Keywords

General Overview of Obesity and Prostate CancerRisk/Incidence, Progression, Mortality

Obesity prevalence in the U.S. has risen dramatically over the past 20 years. Presently, more than one-third of adults are obese (body mass index (BMI) ≥30 kg/m2) and among older men, approximately 40% are obese [1]. Obesity is linked with an increase in cancer-specific mortality and an estimated 14% of cancer deaths in U.S. men are due to obesity [2]. The associations of obesity with prostate cancer risk are complex. Pooled/meta-analyses from prospective studies report no overall association of obesity with total PCa risk [3,4,5,6,7]; however, there is growing evidence that associations of obesity with PCa differ for aggressive and nonaggressive PCa. Numerous studies report that obesity is associated with a decreased risk of non-aggressive (low-grade and/or local stage) disease and an increased risk of aggressive (high-grade and/or advanced stage) disease [3,4,5, 7]. Furthermore, there is strong and consistent evidence for a positive association between obesity and PCa progression and PCa-specific mortality (PCSM) [1, 2, 8,9,10,11,12,13,14,15,16,17,18,19,20,21]. As shown in Table 3.1, obesity is associated with a 20–160% elevation in PCa-specific mortality. Pooled/meta analyses report that for every five-point increase in BMI, there is a corresponding 20% increase in PCSM (95% CI 0.99–1.46) and conclude that “cumulative data is compelling for a strong positive association between obesity and fatal prostate cancer” [23]. A 2011 Institute of Medicine Workshop on Obesity and Cancer Report noted: “evidence is building that obesity and weight gain are risk factors for poor outcome in prostate cancer” [24].

Table 3.1 Studies of obesity and PCa-specific mortality
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The mechanisms underlying the obesity-PCa progression relationship are unknown. However, a number of metabolic changes that occur in obese men may be responsible, including (1) impaired glucose regulation and insulin resistance; (2) altered adipokines (e.g., leptin and adiponectin); (3) sex hormones; and (4) chronic inflammation, among other potential etiologies. It is well recognized that several morbidities are associated with obesity, such that obesity is one of the leading causes of preventable disease and disability in the United States. Obese patients are at higher risk of having diabetes mellitus, hypertension, hypercholesterolemia and cardiovascular disease (Fig. 3.1) [25].

Fig. 3.1
figure 1

Comorbid conditions by obesity level, US 2007–2010 (Plotted from data in Saydah et al. [25])

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Obesity is also associated with several other cardiovascular comorbid conditions in addition to hypertension, including coronary artery disease, heart failure, and arrhythmias. Interestingly, these diagnoses have also been associated with prostate cancer risk and outcomes. Whether it is obesity driving the relationship with prostate cancer, or if there is a separate effect of the comorbid condition is not fully understood, but there has been a great deal of research on the potential mechanisms underlying the links between the comorbidities and prostate cancer. Further, pharmacologic treatment of these conditions may impact the effects of the comorbidities on prostate cancer , either through reduction in the direct effect of the comorbidity, or separately through additional pharmacologic mechanisms.

In this chapter, we review the relationship between common obesity related comorbidities and prostate cancer . We review the literature, where available, for the association between these comorbidities and prostate cancer risk, progression and mortality. If applicable, we also describe the data on medications used to treat these comorbidities and the influence these medications may have on prostate cancer.

Metabolic Syndrome and Prostate Cancer Risk

Metabolic syndrome (MetS ) is as a cluster of several metabolic abnormalities associated with increased risk of cardiovascular disease and diabetes. Components include hypertension, glucose intolerance, obesity, hypertriglyceridemia, and low high density lipoprotein cholesterol, with insulin resistance as the underlying hallmark feature (Table 3.2) [29].

Table 3.2 Definitions of metabolic syndrome
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The prevalence of MetS among US adults in the 2000–2003 National Health and Nutrition Examination Survey was 34% overall [30]. However, among older men the prevalence was much higher, with 41% of men age 40–59 years and 52% of men age 60 or older meeting the criteria for metabolic syndrome [30]. Over the past decade, a growing body of literature suggests that the metabolic syndrome may be involved in the pathogenesis and progression of prostate cancer.

