Cardiovascular and metabolic complications during androgen deprivation: exercise as a potential countermeasure

Abstract

Apart from the well-established adverse musculoskeletal and sexual health effects of androgen deprivation therapy (ADT), evidence is accumulating of substantial ADT-related cardiovascular and metabolic complications, which may impact quality of life and overall survival. In this brief review we discuss (1) the incidence of cardiovascular and metabolic complications during/following ADT from large cohort studies, (2) the increased risk factors for cardiovascular and metabolic disease from cross-sectional and prospective studies and (3) the use of physical exercise as a countermeasure in this new era of ADT-related toxicity. It is clear that exercise has the potential to provide a myriad of benefits to men undergoing ADT that may result in reduced morbidity and mortality, and subsequently improve quality of life.

Introduction

There has been a very substantial increase in the use of temporary androgen deprivation treatment (ADT) in the adjuvant management of prostate cancer to achieve improved prostate-specific antigen relapse-free survival and overall survival.1 However, these benefits only manifest years later, and then only for a small proportion of those treated. Information about potential treatment toxicity is therefore vital for informed decision making. Well-recognized side effects of ADT include vasomotor flushing, anemia, fatigue, gynecomastia, osteoporosis and skeletal fractures, and toxicity-related musculoskeletal deficits impacting on quality of life.2, 3, 4 However, additional information from several large scale observational studies has come to light regarding an increased incidence of significant cardiovascular and metabolic complications associated with temporary ADT.5, 6, 7, 8

To date, a number of cross-sectional and short-term prospective studies of men treated with ADT have consistently reported an increase in risk factors for cardiovascular and metabolic complications such as increased arterial stiffness and abdominal obesity, hyperglycemia, altered lipoprotein profile, as well as an increased incidence of metabolic syndrome.9, 10, 11, 12, 13, 14 Such unfavorable metabolic alterations from testosterone suppression could potentially mediate the mechanisms underlying the higher frequency of cardiovascular events observed in prostate cancer patients undergoing this form of treatment. Moreover, this may be compounded by the failure of testosterone to recover in some men following cessation of ADT, hence ADT-related complications that arise may not be temporary.15, 16

In non-prostate cancer patients, increased levels of physical activity is well known to reduce risk of type 2 diabetes as demonstrated in large cohort studies where a dose–response relationship between exercise and relative risk of developing diabetes have been reported.17, 18 Importantly, the protective effect of physical activity seems to be even stronger in individuals at highest risk for type 2 diabetes, defined as those with a high body mass index (BMI), history of hypertension or a family history of diabetes.17 This could also be the case for prostate cancer patients on ADT where increased fat mass as an adverse effect from therapy is well established. Although studies are yet to be conducted with testosterone-deplete patients examining the effects of exercise on cardiovascular and metabolic complications, there is a strong rationale based on other patient populations, as well as in healthy adults, that exercise may serve to prevent or attenuate ADT-related cardiovascular and metabolic morbidity and mortality.

In this brief review, we discuss (1) the increased incidence of cardiovascular and metabolic disease following ADT, (2) increased risk factors for cardiovascular and metabolic disease (for example, abdominal obesity, high cholesterol) in ADT-treated men from cross-sectional and prospective studies and (3) use of physical exercise as a contemporary patient management strategy in this new era of ADT-related toxicity. Information for this review was obtained by searching PubMed database from 2000 to December 2008 with a combination of the following terms: cardiovascular disease, metabolic syndrome, diabetes, testosterone suppression, cardiovascular training, resistance training, physical activity and prostate cancer. Secondary searching involved scanning the reference lists from the papers identified above and then locating papers, which appeared useful in reviewing the topic.

