ADT, with its resulting severe hypogonadism, causes profound metabolic side-effects. We comprehensively reviewed previous reports using Medline searches of English-language literature (1950 to the present), with the keywords ‘hypogonadism’, ‘testosterone’, ‘androgen deprivation therapy’, ‘hormonal treatment’, ‘prostate cancer’, ‘diabetes’, ‘metabolic syndrome’, and ‘cardiovascular disease’. Men with prostate cancer who undergo long-term ADT are at greater risk of developing dyslipidaemia, insulin resistance, hyperglycaemia and metabolic syndrome. These metabolic and physiological changes are a direct result of the induced severe hypogonadism and might predispose patients to a greater risk of cardiovascular morbidity and mortality. There is a need for prospective studies aimed and designed to investigate the metabolic and cardiovascular adverse effects of ADT, and assess the benefit/risk ratio, especially in special populations such as diabetics.
Cancer of the Prostate Strategic Urological Research Endeavor
body mass index
lean body mass
homeostatic model assessment-insulin resistance
(low-) high-density lipoprotein
Surveillance, Epidemiology and End Results.
Prostate cancer is the most common gender-specific malignancy in men in the USA; the incidence of prostate cancer is increasing with widespread PSA screening . The preferred treatment of locally confined prostate cancer is local surgery or radiotherapy. In 1941 Huggins et al. described the androgen dependence of prostate cancer in their Noble-prize winning work. Androgen-deprivation therapy (ADT) with GnRH agonist or bilateral orchidectomy has since become the main treatment for metastatic or recurrent prostate cancer.
With early screening for prostate cancer there has been a stage migration for newly diagnosed patients. Data from the USA Cancer of the Prostate Strategic Urological Research Endeavor (CaPSURE), a registry of 8685 men with prostate cancer, showed that in 1989–1990 and 2001–2002 the proportion of patients presenting with high-, intermediate- and low-risk disease changed from 40.9%, 28.0% and 31.2%, to 14.8%, 37.5% and 47.7%, respectively (P < 0.001) . The incidence of T1 tumours increased from 16.7% to 48.5%, and that of T3-4 tumours decreased from 11.8% to 3.5%, respectively (P < 0.001). The use of ADT is increasing with the advocacy of adjuvant ADT in otherwise asymptomatic patients with locally advanced prostate cancer, and the inclusion of neoadjuvant temporary ADT in the multimodal treatment of localized prostate cancer. The CaPSURE study shows that the use of primary ADT increased dramatically between 1989 and 2001, from 4.6% to 14.2% in low-risk, 8.9% to 19.7% in intermediate-risk, and from 32.8% to 48.2% in high-risk patients (all P < 0.001). The use of neoadjuvant ADT also increased in association with radical prostatectomy (2.9% to 7.8%, P = 0.003) and external beam radiation therapy (9.8% to 74.6%, P < 0.001) .
The use of adjuvant ADT in men with locally advanced prostate cancer has resulted in decreasing recurrence and improved survival . ADT has also been shown to improve survival in high-risk patients undergoing radiotherapy [6,7].
Although the use of ADT has resulted in improved survival in men with advanced prostate cancer, the resulting hypogonadism is associated with profound adverse effects. As men undergoing ADT have severe hypogonadism, they are more likely to develop complications of hypogonadism. The well-known adverse effects of ADT include hot flashes, gynaecomastia, osteoporosis, decreased libido, erectile dysfunction, changes in body composition, including increase in body mass index (BMI), decrease in lean body mass (LBM) and increase in fat mass [8–11]. Less well-known adverse effects of ADT are increased peripheral insulin resistance, dyslipidaemia and the development of metabolic syndrome that might contribute to an increased risk of diabetes and cardiovascular disease . In this review, we summarize the currently known metabolic and cardiovascular adverse effects of ADT.
We comprehensively reviewed previous reports using Medline searches of English-language literature (1950 to the present) using the keywords ‘hypogonadism’, ‘testosterone’, ‘androgen deprivation therapy’, ‘hormonal treatment’, ‘prostate cancer’, ‘diabetes’, ‘metabolic syndrome’ and ‘cardiovascular disease’. Relevant bibliographies of the selected reports were also reviewed for additional material.