Data on the association between metabolic syndrome and prostate cancer risk are conflicting. Several studies have reported significant positive associations between metabolic syndrome and prostate cancer risk. Two studies from northern Europe that found an increased risk for men with three metabolic syndrome components (RR = 1.56, 95% CI, 1.21–2.00) [31] and OR = 3.36, 95% CI 1.19–9.44) [32], and one study from Finland that reported an increased risk (RR = 1.94, 95% CI 1.06–3.53) among non-diabetic men with metabolic syndrome [33]. Three additional case-control studies reported an increased risk of prostate cancer among men with metabolic syndrome [34,35,36], two of which reported positive associations among African Americans (OR = 1.76, 95% CI = 1.1–2.88 [35] and OR = 1.71, 95% CI 0.97–3.01 [36]). In contrast, a number of studies reported an inverse relationship between metabolic syndrome and prostate cancer risk. In two large cohorts, men with three or more metabolic syndrome components had a significantly lower risk of total prostate cancer than men with less than three components (RR = 0.77, 95% CI 0.60–0.98 [37] and OR = 0.69, 95% CI 0.58–0.82) [38]. In the REDUCE trial , men with one metabolic syndrome component had a lower risk of overall prostate cancer (OR = 0.87, 95% CI 0.76–0.99), although two or three to four components were not significantly related to prostate cancer risk [39]. In a large Swedish cohort, a composite score of five metabolic syndrome factors was associated with a 7% lower risk of overall prostate cancer (RR = 0.93, 95% CI = 0.89–0.97) [40]. In addition, several cohort studies have reported no significant associations between metabolic syndrome and overall prostate cancer risk [41,42,43,44,45,46]. It is likely that the inconsistencies in these associations may be due, at least in part, to differences in the populations studied, definitions of metabolic syndrome or methodologies used.

Three meta-analyses have also evaluated the association of metabolic syndrome with risk of prostate cancer; one of which reported a significant increased risk of overall prostate cancer (RR = 1.54, 95% CI 1.23–1.94) [3] and two reported no overall association [47, 48]. One meta-analysis also evaluated associations of metabolic syndrome with prostate cancer risk among by region, and reported that metabolic syndrome was associated with a reduced risk of total prostate cancer among studies conducted in U.S. (primarily white) populations (RR = 0.79, 95% CI: 0.69–0.91) [47].

Few prospective studies have examined the association of metabolic syndrome and prostate cancer severity defined by grade, stage, and/or aggressiveness. In a large Canadian cohort, metabolic syndrome was associated with a reduced risk of low-grade (RR = 0.69, 95% CI 0.52–0.82) and high-grade (RR = 0.75, 95% CI 0.60–0.94) prostate cancer [38]. Similar associations of metabolic syndrome and a reduced risk of low- and high-grade prostate cancer were reported in the REDUCE trial [39]. However, one case-control study among African Americans in the US reported a significant increased risk of organ confined prostate cancer among men with metabolic syndrome, compared to men without (OR = 1.82 95% CI 1.02–3.23), and no association with advanced prostate cancer [35]. Similarly, a case-control study from Italy reported metabolic syndrome was associated with a significant increased risk of low-grade (Gleason <7; OR = 1.48, 95% CI 1.48–3.17) and high-grade (Gleason ≥7; OR = 1.80, 95% CI 1.17–2.78) prostate cancer [34]. In addition, several cross-sectional studies of men undergoing biopsy or treatment of prostate cancer (radical prostatectomy) have reported positive associations for metabolic syndrome with the presence of higher grade/stage or more aggressive prostate cancer [49,50,51,52,53,54,55].

Lastly, four studies have also examined the association of metabolic syndrome with prostate cancer specific mortality, of which one reported an increased risk (RR = 1.86, 95% CI 1.59–2.19) [46], one reported a decreased risk (RR = 1.14, 95% CI = 1.01–1.28), and two reported no association [45, 56].

