1Department of Urology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece, 2Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 3Department of Endocrinology and Metabolic Diseases, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
Prostate cancer is the most common cancer among men and androgen deprivation therapy (ADT) is the most effective treatment for this disease. The cornerstone of the treatment of prostate cancer is inhibition of testosterone production which interrupts testosterone-induced growth of the prostate tumor. The dramatic decrease in testosterone levels, however, has several undesirable effects on the metabolic profile and bone metabolism and can also lead to fatigue, loss of libido, gynecomastia, and anemia, provoke vasomotor flushing, and generally affect the quality of life. Due to the long-term survival rates of patients with prostate cancer, treatment-related adverse effects are highly relevant and thus, in each clinical setting, the benefits of ADT must be weighed against treatment-related adverse effects. The current review focuses on the more recently described metabolic complications of androgen deprivation therapy, including obesity, diabetes, lipid alterations, metabolic syndrome, and cardiovascular disease. In addition, it provides practical management recommendations drawn from the available guidelines issued by the American Diabetes Association and American Heart Association.
Androgen deprivation therapy, Diabetes, Metabolic complications, Prostate cancer
INTRODUCTION
Prostate cancer is the most common cancer among men, with a median age at diagnosis of 68 years. Effective systematic treatments of prostate cancer have greatly improved life expectancy for these patients and, with the exception of patients with metastatic disease, the 5-year relative survival rate is today 98.8%.1
Androgen deprivation therapy (ADT) is the cornerstone treatment for men with prostate cancer (PCa), inhibiting testosterone production and interrupting testosterone regulation of the prostate tumor. It is estimated that 50% of men with prostate cancer will undergo ADT at some point of their treatment.2 ADT improves the 10 years’ overall survival rate by up to 26% in patients with localized and locally advanced disease when administered in combination with external beam radiation therapy,3,4 though in men with metastatic disease it contributes mainly to pain management.5-7
The aim of ADT is hypogonadism, which is achieved either surgically with bilateral orchiectomy or medically using LHRH agonists or antagonists. LHRH analogues initially stimulate pituitary receptors, causing a temporary rise in LH and FSH, but chronic exposure leads to the down-regulation of LHRH-receptors and decrease of LH, FSH, and testosterone. LHRH antagonists bind immediately and competitively to LHRH receptors in the pituitary gland, resulting in a rapid hormonal decrease.8-10 However, the dramatic decrease in testosterone levels can have several undesirable effects on the metabolic profile and bone metabolism, leading to fatigue, loss of libido, gynecomastia and anemia, causing vasomotor flushing and affecting the quality of life.11 Due to the long-term survival rate of patients with prostate cancer, treatment-related adverse effects are highly relevant and thus, in each clinical setting, the benefits of ADT must be weighed against treatment-related adverse effects.
The current review focuses on the more recently described metabolic complications of androgen deprivation therapy including obesity, diabetes, lipid alterations, metabolic syndrome, and cardiovascular disease. In addition, it provides practical management recommendations drawn from available guidelines issued by the American Diabetes Association (ADA) and American Heart Association (AHA).
ADT AND OBESITY
Androgens are important determinants of body composition in men, promoting growth of lean mass and suppressing fat deposition.12 Epidemiological studies have observed a bidirectional relationship between low testosterone levels and obesity.13 Obesity is the single most powerful predictor of low testosterone levels in men, and low levels of testosterone and SHBG can predict accumulation of intra-abdominal fat, development of central obesity, and increased risk of metabolic syndrome.14
Several studies have shown that in men on ADT, body weight and body composition changes occur mainly during the first year of treatment and subsequently continue for 1 to 2 years.15 It has been reported that weight gain after a year on treatment is about 1.5-4 k and it seems to be greater in younger patients (<65 years of age) and in non-obese patients (BMI <30Kg/m2).15 Changes in body composition also occur early, with an increase in total body fat of up to 10% and a reduction in lean body mass of 2.7%.16 The fat accumulation is mainly subcutaneous, although both visceral and subcutaneous fat accumulations have been observed. Subcutaneous fat accumulation represents 94% of the total abdominal fat gained during the treatment.15 On the other hand, reduced muscle mass can result in reduced muscle strength and produce weakness and fatigue.17 The term sarcopenic obesity is used in the literature to describe the increase of abdominal obesity accompanied by reduced muscle mass in men undergoing ADT18 and is found to be associated with an increase in all-cause mortality.19
The underlying mechanisms of increased abdominal fat with ADT are not well understood. Visceral adipocytes are known to have androgen receptors and it has been proposed that testosterone might be directly involved in fatty acid mobilization.20 Changes in fat distribution during ADT may be due to loss of androgen-mediated inhibition of stem cell differentiation into adipocytes.21 It has also been suggested that accumulation of visceral fat in these men could be due to reduced lipolysis as a result of the low testosterone levels.22
No evidence-based prevention or treatment strategies currently exist for ADT-associated changes in body composition. However, there is strong evidence concerning men with advanced disease on ADT which suggests that physical exercise is efficacious in improving cancer-specific quality of life, fatigue, and exercise capacity.23 In the Culos-Reed study, patients who increased their physical activity had positive changes in girth measurements and blood pressure.24 Additionally, there is evidence indicating that a 6-month combined aerobic and resistance exercise program has a significant favorable impact on resting fat oxidation, glucose, and body composition despite parallel treatment with ADT.25
ADT, INSULIN RESISTANCE, AND DIABETES
It is well established today that low testosterone levels in men are associated with insulin resistance and type 2 diabetes. In fact, there is a complex and multiparametric correlation between testosterone deficiency and obesity, which represents a risk factor for cardiovascular disease.26,27 Furthermore, studies have shown that testosterone replacement improves insulin sensitivity and glycemic profiles in hypogonadal men.