Incidence of cardiovascular diseases and diabetes during and following ADT

Four recent and large cohort studies have examined the association between ADT and increased incidence of cardiovascular disease and diabetes.5, 6, 7, 8 Keating et al.5 reported results from the first large population-based cohort of 73 196 localized prostate cancer patients using the Surveillance, Epidemiology and End Results (SEER) Medicare data examining whether ADT in the form of gonadotropin-releasing hormone (GnRH) agonist or bilateral orchiectomy was associated with coronary heart disease, myocardial infarction, diabetes and sudden cardiac death. In Cox proportional hazards models adjusted for a number of potential confounders, such as age, race, tumor grade, comorbidity score, year of primary diagnosis and primary surgical therapy but not disease-related risk factors such as blood lipids, tobacco use and hypertension, GnRH agonist administration was associated with an increased risk of coronary heart disease, myocardial infarction, sudden cardiac death and diabetes by 16, 11, 16 and 44%, respectively. Moreover, the increased risk for incident diabetes and coronary heart disease was apparent with as little as 1–4 months treatment.

Saigal et al.7 also examined risk of cardiovascular morbidity using the SEER registry. After controlling for a number of factors including patient and tumor characteristics, comorbidity score and pretreatment cardiac disease, men who received ADT had a 20% increased probability of cardiovascular morbidity and this increased risk was observed within the initial 12 months of ADT.

D'Amico et al.8 reported pooled results from three randomized trials including cohorts from Australia and New Zealand (n=802),19 Canada (n=364) and United States (n=206), and examined the time to fatal myocardial infarction following three to eight months of ADT (combination of a luteinizing hormone-releasing hormone agonist and a nonsteroidal antiandrogen) in men who were also receiving external beam radiotherapy. Six months of ADT lead to a shorter time to fatal myocardial infarction in men aged 65 years or more compared to men aged 65 and more not undertaking ADT and to all men less than 65 years. Further, in those aged 65 or more similar time to fatal myocardial infarction was observed between 3 and 6 to 8 months ADT suggesting an increased risk of cardiovascular-related toxicity even after short-term ADT.

Tsai et al.6 using data from the Cancer of the Prostate Strategic Urologic Research Endeavor retrospectively examined whether ADT use was associated with death from cardiovascular-related causes in localized prostate cancer patients. A total of 1015 patients were treated with ADT in combination with local therapy (external beam radiation therapy, brachytherapy, cryotherapy or radical prostatectomy) whereas 3877 were not treated with ADT. After a median follow-up time of 3.8 years and median ADT duration of 4.1 months, patients aged 65 or more who underwent both radical prostatectomy and ADT had a 5-year cumulative incidence of cardiovascular death of 5.5% compared to 2% for those undergoing radical prostatectomy but not ADT. Further, men younger than 65 years undergoing the same treatment had a cumulative incidence of 3.6% compared to 1.2% in those not receiving ADT. However, given the retrospective nature of the study, a number of factors that may contribute to cardiovascular death, such as family history, hypercholesterolemia and smoking status were not controlled for in the analyses.

The findings from these four studies extend beyond the well-established adverse effects related to the musculoskeletal system by reporting novel toxicities of ADT on incidence of coronary and metabolic disease and related mortality.5, 6, 7, 8 This is of considerable concern to patients and clinicians, as survival of the comorbidities exacerbated by ADT becomes a greater threat than the prostate cancer. However, despite the increased incidence of cardiovascular and metabolic disease, two recent reports by Efstathiou and colleagues20, 21 of men with locally advanced prostate cancer participating in the Radiation Therapy Oncology Group trials have indicated no increased cardiovascular mortality following ADT. In both studies, cardiac risk factors, such as prevalent cardiovascular disease and diabetes, were associated with cardiovascular death; however, with up to 9 years of follow-up there was no increase in cardiovascular mortality in ADT-treated men. Consequently, the results of studies relating ADT treatment to cardiovascular mortality are mixed and this area requires further investigation.