Diabetes Mellitus and Prostate Cancer Risk

Diabetes mellitus commonly co-exists with obesity, and there is a large body of epidemiologic evidence providing strong support for the notion that diabetes mellitus is associated with a decreased risk for prostate cancer. To date, three meta-analyses have reported a statistically significant inverse association of diabetes mellitus with risk of total prostate cancer [57,58,59]. The most recent of these analyses, which reviewed 45 studies (29 cohort and 16 case-control) of more than 132,000 total prostate cancer cases, reported a 15% lower risk of overall prostate cancer (95% CI 0.82–0.89) for type-2 diabetes mellitus compared to non-diabetics [57]. Although many studies did not indicate the type of diabetes mellitus, given that type-2 is far more common than type-1, the associations between diabetes mellitus and prostate cancer risk are generally interpreted in terms of type-2 [60].

The inverse association is fairly consistent across various ethnic groups within the US [61, 62]; although evidence is limited to two studies with sufficient numbers of minority participants. Data from populations outside of the US are less consistent with some studies reporting no association [63, 64] or positive associations [65, 66] between diabetes mellitus and prostate cancer. In addition, one meta-analysis reported the opposite association of diabetes mellitus with prostate cancer risk between western studies (RR = 0.81; 95% CI 0.76–0.85) and Asian studies (RR = 1.64; 95% CI 1.00–2.88) (p-interaction = 0.01) [57].

Many studies have also examined the association of diabetes mellitus and prostate cancer severity defined by grade, stage, and/or aggressiveness. Among studies reporting inverse associations between diabetes mellitus and total prostate cancer risk, most reported similar associations by prostate cancer grade, stage or aggressiveness [61, 62, 67,68,69,70,71]. One recent meta-analysis reported the risk of low-grade (RR = 0.74; 95% CI 0.64–0.86) and localized disease (RR = 0.72; 95% CI 0.67–0.76) was modestly stronger than for high grade (RR = 0.78; 95% CI 0.67–0.90) and advanced disease (RR = 0.85; 95% CI 0.75–0.97) [72]. In contrast, a small number of studies found no differences in associations between diabetes mellitus and prostate cancer aggressiveness. At least three large studies reported significant inverse associations for low-grade, localized or less-aggressive disease only [67, 73,74,75]. One study reported an increased risk for diabetes mellitus with early-stage disease (stage A), but inverse association for higher stage (stages B–D) disease [76], and one study reported a positive association between diabetes mellitus and risk of advanced prostate cancer [65]. Given the relatively small proportion of advanced tumors in many of the studies with screen-detected cases, additional epidemiologic studies are needed to more fully explore the association of diabetes mellitus with more advanced prostate cancer.

In contrast to the relatively consistent inverse associations reported between diabetes mellitus and risk of total and low-risk prostate cancer, multiple studies have reported that diabetes mellitus is associated with an increased risk of both all-cause and prostate cancer-specific mortality in men with prostate cancer. A recent meta-analysis of these data concluded that diabetes mellitus was associated with a 29% increase in risk of prostate cancer-specific mortality (RR = 1.29; 95% CI 1.22–1.38) and a 37% (RR = 1.37, 95% CI 1.29–1.45) increase in all-cause mortality [77]. Although individual findings are consistent across the majority of studies, many did not account for potentially important confounders such as prostate cancer characteristics (grade and stage), prostate specific antigen (PSA), prostate cancer treatment(s) or the possible impact of competing risks from other diabetes mellitus-related co-morbidities on the association of diabetes mellitus with prostate cancer-specific mortality . Few studies have evaluated the association of diabetes mellitus prostate cancer mortality among men without prostate cancer at baseline. In a study of almost 18,000 men in London, UK, with 40 years of follow-up, neither impaired glucose tolerance nor diabetes mellitus were associated with prostate cancer-specific mortality [78]. In a study of approximately 2000 male American Indians, diabetes mellitus was associated with an increased risk of prostate cancer mortality; however, among men without diabetes mellitus, a higher level of insulin resistance (measured by homeostasis model assessment to quantify insulin resistance (HOMA-IR)) was associated with a lower risk of prostate-cancer specific mortality [79].