One of the emerging complications of hypogonadism is insulin resistance and type II diabetes. Insulin resistance has been independently associated with cardiovascular mortality [13,14]. Pitteloud et al. reported a positive correlation between serum testosterone levels and insulin sensitivity. In their study, men with hypogonadal testosterone levels were twice as insulin resistant as their eugonadal counterparts, and 90% fulfilled criteria for the metabolic syndrome. This association is also supported by interventional studies in which testosterone-replacement therapy (TRT) in hypogonadal men resulted in an improvement in insulin sensitivity [11,16]. In the first double-blind placebo-controlled crossover study of TRT in diabetic patients, Kapoor et al. showed that TRT not only improved glycosylated haemoglobin (HbA1c) and fasting glucose levels, but also resulted in a significant improvement in insulin resistance, as assessed by homeostatic model assessment-insulin resistance (HOMA-IR), total cholesterol, waist circumference and waist/hip ratio. These factors represent an overall reduction in cardiovascular risk.
Epidemiological studies have shown that in men, hypogonadism is an independent risk factor for the subsequent onset of diabetes mellitus (DM) [12,17–19]. In the Massachusetts Male Aging Study the odds ratio for developing DM after a median follow-up of 8.9 years was 1.6 for patients with a 1 sd decrease in their free testosterone level . In a large cross-sectional study, lower serum testosterone levels were found in men with DM and there was an inverse relationship between total testosterone levels and HbA1c . This relationship was also apparent in another large cross-sectional study in which men in the lowest tertile of either free or bioavailable testosterone level were about four times more likely to have prevalent DM, after adjusting for age, adiposity, race and ethnicity .
Men receiving ADT are at greater risk of developing insulin resistance and hyperglycaemia. In a small cross-sectional study, men receiving ADT had significantly higher fasting glucose and insulin levels after adjustment for age and BMI . Furthermore, in a 12-week prospective study of 25 non-diabetic men with prostate cancer started on ADT, the mean insulin sensitivity by HOMA-IR decreased by 12.8% from baseline . At the same time, fasting plasma insulin levels increased by 25.9% with a small increase of HbA1c. This is alarming, as an elevated HbA1c level is a known risk factor for cardiovascular morbidity in patients with DM, and is a significant predictor of mortality . Indeed, an increase of 1% in HbA1c is associated with a 28% increase in the risk of death from all causes among patients with or without DM, independent of age, blood pressure, serum cholesterol, BMI and smoking habit (P < 0.002) .
ADT has also been associated with a greater risk of developing DM. In a retrospective study of 29 insulin-dependent diabetic men diagnosed with prostate cancer, after starting ADT, the fasting glucose, HbA1c and insulin requirements all deteriorated in the ensuing 24 months . The mean fasting glucose level increased from 143 to 187 mg/dL, the mean HbA1c increased from 6.3 to 9.3, and the daily insulin dose increased from 26 to 48 units. In addition, all cardiovascular biochemical risk markers measured, including total cholesterol, C-reactive protein, plasminogen activator and plasminogen activator inhibitor-1 deteriorated. Furthermore, in a recent retrospective study of 396 patients receiving ADT for prostate cancer, the incidence of new-onset DM was 11.3%. In patients with pre-existing DM, there was an increase of >10% in HbA1c or fasting glucose levels in 20% and 29% of the patients, respectively. On multivariate analysis, a BMI of >30 kg/m2 was associated with 4.65 times the risk of new-onset DM. Finally, in another large retrospective study, the relative risk of being diagnosed with DM in the 12 months after ADT was 1.36, after multivariate analysis (P = 0.01) .
Hypogonadism is associated with the metabolic syndrome and changes in body composition, which includes an increase in BMI, a decrease in LBM and increase in fat mass. According to the Adult Treatment Panel – III criteria, a man is considered to have metabolic syndrome if he has three of the following five criteria : fasting plasma glucose level of >110 mg/dL, a serum triglyceride level of at ≥150 mg/dL, a serum high-density lipoprotein (HDL) level of <40 mg/dL, a waist circumference of >102 cm, and a blood pressure of ≥130/85 mmHg. This syndrome is strongly associated with an increased risk of coronary heart disease .