Risk factors for cardiovascular/metabolic complications following ADT

An increasing number of studies have examined the effects of ADT on metabolic profile and risk factors for cardiovascular disease in prostate cancer patients.9, 10, 11, 22, 23, 24, 25 An overview in chronological order of the cross-sectional and prospective studies is presented in Table 1. A number of studies have consistently reported alterations in body composition with increases in whole body fat and reduction in lean body mass ranging from 6.6 to 13.8% and 2 to 3.6%, respectively, following the initial year of androgen suppression.11, 22, 23, 26, 27 Further, abdominal fat and abdominal subcutaneous fat assessed by computed tomography (CT) has been shown to increase by 3.9 and 11.1%, respectively, whereas regional trunk fat assessed by dual energy X-ray absorptiometry has increased by 12%.11, 23 Further, both studies using CT have indicated a preferential increase in subcutaneous fat rather than visceral fat in the abdomen region.11, 22 Men on ADT have showed a 5.5-fold increased risk of being obese (BMI >30 kg/m2) compared to controls after adjusting for age.28 Other reports have showed that nearly 80% of prostate cancer patients on ADT have a waist circumference 102 cm and more than 50% of these patients have metabolic syndrome.13 Not surprisingly, studies have also indicated that men undergoing long-term ADT can develop insulin resistance and hyperglycemia and these metabolic alterations are independent of age and BMI.14 Alterations in glucose metabolism with reduction in insulin sensitivity and concomitant increases in fasting insulin and glycosylated hemoglobin levels have also been reported following short-term ADT in nondiabetic prostate cancer patients with locally advanced or recurrent disease.9, 29 Other reports have indicated large increases in fasting insulin by 66 and 63% following 12 and 24 weeks of ADT, respectively.10, 24 Changes in glucose metabolism in ADT patients also vary based on diabetic status with greater increases in those with diabetes (48%) compared to nondiabetic patients (7%) following a median ADT treatment duration of 44 weeks.30

Table 1 Cross-sectional and prospective studies indicating increased risk factors of cardiovascular and metabolic complication following ADT

Further, ADT-induced hypogonadal men have shown higher fasting levels of total cholesterol, low-density lipoprotein (LDL) cholesterol and non-high-density lipoprotein (HDL) cholesterol than non-ADT prostate cancer men and age-matched controls.12 However, contrasting the classical pattern of metabolic syndrome, concomitant increases in both LDL and HDL cholesterol have also been reported.11, 22 In addition, an increase in arterial stiffness, a risk factor for cardiovascular disease, has been reported and may contribute to ADT cardiovascular-related toxicity. Smith et al.24 reported an increase in the augmentation index, an indicator of arterial stiffness, following 24 weeks of ADT. Dockery et al.10 also reported a significant reduction in systemic artery compliance between ADT- and non-ADT-treated patients following 12 weeks of treatment indicating an increase in arterial stiffness. Moreover, increased aortic artery stiffness has been reported in cross-sectional comparisons between ADT- and non-ADT-treated prostate patients.31 However, the effects on systolic and diastolic blood pressures are less clear with modest or negligible effects being reported following the administration of ADT.22, 24 Most of these ADT-induced adverse effects (abdominal obesity, high glucose levels, high serum triglycerides and possible high blood pressure) are characteristics of metabolic syndrome as indicated by the Adult Treatment Panel III report.32 Details of specific cut-off points for metabolic syndrome risk factors for men are listed in Table 2.

Table 2 Details of cut-off points for metabolic syndrome risk factors for men and possible effects of exercise