Timing of Diabetes Mellitus and Prostate Cancer Risk

There is growing evidence to suggest that the association of diabetes mellitus with prostate cancer risk may differ by duration of diabetes mellitus. The early stage of type 2 diabetes mellitus is characterized by hyperinsulinemia, which is accompanied by increased levels of circulating insulin like growth factor 1 (IGF-1) and testosterone, and decreased levels of insulin-like growth factor binding protein 3 (IGF-BP3) and serum hormone binding globulin (SHBG) [80]. In contrast, as diabetes mellitus progresses, insulin levels decline and IGF-1 and testosterone levels decrease, and IGF-BP3 and SHBG levels increase [81, 82]. Numerous studies have reported data on duration of diabetes mellitus and risk of prostate cancer, the majority of which report stronger inverse associations of diabetes mellitus and prostate cancer risk with an increasing number of years elapsed since diabetes mellitus diagnosis [68,69,70,71, 76, 80]. Others have reported no meaningful differences [74, 75, 83] and two studies have reported positive associations of PCa risk with increasing duration of diabetes mellitus [84, 85]. Many of the studies reporting stronger inverse associations with increasing duration of diabetes mellitus have also reported a positive association between prostate cancer and recently diagnosed diabetes mellitus [63, 68, 70, 86], which is likely attributable to increased surveillance and health care utilization around the time of diabetes mellitus diagnosis. Larger studies have also examined associations of diabetes mellitus duration and different prostate cancer stage, grade or aggressiveness. All have reported similar associations between diabetes mellitus duration and prostate cancer severity [69, 71, 83]. Notably, few of the studies evaluating diabetes mellitus duration and prostate cancer risk directly assessed diabetes mellitus duration (as opposed to evaluating length of follow-up during the study) [68, 71, 74,75,76, 87], although the findings of these studies do not differ substantively from the overall literature.

Diabetes Mellitus Treatment and Prostate Cancer Risk and Outcomes

It is unknown whether the observed findings above between diabetes and prostate cancer are due to the diabetes, or due to the pharmacologic treatment of diabetes mellitus. Metformin is the most commonly used medication for diabetes mellitus and a great deal of interest exists on its potential anti-cancer properties. Metformin has several potential mechanisms that may influence cancer, including increased AMP-activated protein kinase (AMPK) activation , decreased hepatic gluconeogenesis (with resultant decrease in hyperinsulinemia), and improved insulin sensitivity [88, 89]. AMPK is activated in response to cellular stress [90] leading to a reduction of mammalian target of rapamycin (mTOR) activation, protein synthesis and cellular proliferation [91, 92]. Hyperglycemia and hyperinsulinemia have been associated with multiple malignancies [93,94,95,96,97,98,99]. As metformin use results in lower serum insulin levels [89, 93, 100, 101] the result may produce decreased downstream activation of these mitogenic pathways and potentially, a decrease in PCa growth (Fig. 3.2 [92]).

Fig. 3.2
figure 2

Mechanism of action of metformin in cancer

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Several studies of metformin and prostate cancer risk have been performed with some finding a reduction in prostate cancer risk [102,103,104,105] and others finding no effect [40, 106,107,108,109]. Two meta-analyses [110, 111] found no evidence for an effect of metformin on prostate cancer risk with similar odds ratios (OR 0.96, 95% CI 0.87–1.05; and OR 0.93, 95% CI 0.82–1.05, respectively). It should be noted that the main indication for metformin is the treatment of diabetes mellitus, so comparing metformin users to non-users may just be comparing diabetics to nondiabetics, which makes interpreting results for use of any diabetes medication difficult.

There are stronger data for an effect of metformin on prostate cancer outcomes, and several meta-analyses have been performed with evidence of metformin leading to a reduction in the risk of biochemical recurrence after primary therapy and also a reduction in both prostate cancer-specific and overall mortality [112,113,114,115,116]. In the meta analysis by Coyle et al., the reduction in risk of recurrence after primary treatment was seen following radiation therapy (HR 0.45, 95% CI 0.29–0.70) but not following radical prostatectomy (0.94, 0.77–1.15) [115].