In a cross-sectional study comparing 20 men undergoing ADT for ≥1 year, 18 age-matched men who received local treatment for localized prostate cancer and 20 aged-matched controls, the prevalence of metabolic syndrome was higher in the ADT than in the no-ADT (P < 0.01) and control (P = 0.03) groups . Among the components of metabolic syndrome, men on ADT had a higher prevalence of abdominal obesity, hyperglycaemia and elevated triglyceride than the controls (P = 0.02). In a prospective study, 49 patients with localized prostate cancer had total androgen blockade with a combination of LHRH agonist (35), or bilateral orchidectomy (seven), with oral flutamide as a neoadjuvant therapy for 6 months before radical therapy . Compared to their baseline levels, the mean body weight (P = 0.037), fasting blood glucose (P = 0.014) and total cholesterol (P = 0.017) levels all increased significantly. In a large population-based study of non-obese men, hypogonadism was shown to be an independent risk factor for developing metabolic syndrome . That study showed that hypogonadism is a risk factor for developing metabolic syndrome and not only a consequence of obesity. Furthermore, a prospective study of 40 men with locally advanced prostate cancer who had ADT showed an increase in average weight, percentage fat body mass and a decrease in percentage LBM . While there was an increase in cross-sectional areas of the abdomen and abdominal subcutaneous fat (P = 0.003), the cross-sectional area of intra-abdominal fat did not change significantly (P = 0.94).
Several recent studies reported a correlation between hypogonadism and dyslipidaemia. Interventional studies have also shown that TRT in hypogonadal men results in a significant improvement in lipid profile [34,35]. Furthermore, in a cross-sectional study comparing 16 men undergoing ADT for at ≥1 year, 14 age-matched eugonadal men with localized prostate cancer who had local therapy, and 14 age-controlled eugonadal men with no previous history of diabetes or dyslipidaemia, men on ADT had a higher BMI than the other groups . Men undergoing ADT also had significantly higher levels of total cholesterol than the other groups (P = 0.03). After adjusting for BMI, men on ADT continued to have significantly higher fasting levels of total cholesterol (P = 0.02), low DL cholesterol (P = 0.04) and non-HDL cholesterol (P = 0.03) than the control group.
In a prospective clinical trial of 1102 men comparing medical castration between GnRH antagonist abarelix (a GnRH agonist) and leuprolide acetate, vs leuprolide acetate and antiandrogen bicalutamide, fasting serum lipid, glucose levels and HbA1c were determined at baseline and on treatment days 85 and 169 . There were significant increases in total cholesterol, triglyceride and HDL in patients on leuprolide acetate or abarelix, but not in patients on leuprolide acetate plus bicalutamide. No consistent changes in LDL were detected. HbA1c increased from baseline to day 85 only and there were no changes in fasting glucose level.
There is increasing understanding of the effects of ADT on cardiovascular morbidity. Men with coronary artery disease have been shown to have significantly lower bioavailable and free testosterone than men with a normal coronary angiogram, after controlling for age and BMI . In an observational study, 73 196 Medicare patients aged ≥66 years who were diagnosed with locoregional prostate cancer between 1992 and 1999 were observed to 2001 . More than a third of men received a GnRH agonist; GnRH agonist use was associated with an increased risk of incidence of diabetes (adjusted hazard ratio, 1.44, P < 0.001), coronary heart disease (1.16, P < 0.001), myocardial infarction (1.11, P = 0.03), and sudden cardiac death (1.16, P = 0.004). In another retrospective population-based study of 22 816 patients with newly diagnosed prostate cancer, in a linked database of Medicare and Surveillance, Epidemiology and End Results national cancer registry (SEER), men who received ADT had a 20% higher risk of cardiovascular morbidity . Furthermore, in a multi-institutional study of 1372 patients pooled from three randomized trials, D’Amico et al. showed that the use of ADT for 6 months in men aged ≥65 years was associated with a higher risk and a shorter time to a fatal myocardial infarction than were men who did not receive ADT. Finally, in a recent observational study using the CaPSURE database, among men aged ≥65 years who had radical prostatectomy, the 5-year incidence of cardiovascular mortality was 5.5% for those who received ADT and 2% for those who did not . These studies indicating an increased cardiovascular morbidity in patients on ADT are especially concerning, as death unrelated to cancer might now surpass cancer-related death in men with prostate cancer. In one study, about half of the men diagnosed with prostate cancer died from some other cause . Indeed, cardiovascular disease is the main cause of death unrelated to cancer in patients with prostate cancer [44,45]. In a population-based study using combined the Medicare and Virginia Cancer Registry of 1996 patients aged >67 years and diagnosed with prostate cancer between 1987 and 1989, prostate cancer accounted for only 39% of 1207 deaths . In this group, heart disease contributed to ≈39% of deaths unrelated to prostate cancer.