Physical exercise as potential countermeasure

Cardiorespiratory fitness is a strong independent predictor of cardiovascular disease-related mortality and overall mortality in both clinically healthy men and those with established risk factors for coronary heart disease.33, 34 Aerobic exercise (for example, walking, running, cycling activities) is known to improve insulin sensitivity acutely35 (immediately following an exercise session) and chronically36 (repeated exercise exposure) in patients with type 2 diabetes and reduces risk factors for cardiovascular disease (for example, improvements in cardiorespiratory capacity, reduction in blood pressure and body fat) in sedentary individuals.37 In addition, aerobic exercise has been endorsed as a nonpharmacological strategy to improve lipoprotein metabolism which is another major risk factor for cardiovascular complications.38 Further, since the early work by Paffenbarger and Hale39 in the 1970s an extensive number of long-term prospective studies have indicated a protective effect of physical activity and aerobic capacity on all-cause death including those from cardiovascular disease.40, 41, 42, 43 Moreover, even in individuals with well-known risk factors for cardiovascular disease (for example, hypertension, diabetes, smoking, high total cholesterol), those with greater cardiorespiratory capacity appear to be at lower risk for premature death than individuals with lower cardiorespiratory capacity (for example, sedentary) but without other risk factors for cardiovascular disease.34 A summary of the effects of exercise on metabolic syndrome risk factors is shown in Table 2.

Apart from the protective effects of cardiorespiratory fitness on death from all causes, muscle strength has now been shown to be inversely associated with risk of death from all causes including cancer in men.44 Further, in the recent prospective study by Ruiz et al.,44 the age-adjusted death rate in men with high levels of combined cardiorespiratory fitness and muscle strength was 60% lower than the death rate in the group of unfit men with the lowest levels of muscle strength. Cross-sectional studies have also shown an inverse relationship between muscle strength and incidence of metabolic syndrome in men.45, 46 Extensive scientific literature supports resistance training (also known as weight training or strength training where an individual's muscles contract against a resistance – the resistance could be via a weight-training machine, free weights, bodyweight or elastic bands) as being the most effective exercise method available for enhancing muscle strength, muscle hypertrophy and physical function, and contributes to skeletal health.47, 48 Further, even in those with established and controlled cardiovascular disease, resistance training is beneficial and has been endorsed by the American Heart Association Council on Clinical Cardiology.49

Resistance exercise has considerable potential to counteract the catabolic side effects of ADT by promoting positive effects on the musculoskeletal system.50 Further, the use of resistance exercise has been reported in the management and prevention of a range of chronic conditions including overweight and mild obesity, diabetes, hypertension and atherosclerotic coronary heart disease.51, 52, 53, 54, 55 Preliminary work50, 56, 57 supports the potential beneficial role of resistance exercise in patients diagnosed with prostate cancer undertaking ADT, with improvements in muscle strength, functional performance and psychological outcomes (for example, improvements in quality of life), without compromising androgen suppression and treatment intent.

Moreover, we have reported that patients undergoing 20 weeks of anabolic or resistance training improved their cardiorespiratory capacity by reducing the time to complete a 400-meter corridor walk test by 7.4%.58 This test for older adults has been shown to be a strong predictor of mortality, cardiovascular disease and mobility limitations in older adults.59, 60, 61 Further, a recent study using an animal model has found that aerobic exercise has the potential to provide a protective effect against cardiac dysfunction during ADT.62 Thus, aerobic and resistance exercise may be an effective method to minimize or overcome ADT cardiovascular-related toxicities.63 Although it has long been known that physical exercise is an essential lifestyle contributor to significantly reduce cardiovascular and metabolic diseases, efficacy for patients receiving ADT has not been established. A theoretical model of exercise as a countermeasure to ADT-induced cardiovascular- and metabolic-related toxicities is presented in Figure 1. Combined resistance and aerobic exercise have been shown to reduce both systolic and diastolic blood pressures each by 13 mm Hg in middle-aged men with hypertension and decrease total and LDL cholesterol.64 We have recently reported that resistance training as a sole exercise mode in older adults may reduce the risk for adverse cardiovascular events by attenuating cardiac afterload.65 In this study, older men and women underwent a 20-week program of high-intensity resistance exercise with the primary endpoints being brachial and central blood pressures, and arterial stiffness using pulse wave analysis. Following training, we noted a significant reduction in central systolic and diastolic blood pressures of 6 and 3 mm Hg, respectively, with no adverse effects on arterial stiffness. These changes were also independent of heart rate and body mass and were likely related to a reduction in peripheral vascular resistance.