Evidence concerning insulin sensitivity in patients receiving ADT is limited and the studies are quite heterogeneous as to design (different types of ADT, presence or absence of control group, short and long duration, etc.) and the results are conflicting. Nevertheless, it seems that ADT decreases insulin sensitivity in non-diabetic men within 12 weeks of initiating treatment.18,22,28,29 The exact mechanism by which ADT increases insulin resistance is not yet clearly understood. The observed increase in fat mass, and particularly in the abdomen, in these men is thought to contribute to the reduced insulin sensitivity. Moreover, it has been speculated that certain pro-inflammatory adipokines such as TNF-a, IL-6, and resistin are increased in patients on ADT and might play a role in insulin resistance.30,31
Although insulin resistance appears early in men undergoing ADT, it seems that fasting hyperglycemia and frank diabetes need a year or more to develop. However, randomized studies on this subject are lacking.
Data from the Surveillance Epidemiology and End Results (SEER) database including 73,196 men with local or locoregional prostate cancer treated with LHRH agonists (36%) or orchiectomy (7%) reported a higher diabetes incidence (adjusted hazard ratio 1.42) in these men.32 The results from the Canadian database analysis of 20,000 men are similar.33 Keating et al in an observational study of 14,597 veterans also found that treatment with LHRH agonists was associated with a statistically significant increased incidence of diabetes.34 Recently, a retrospective cohort study of 12,191 men diagnosed with localized prostate cancer showed that ADT may increase diabetes risk by 60%.35 Additionally, it has been found that ADT might worsen glycemic control and increase glycosylated hemoglobin levels in patients with pre-existing diabetes.36,37
As the risk for diabetes development during ADT is high, the need for diabetes screening among men with prostate cancer under long-term treatment is obvious. In the absence of evidence-based recommendations, risk-adapted screening and intervention according to the guidelines from the ADA may be applied to this specific population.38 Screening men at baseline and again in a year for those treated with long-term ADT and using fasting plasma glucose and hemoglobin A1c as screening tests seem reasonable. Individuals with hemoglobin A1c between 6.0% and 6.5% or impaired fasting glucose (fasting glucose, 100-125 mg/dL) should be considered to be at high risk for developing diabetes and need to be counseled to lose weight and undertake moderate physical activity.39 In those with pre-existing diabetes, intensification of their hypoglycemic treatment and a more frequent follow-up might be necessary, depending on their blood glucose and HbA1c levels.