Small clinical trials of metformin and prostate cancer outcomes have been completed and several studies are ongoing. One trial of 40 men starting ADT randomized men to either ADT alone or ADT in combination with metformin and a lifestyle intervention (diet and exercise) [117]. After 6 months, men in the intervention arm had significant improvements in weight, BMI, abdominal girth and blood pressure [117]. Metformin is being studied in various stages of prostate cancer (pre-prostatectomy, active surveillance, adjuvant for high risk localized disease, biochemical recurrence, at time of salvage radiation, castrate resistant prostate cancer, advanced hormone sensitive) (https://www.clinicaltrials.gov/).

Use of other medications for diabetes mellitus has also been studied with regards to prostate cancer. Several studies have investigated insulin and prostate cancer risk. A meta-analysis of 11 non-randomized studies from 2007 to 2013 and found that compared to use other glucose lowering agents, insulin was not associated with a reduction in risk of prostate cancer [118]. Sulfonylurea, which is an insulin-secretagogue, has also been studied with most showing no effect on prostate cancer risk compared to patients with diabetes mellitus taking metformin [119, 120], non-sulfonylurea therapy [121] or non-diabetes mellitus patients [122]. Recently, a study from Sweden found that those subjects with >1 year of diabetes mellitus and taking insulin/sulfonureas for >1 year had a reduction in the risk of prostate cancer compared to those not taking diabetes medications (OR 0.73, 95% CI 0.55–0.98) [40]. However, a study from the Finnish Randomized Study of Screening for Prostate Cancer found that use of sulphonylureas was associated with an increase in the risk of metastatic prostate cancer compared to other oral medications for diabetes mellitus (HR 2.04, 95% CI 1.11–3.77) [123]. Further research is needed to define the role of sulfonylurea and prostate cancer. Another class of diabetes medications, thiazolidinediones , are PPAR gamma ligands which can have anti-cancer properties and several preclinical studies have shown these agents to be active against prostate cancer cells [124]. Interestingly, higher levels of Peroxisome proliferator-activated receptor gamma (PPAR-γ)receptors have been identified on prostate cancer cells as opposed to benign prostate cells [125]. With prostate cancer, the data has suggested an increased risk [126, 127] or no effect [128, 129].

Hyperlipidemia and Prostate Cancer Risk

Hyperlipidemia is a well-established consequence of obesity, and there is growing evidence to suggest that men with hypercholesterolemia are at increased risk of high-grade or advanced prostate cancer. Several large prospective studies from various populations have reported that increasing cholesterol concentrations are associated with a greater risk of high-grade [130,131,132,133,134] and aggressive [135,136,137] prostate cancer. Two of these studies reported that the positive association between cholesterol level and high-risk prostate cancer was limited to overweight/obese men [133, 134]; although other studies have not reported differences in associations by obesity status [130, 131]. In an attempt to evaluate whether the use of cholesterol-lowering medications could explain associations between cholesterol concentrations and high-risk prostate cancer, three studies conducted analyses excluding men who reported use of these medications [130, 134, 136]. Associations were similar after excluding men who reported use of these medications, although no longer statistically significant in one study [130]. Few prospective studies have evaluated the relationship of cholesterol concentration with prostate cancer mortality. The majority report no association [45, 138]; however, one reported a significant increased risk for increasing total cholesterol concentrations [78].

The relationship between circulating cholesterol concentrations and total prostate cancer, however, is less clear. Initial studies of the association of cholesterol with risk of total prostate cancer , many of which were based on a small number of prostate cancer cases, reported no association [78, 139,140,141,142] or an inverse association [143, 144]. Since then, several prospective studies based on much larger sample sizes have confirmed findings from early studies [45, 130, 131, 133, 134, 145,146,147,148]; however, several recent studies have reported a significant increase in risk of total prostate cancer with increasing total cholesterol concentrations [132, 135,136,137].

Few prospective studies have evaluated associations of other lipids , such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) , with risk of prostate cancer. Studies evaluating the relationship between HDL concentrations and risk of prostate cancer have been inconsistent. Some have reported a reduced risk of total prostate cancer [135, 148], while other report no association [45, 145] or an increased risk of total [132], high-risk [132] or low-risk [136] prostate cancer. Studies of the relationship between LDL concentrations and prostate cancer risk are also conflicting, with some studies reporting no association [45, 145, 148], and others reporting increased risks for total [132] and high-grade prostate cancer [132, 136]. The relationship of triglyceride concentrations with risk of prostate cancer has only been evaluated by three studies, all of which reported no association [45, 136, 147]. Only one study evaluated associations of apolipoproteins with risk of prostate cancer, and found a slight inverse association of apolipoprotein A-1 with risk of total cancer, but no association for apolipoprotein-B [148].