The adverse effects of hypogonadism on coronary artery disease are probably due to long-term changes in cardiovascular risk factors and heart function. ADT has been shown to lead to an increase in arterial stiffness . TRT has been shown to improve angina pectoris and the outcome of acute myocardial infarction. TRT in hypogonadal men with angina has been shown to delay the time to ischaemia and improve the quality of life . Short-term TRT was shown to have a beneficial effect on exercised-induced myocardial ischaemia in men with coronary artery disease [48,49]. In a randomized double-blind placebo-controlled study of 76 patients with heart failure, TRT improved functional capacity and symptoms . Symptoms improved by at least one functional class in 35% of the TRT group, vs 8% of the placebo group. In patients with heart failure, TRT reduced QT dispersion, an independent risk factor for arrhythmic cardiac death .
Furthermore, low testosterone levels have been associated with increased mortality. In a study of 858 male veterans aged ≥40 years and with no prostate cancer, followed for a mean of 4.3 years, men with low testosterone levels had 88% greater mortality after adjusting for age, medical morbidity, BMI, race and other clinical factors . After excluding deaths in the first year, patients with low testosterone levels continued to have a 68% greater mortality than eugonadal patients, suggesting that the observed difference in mortality rate was not merely due to acute illness. A prospective population-based study of 794 men with a median age of 73.6 years, followed for a mean of 11.8 years, showed that men whose total testosterone levels were in the lowest quartile (<241 ng/dL) had a 44% (P = 0.002) greater all-cause mortality than those with higher testosterone levels, independent of age, adiposity and lifestyle . The low testosterone-mortality association was found to be independent of metabolic syndrome, diabetes and prevalent cardiovascular disease. In a cause- specific analysis, low testosterone levels predicted the increased risk of cardiovascular (hazard ratio 1.38, 95% CI 1.02–1.85) and respiratory disease (2.29, 1.25–4.20) mortality.
The increased risk of developing osteopenia and osteoporosis in patients on ADT is well established. In a retrospective population-based study of 50 613 patients in the linked database of SEER and Medicare, of men surviving ≥5 years after diagnosis, 19.4% of those who received ADT had a fracture, compared with 12.6% of those not receiving ADT (P < 0.001) . In addition, there was a statistically significant correlation between the number of doses of GnRH and the risk of fracture. In another study, patients on ADT had a three times greater rate of osteoporotic fractures . For further reading on the effects of ADT on bone health, see [55–57].
LIMITATIONS AND GAPS IN KNOWLEDGE
There is evidence supporting the emerging adverse effects of ADT, e.g. insulin resistance, hyperglycaemia, dyslipidaemia, and metabolic syndrome. However, for the most part these data come from small short-term prospective studies. The link between ADT and cardiovascular mortality is supported by large population-based studies that might have other confounding elements. There is a need for a long-term prospective study to assess the effects of ADT on insulin resistance, dyslipidaemia, metabolic syndrome and hyperglycaemia. In addition, there is a need for prospective studies to assess the reversibility of such adverse effects after discontinuing ADT. Such knowledge would be important in patients considering temporary ADT, e.g. in conjunction with radiotherapy.
CONCLUSIONS AND SUMMARY
In conclusion, men with prostate cancer who undergo long-term ADT are at greater risk of developing dyslipidaemia, insulin resistance, hyperglycaemia and metabolic syndrome. These metabolic and physiological changes are a direct result of the induced severe hypogonadism and might predispose patients to a higher risk of cardiovascular morbidity and mortality. Although studies have shown that ADT results in improved survival of the general population of patients with metastatic prostate cancer, there is a need to investigate whether such findings would apply to special populations, such as diabetics and patients with cardiovascular disease. Furthermore, there is a need for a large prospective study on metabolic and cardiovascular effects of ADT in diabetic patients, as men with DM have higher cardiovascular morbidity and mortality. Understanding such adverse effects will help clinicians to better determine the benefit/risk ratio of ADT. There is also a need to further investigate intermittent ADT and its possible impact on diminishing the adverse effects of this therapy. Finally, there is a need to investigate the reversibility of the metabolic and cardiovascular adverse effects of ADT.
CONFLICT OF INTEREST