ADT AND DYSLIPIDEMIA
Several studies have documented changes in the lipid profile of men on ADT, but the results are not consistent and depend on the duration of treatment and the method used for ADT.40 Also, in some studies the number of subjects studied was small. Although the findings are not universal, ADT seems to increase total cholesterol, LDL, HDL, and triglyceride levels.22,40-42 Studies have demonstrated a significant increase in triglycerides levels (by about 26%), in total cholesterol (by about 10%), and in HDL (by approximately 8%-10 %), but no change in LDL levels, after 3, 6, and 12 months of ADT.22,42,43 On the other hand, prospective studies have shown an increase in LDL, total cholesterol, and triglyceride levels with or without any changes on HDL levels.16,28
Hyperinsulinaemia could be responsible for some of the alterations in the lipid profile of men receiving ADT but it cannot explain the changes in HDL cholesterol. Therefore, some other factors might be involved, such as the observed increase in adiponectin levels in these patients. Adiponectins are considered to be atherothrombotic risk factors in obese subjects, being related to hemostatic markers and common carotid wall thickness.44 However, the effect of these changes on cardiovascular risk is unknown and further studies are needed to establish this relationship.22,42 However, for patients undergoing ADT, diet and lifestyle changes are recommended as first-line interventions if hyperlipidemia is present in order to achieve LDL concentrations at the target level. If these measures fail, drug therapy with statins is recommended.45 Recently, selective estrogen receptor modulators (SERMs), which are used for their effects on bone mineral density (BMD) and fracture prevention in men on ADT, have been found to affect serum lipid levels as well. In a randomized, placebo-controlled trial, toremifene was given for fracture prevention to men on ADT, and the planned interim analysis at one year exhibited a decrease in LDL cholesterol and triglyceride levels and an increase in HDL levels in the tamoxifen group.46
ADT AND HYPERTENSION
In a recent systematic review of studies in hypogonadal men low testosterone levels were well correlated with hypertension.47 Hypogonadism is the key finding in men undergoing ADT, but only a few studies have examined its effect on blood pressure. The results of these studies are conflicting, with some studies showing no effect and others showing an increase in blood pressure after a year on ADT.48,49
ADT AND METABOLIC SYNDROME
Metabolic syndrome is a cluster of conditions, such as abdominal obesity, high triglyceride level, low HDL cholesterol level, high blood pressure, and high fasting blood sugar, that raise the risk for heart disease. Three out of these five main factors are needed for a diagnosis of metabolic syndrome and its prevalence in the adult population is estimated at about 20-25%.50 Male hypogonadism is an independent risk factor for metabolic syndrome, while low testosterone and SHBG levels can predict metabolic syndrome in men.51,52 Additionally, as mentioned above, ADT causes a high degree of alteration in the metabolic parameters and thus it is possible that ADT increases the risk of metabolic syndrome. Indeed, some studies have shown that about 36-55% of men receiving ADT for more than a year will develop metabolic syndrome, independent of age, race, and stage of PCa.41,53,54 A recent meta-analysis including nine observational studies50 and a cohort study35 found an even higher incidence of metabolic syndrome, of up to 60-75%, in this population.
As noted above, an increase in adiposity and visceral adiposity, elevated hepatic lipolysis, and insulin resistance and an increase in pro-inflammatory factors might contribute to the development of metabolic syndrome during ADT. Additionally, it has been found that the CAG repeat polymorphism within the androgen receptor (AR) gene can also play a role in the development of metabolic syndrome. There is an inverse relationship between the length of the CAG repeat in the AR and its transcriptional activity on testosterone target genes.55 Some studies even suggest that serum levels of testosterone can be correlated with the CAG repeat of AR, pointing to the negative-feedback loop mediated by AR to regulate testosterone levels.56,57 The polymorphism of AR CAG repeats is reported to influence insulin sensitivity and components of metabolic syndrome in men. These findings provide additional support for the critical role of AR in androgen/AR signaling in the regulation of metabolism.58,59
Metabolic syndrome due to ADT has some differences to the classically defined metabolic syndrome. In classic metabolic syndrome, HDL is decreased by about 5%, while an increase in HDL is observed in the type associated with ADT.16,48 Metabolic syndrome is related to low adiponectin levels60 and increased C-reactive protein levels,28 while in patients on ADT adiponectin levels are increased and C-reactive protein levels are unchanged.61,62 The clinical significance of these differences is yet to be defined.
Finally, one must keep in mind that ADT might worsen pre-existing metabolic syndrome in these high-risk patients. Thus, screening for metabolic abnormalities before the initiation of ADT as well as close follow-up and appropriate treatment depending on the presence and the severity of the metabolic changes are essential.