Hyperlipidemia Treatment and Prostate Cancer Risk

Statins use for high cholesterol has risen to almost 30% of US adults [149]. The potential mechanisms by which statins may reduce prostate cancer development and progression are multiple and can be divided into cholesterol-mediated pathways (e.g., reducing intra-tumor level of cholesterol precursor to androgens; altering cell membrane signaling) or non-cholesterol-mediated pathways (e.g., pro-apoptosis; lowering mevalonate levels and subsequent production of farnesyl and geranyl pyrophosphate which would block cellular proliferation and survival) (Fig. 3.3) [151].

Fig. 3.3
figure 3

Mechanism of action of statins in prostate cancer (from [150])

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Several studies have explored the relationship between statin use and primary prevention of incident prostate cancer. A meta analysis published in 2012 of 27 studies found that use of statins reduced incident prostate cancer (RR 0.93, 95% CI 0.87–0.99) and had a greater effect on reducing the risk of advanced prostate cancer (RR 0.80, 95% CI 0.70–0.98) [152]. Studies published since this meta analysis have been mixed with some showing a reduced risk of prostate cancer [153, 154] but several showing no protective effect [106, 155,156,157,158].

Tertiary prevention of prostate cancer recurrence and studies of prostate cancer specific mortality have also been performed. In a recent meta-analysis [159] of 22 studies of biochemical recurrence, use of statins was associated with a reduced risk of prostate cancer recurrence (HR 0.88, 95% CI 0.77–1.00). Interestingly, the effects were limited to treatment with radiation (HR 0.67, 95% CI 0.48–0.86; 7 studies) with no effect seen in those undergoing prostatectomy (HR 0.96, 95% CI 0.83–1.09). Whether statins (1) act as a radiosensitizer, or (2) if statins influence the effects of concomitant androgen deprivation therapy (ADT) use with radiation (ADT was used in 6 of 7 radiation studies with the proportion of men in those studies receiving ADT along with their radiation therapy ranging from 26 to 67%), or (3) if the statins association is due to unmeasured confounding is unknown. In a separate meta-analysis of mortality from 13 studies, use of statins reduced both overall (HR 0.56, 95% CI 0.38–0.83) and prostate cancer specific mortality (0.53, 95% CI 0.36–0.77) [160], with the effect observed for both pre and post-treatment use of statins.

An interesting interaction has recently been identified in steroid transport, statins and prostate cancer. The organic anion transporter, SLCO2B1, is involved in cellular uptake of several substrates, including steroid hormones such as dehydroepiandrosterone (DHEA) that prostate cancer cells can use as a precursor to dihydrotestosterone (DHT). Castrate resistant prostate cancer metastases have increased expression of SLCO genes compared to primary prostate cancer and genetic variants of SLCO transporters have been found to be associated with prostate cancer-specific mortality [161,162,163]. Statins are also a substrate for SLCO2B1 and act as a competitive inhibitor to DHEA for transport into prostate cancer cells [164]. In a study of 926 men starting ADT for advanced disease, use of statins (31% of cohort) had a longer time to progression compared to those not taking statins (adjusted HR 0.83, 95% CI 0.69–0.99) [164]. However, in castrate resistant disease, a common medication utilized is abiraterone, which is a CYP17A1 inhibitor that results in blocking all androgen production including DHEA. In this scenario, if adrenal DHEA is acting as an androgen source for prostate cancer cells in the setting of ADT, and abiraterone is blocking the production of DHEA, one would expect to not see a benefit to statin use if SLCO2B1 transport inhibition is the mechanism of statin effect on prostate cancer. In a study of 108 men receiving abiraterone, there was no difference in the percent experiencing >50% decline in PSA or in progression-free survival or overall survival between those with (n = 21) or without (n = 87) statin use [165]. Further study is needed to confirm these findings.