Figure 1
figure1

Theoretical model of exercise as a countermeasure to androgen deprivation therapy (ADT)-induced cardiovascular- and metabolic-related toxicities. ↑, increase; ↓, decrease; ↔, no change; TC, total cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein.

Exercise prescription recommendations and guidelines that could potentially benefit large number of patients currently on or previously treated with ADT have been suggested.50 Men on ADT should initiate a program of resistance training incorporating 7–10 exercises, undertaken 1–3 times per week, using 1–4 sets per muscle group (sets refers to a series of repetitions performed without stopping; for example, 8 repetitions/set), at an intensity of 50–80% of 1 RM or 6–12 RM (RM refers to the maximal number of repetitions that can be performed at a given resistance load).50 It is also recommended that patients undertake aerobic exercise (for example, walking, cycling) programs with intensity, volume and frequency similar to those we have previously reported (50–90% maximal heart rate, 20–60 min of continuous or intermittent exercise and 3–5 times per week).66 Specific recommendations for cancer patients including ADT-treated men can be found in Table 3.66 Aerobic and resistance-training activities when undertaken during therapy are safe and feasible for cancer patients and can lead to a range of positive physiological and psychological benefits.66, 67 Although not definitively confirmed these same protective effects should be realized in patients receiving ADT and thus reduce cardiovascular and metabolic morbidity in this population.5, 6, 7, 8 Further details on exercise training variables, practical examples of structured resistance programs based on previous studies with ADT-treated men,56, 58 as well as availability of resources (for example, free weights, elastic bands, gravitational weight force machines) have been published elsewhere.50 Pictorial examples of resistance exercises tailored to cancer patients are available on request by The Cancer Council of Western Australia – http://www.cancerwa.asn.au/. Undertaking resistance exercise in small groups will facilitate adherence and compliance, and also reduce the financial cost to the patient, and this can be suggested to patients. In addition, varying components of the program from time to time will assist with motivation. However, it is important for both the specialist and the general practitioner to provide a consistent message regarding exercise and physical activity, and to monitor the patient's progress.

Table 3 Specific exercise recommendations for cancer patients are as follows:66

In the United States, the American College of Sports Medicine (ACSM – www.acsm.org) provides registered professionals with University qualifications in exercise science or related area. Similarly, other countries, such as Australia and United Kingdom possess organizations (Australian Association for Exercise and Sports Science (AAESS) – www.aaess.com.au/ – British Association of Sport and Exercise Sciences (BASES) – www.bases.org.uk/) that provide registered exercise professionals with University qualifications who are able to conduct exercise training with this patient population.

In summary, ADT is associated with a number of adverse effects in men, including cardiovascular and metabolic complications. The general assumption that cessation of ADT will be sufficient for treatment-related morbidity to recover appears to be incorrect as testosterone needs to recover. The result is that the consequences of ADT may be greater than the benefits derived, and may deter men from using this form of therapy. However, a lifestyle activity, exercise, has a powerful beneficial effect that ameliorates certain soft tissue morbidities in the androgen-suppressed state and may potentially counter a number of the risk factors associated with cardiovascular and metabolic diseases. Lifestyle choices, such as exercise, that ameliorate treatment toxicity introduce an interesting covariate to the process of informed decision making. When the benefits of ADT intervention are future based and small, in addition to the risks of morbidity, the patient will need consider their commitment to undertaking lifestyle strategies that ameliorate those toxicities.

Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We thank the Cancer Council of Western Australia, Cancer Council of Queensland and Prostate Cancer Foundation of Australia.

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Correspondence to D A Galvão.

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Galvão, D., Taaffe, D., Spry, N. et al. Cardiovascular and metabolic complications during androgen deprivation: exercise as a potential countermeasure. Prostate Cancer Prostatic Dis 12, 233–240 (2009). https://doi.org/10.1038/pcan.2009.12

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Keywords

  • androgen deprivation
  • cardiovascular disease
  • metabolic syndrome
  • physical exercise
  • prostate cancer

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