ADT AND THE RISK OF CARDIOVASCULAR DISEASE
The increased rates of obesity, insulin resistance, diabetes, hyperlipidemia, and metabolic syndrome observed in patients on ADT would support the hypothesis of a similar effect on cardiovascular disease (CVD) disease.63 Moreover, this hypothesis might well be strengthened by recent findings indicating that several biological mechanisms induced by ADT, such as increased inflammation, atherogenic plaque formation, and plaque destabilization, could further promote CVD development in these patients.64
Large randomized control trials are lacking and the existing evidence regarding CVD morbidity and mortality for patients receiving ADT is rather controversial. Data from observational studies indicate overall a positive relationship between ADT and CVD. In a large population-based cohort study of 185,106 men, it was found that ADT was independently associated with an increased risk of myocardial infarction (MI) and diabetes.65 A retrospective analysis, however, using data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) and including men with prostate cancer treated with radical prostatectomy followed or not with ADT found a significant correlation of ADT with increased CV mortality, but only among patients over 65 years old (p=0.002).66 Furthermore, a recent meta-analysis of randomized controlled trials and observational studies showed that antiandrogen was associated with a 30% decreased risk for myocardial infarction compared to GnRH agonists, while combined androgen blockade was associated with a 10% increased risk for stroke when compared to antiandrogen.67
In the Radiation Therapy Oncology Group (RTOG) study protocol 85-31,68 patients with advanced prostate cancer who had either radiotherapy alone or in combination with indefinite ADT were enrolled and demonstrated no statistically significant difference regarding mortality related to CVD between the two groups (p=0.17). The RTOG trial 86-1069 involved patients with locally advanced prostate cancer who had received a 4-month scheme of ADT plus radiation treatment (RT) versus those who had RT alone. Again, there was no statistical difference between the treatment groups as regards CV mortality (p=0.32). The RTOG protocol 92-0270 also included patients with locally advanced prostate cancer, but both groups received ADT in addition to RT (28 months and 4 months). As above, there was no significant difference in CV mortality between the two groups (p=0.58). All these results were fully supported by a meta-analysis of eight randomized control trials (RCTs) of ADT versus no or delayed ADT in patients with non-metastatic prostate cancer which showed that sudden death due to CVD in patients receiving ADT was not different to those with no or delayed therapy.71 Similar findings were reported in the European Organization for Research and Treatment of Cancer (EORTC) analysis.72
Preexisting comorbidities and different duration of the ADT could explain the observed result discrepancy among the studies. Comorbidities are important independent prognostic factors for patients with cancer and the inclusion of the existing comorbidities in hospital-based cancer registries will increase the value and use of observational research.73
Regarding LHRH antagonists, Smith et al74 found that the use of degarelix in ADT for prostate cancer did not affect the CV events in the overall population (p=0.45), although in the subgroup of patients with underlying CV disease the incidence of those events was increased significantly after the use of degarelix (p=0.0013). In Albertsen’s reanalysis of six RCTs, degarelix was shown to be superior to leuprolide, being associated with fewer CV events in patients with or without coexisting CVD (p=0.016 and p=0.025, respectively).75 These studies appear to point to LHRH antagonists as an ideal alternative in ADT for high-risk patients with CVD.
It is well known that in the general population, individuals with reduced risk factors for cardiovascular disease have a lower incidence of heart disease and stroke76 and, although strong data on ADT-attributable risk for cardiovascular events and mortality are inconsistent, the use of the AHA guidelines can be considered in this population. According to these guidelines, primary prevention should feature total tobacco cessation and appropriate management of hypertension. Low-dose aspirin is recommended for men with a 10% or greater 10-year risk for coronary heart disease. Lifestyle modification should feature weight control and low intake of saturated fat and cholesterol. If such modifications fail to achieve target LDL, statins should be used as first-line drug treatment of hyperlipidemia.77
Regular physical activity could be a key factor for the prevention of CVD in prostate cancer patients. More specifically, exercise interventions that apply sound aerobic and resistance training principles should be suggested as being quite effective.78,79 In fact, all exercise programs are likely to reduce fatigue and enhance vitality, especially among patients with the highest levels of fatigue and lowest vitality. Men with prostate cancer could improve their strength, physical functioning, and cardiovascular health by increasing their physical activity.80,81 Finally, physical exercise significantly improves QoL, although it is not entirely clear whether it affects metabolic risk factors in patients with androgen deprivation therapy-treated prostate cancer.82
CONCLUSION
It is now well established that ADT improves survival in men with prostate cancer, but this benefit comes at the cost of harmful metabolic changes such as obesity, insulin resistance and diabetes, dyslipidemia and cardiovascular disease. Patients need to be well informed about these risks and the potential benefits of therapy should be carefully considered before ADT begins. Optimal management for these metabolic changes has not as yet been defined. Increase of physical activity, weight loss, and lifestyle changes are very important for the management of these metabolic aberrations of patients on ADT and should be recommended to all patients undergoing ADT. Further studies focusing on an ideal strategy of patient selection for ADT and on an optimal way for treating ADT side effects are needed.
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Address for correspondence:
Tzortzis Vasileios, University of Thessaly, School of Health Sciences, Faculty of Medicine, Larissa, Greece; E-mail: tzorvas@otenet.gr
Received: 30-03-2017, Accepted: 03-04-2017