Hypertension and Prostate Cancer

Epidemiologic studies have reported inconsistent findings regarding the association of high blood pressure with risk of prostate cancer. The majority of studies have reported no significant association with incident [31, 32, 37, 166,167,168,169,170] or fatal [169, 171] prostate cancer, although some studies have reported an increased risk of total [32, 172, 173] or advanced prostate cancer [172], and at least one study reported an inverse association for total and non-aggressive prostate cancer [174].

Treatment for Hypertension and Prostate Cancer

Several classes of drugs are commonly used individually or in combination as pharmacological treatment for high blood pressure, including diuretics, beta-blockers (BBs) , calcium channel (CC) blockers , angiotensin-converting enzyme (ACE) inhibitors , and angiotensin II-receptor (AR) blockers. Many of these medications have been shown to either suppress prostate cancer cell growth and proliferation, angiogenesis in vitro, and inhibit migration of PC-3 human prostate carcinoma in vivo [175]. Thus, numerous studies have evaluated the association of antihypertensive medication use with prostate cancer risk. For overall antihypertensive medication use, four large prospective studies found no evidence of an association with risk of prostate cancer [166, 172, 173, 176]. However, in one large population-based cohort, current use of any antihypertensive medication was associated with a slight decreased risk of total (RR = 0.90, 95% CI 0.83–0.98) and organ-confined low-grade prostate cancer (RR = 0.89, 95% CI 0.81–0.99) [177].

Studies on individual classes of antihypertensive medications and prostate cancer risk have also produced mixed results. Among studies evaluating the association of ACE inhibitor use and prostate cancer incidence, most have found no association [166, 167, 178,179,180,181,182], two found an inverse association [176, 177], although the inverse association was limited to one individual ACE inhibitor (captopril) in one study [176] and in the second one was no longer statistically significant after adjustment for other antihypertensive use [177], and two study reported a significant positive association for total prostate cancer only [183, 184]. A recent meta-analysis of the prospective studies found that use of ACE inhibitors or AR blockers was associated with a significant decreased risk of overall prostate cancer (RR = 0.88, 95% CI 0.80–0.97), [185] although two additional meta-analyses of data from clinical trials did not find an association with risk of prostate cancer for ACE inhibitor use [186, 187]. For calcium channel blockers, several large population-based cohort studies and a case-control study have reported no association with risk of total [167, 177, 183, 184, 188, 189], low-grade [177] or aggressive/fatal prostate cancer [177, 190]. Only one study reported a significant inverse association for CC blocker use with total prostate cancer risk (OR = 0.55; 95% CI, 0.31–0.97) [191]. The majority of studies evaluating the association of BB use and prostate cancer risk have also found no association [166, 167, 176, 177, 191]. However, in two observational studies, BB use was associated with lower overall prostate cancer risk (OR = 0.80; 95% CI, 0.70–1.0) [183], and in one was associated with a slight increased risk (OR = 1.16; 95% CI, 1.12–1.21) [184].

Heart Disease and Prostate Cancer Risk

An additional comorbidity that occurs with, or as a result of obesity, is heart disease. There are some data that a history of coronary artery disease (CAD) is associated with an increased risk of prostate cancer. In a secondary analysis of the REDUCE trial (a randomized controlled trial of dutasteride versus placebo for reducing the risk of prostate cancer in men with a prior negative biopsy), 9% of men had a history of CAD and this was associated with a 35% increased risk of prostate cancer in the multivariate model [192]. Men with CAD also were more likely to be obese, have diabetes mellitus, hypertension and hypercholesterolemia.

Treatment of Heart Disease and Prostate Cancer Risk

The cardiac glycosides (e.g., digoxin ) are used in the treatment of congestive heart failure and cardiac arrhythmias. Cardiac glycosides also have been found to alter serum androgen levels [193, 194], inhibiting tumor growth and development, [195] and have inhibitory effects on prostate cancer cell lines [196,197,198,199]. In a study that screened a medication library for growth inhibition in prostate cancer cell lines, cardiac glycosides were among the most potent [199]. Although an analysis of the Health Professionals Follow-up Study found a significant reduction in the risk of prostate cancer for digoxin users (HR 0.76, 95% CI 0.60–0.95) [199], other studies have not shown a statistically significant reduction in prostate cancer risk [200, 201]. With regards to prostate cancer-specific mortality , the literature does not support a protective role for digoxin, with two of the studies showing non-significant increases in prostate cancer-specific mortality among users [202, 203]. Sotalol , a BB and potassium-channel inhibitor used for arrhythmias has commonly been studied along with glycosides, with one study finding a reduction in the risk of advanced prostate cancer associated with sotalol use [204].

Individuals with heart disease are often recommended to take aspirin daily to prevent to reduce the risk of vascular events (heart attack, stroke) [205]. There are several studies on aspirin use and cancer risk and mortality, with the strongest data present for colorectal cancer risk. The anti-cancer mechanisms for aspirin are hypothesized to include induction of apoptosis, reduced prostaglandin production with effects on angiogenesis, proliferation and host immunity [206, 207]. A meta analysis of the effects of aspirin on prostate cancer risk and mortality was published in 2014 [208]. Overall, use of aspirin was associated with a reduction in the incidence of total prostate cancer (OR 0.92, 95% CI 0.87–0.97) and advanced prostate cancer (OR 0.81, 95% CI 0.73–0.89). In a recent study with TMPRSS2:ERG fusion status available, aspirin users had a 37% reduction in the risk of TMPRSS2:ERG fusion positive tumors (95% CI 0.43–0.93) with dose effect present, whereas no association was seen with TMPRSS2:ERG fusion negative tumors and aspirin use (OR 0.99, 0.69–1.42) [209]. TMPRSS2:ERG fusion is the most common gene rearrangement in prostate cancer, present in approximately 50% of cases. As aspirin reduces the level of reactive oxygen species in a cell (which can create dsDNA breaks), use of aspirin may protect against DNA strand breaks required for TMPRSS2:ERG fusion. In a recent meta-analysis, use of aspirin was associated with a modest reduction in the risk of prostate cancer specific mortality (OR 0.86, 95% CI 0.78–0.96 for total prostate cancer; OR = 0.81, 95% CI 0.71–0.92 for advanced prostate cancer) [208].

Potential Biases of Associations of Obesity-Related Metabolic Conditions and Risk of Prostate Cancer

When considering the potential mechanisms that underlie the inverse association between comorbid conditions and prostate cancer, non-causal explanations should also be considered. Many obesity-related metabolic conditions have been associated with lower prostate-specific antigen (PSA) levels . For example, PSA has been shown to be lower in diabetics and lowest in individuals with a long duration of disease [62, 70, 210,211,212,213,214,215]. Similarly, obesity, which commonly coexists with diabetes, is believed to lowers PSA due to hemodilution [216,217,218,219]. Furthermore, some medications, such as statins and 5-alpha reductase inhibitors have been associated with lower PSA levels [220,221,222]. Because PSA drives biopsy recommendations and subsequent PCa detection in clinical practice, lower PSA in men with obesity-related medical conditions could lead to fewer biopsies and consequently to less diagnoses of cancer. Thus, it is possible that the observed associations between obesity-related metabolic conditions and prostate cancer risk are attributable, at least in part, to the effects of these conditions and/or their treatments on PSA values.

Conclusions

Obesity and prostate cancer are two common conditions in men over the age of 50 today and there appears to be a relationship between the two, with obesity potentially influencing the risk, aggressiveness and outcomes of men with prostate cancer. As our understanding of the mechanisms between these conditions grows, the appreciation of the complexity of the relationship and the likely contribution from multiple factors also increases. With obesity, a number of comorbid conditions also become more common. The observed associations between these diagnoses or their treatments and prostate cancer could be explained by confounding by the obesity:prostate cancer relationship. Or, these diagnoses and treatments may influence prostate cancer development and progression independent of obesity. Further research will help define the complex interplay. Until then, care of men at risk for, or with prostate cancer, should also include attention to weight management, glucose and lipid control, to promote both overall and prostate-cancer specific health.