The Correlation Between Metabolic Syndrome and Prostatic Diseases eulogo1

By: Cosimo De Nunzioa lowast , William Aronsonb, Stephen J. Freedl, c, Edward Giovannuccid and J. Kellogg Parsonse

Published online: 01 March 2012

Keywords: Prostate, Prostate cancer, Benign prostatic hyperplasia, Metabolic syndrome, Insulin resistance, Obesity

Abstract Full Text Full Text PDF (399 KB)



Metabolic syndrome (MetS), a cluster of several metabolic abnormalities with a high socioeconomic cost, is considered a worldwide epidemic. Recent epidemiologic and clinical data suggest that MetS is involved in the pathogenesis and progression of prostatic diseases such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa).


This review evaluates the available evidence of the role of MetS in BPH and PCa development and progression and discusses possible clinical implications for the management, prevention, and treatment of these diseases.

Evidence acquisition

A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between 1995 and September 2011 was performed by combining the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, metabolic syndrome, prostate, benign prostatic hyperplasia, prostate cancer, prevention, diagnosis, treatment, and prognosis. Additional references were obtained from the reference list of full-text manuscripts.

Evidence synthesis

MetS is a complex, highly prevalent disorder and a worldwide epidemic. Central obesity, insulin resistance, dyslipidemia, and hypertension are the main components of MetS. Notwithstanding all the attempts made to correctly define MetS, a major problem related to most definitions remains the applicability to different populations and ethnic groups. Although there is growing evidence of the association of MetS with the initiation and clinical progression of BPH and PCa, molecular mechanisms and effects on treatment efficacy remain unclear. Further research is required to better understand the role of MetS in BPH and PCa.


Data from the peer-reviewed literature suggest an association of MetS with BPH and PCa, although the evidence for a causal relationship remains missing. MetS should be considered a new domain in basic and clinical research in patients with prostatic disorders.

Take Home Message

Recent data support the hypothesis that metabolic syndrome (MetS) may be involved in the development and progression of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), although proof of causal relationship is still missing. Research evaluating the effect of treating MetS on PCa and BPH is under way.

Keywords: Prostate, Prostate cancer, Benign prostatic hyperplasia, Metabolic syndrome, Insulin resistance, Obesity.

1. Introduction

Metabolic syndrome (MetS) is a complex disorder with a high socioeconomic cost; indeed, it is considered a worldwide epidemic. MetS describes the combination or clustering of several metabolic abnormalities, including central obesity, dyslipidemia, hypertension, insulin resistance with compensatory hyperinsulinemia, and glucose intolerance [1]. MetS is directly associated with an increase in the risk of coronary artery disease, cardiovascular atherosclerotic diseases, and diabetes mellitus type 2 (DMT2) [2]. Recently, epidemiologic, histopathologic, molecular pathologic, and clinical studies have provided emerging evidence of a possible role of MetS and its components in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) pathogenesis [3] and [4].

PCa and BPH are significant health concerns and increase in prevalence as the population ages. PCa is the leading cause of nonskin cancer among men worldwide and, after lung, is the second most common cause of death from cancer in men in the United States [5], [6], and [7]. Symptomatic BPH represents the most common urologic disease among elderly males, affecting about one-quarter of men in their 50s, one-third of men in their 60s, and about half of octogenarians [6], [8], and [9].

BPH and PCa are considered chronic diseases with early initiation and slow progression. BPH starts as a simple micronodular hyperplasia and evolves into a macroscopic nodular enlargement that may result in bladder prostatic obstruction, causing lower urinary tract symptoms (LUTS) [8] and [9]. Similarly, PCa develops through early and late precancerous histologic modifications [10].

The molecular and cellular mechanisms involving stromal and epithelial components of the prostate leading to BPH remain unclear. However, a causative role of metabolic disturbances such as obesity, hyperinsulinemia, and insulin resistance in the pathogenesis of BPH has been suggested [4]. Today, although the molecular pathways potentially linking BPH and MetS are not yet completely defined, recent studies have suggested a possible association between MetS and LUTS related to BPH, with possible new targets for prevention and treatment of these disorders [1] and [11].

The only established risk factors associated with PCa are age, race, and family history, although large geographical variations in PCa risk suggest that lifestyle and environmental factors may also contribute to its aetiology. It has been hypothesised that the increased prevalence of MetS resulting from changes associated with a Western lifestyle (including physical inactivity and higher intakes of dietary fat, meat, refined carbohydrates, and excess calories) may explain in part the rising rates of PCa in Asian populations living in the United States [12]. The possibility of preventing and treating MetS led to novel therapeutic approaches that have been proposed as a new frontier in the prevention and treatment of PCa [12] and [13].

In this nonsystematic review, we evaluate the most recent evidence regarding MetS as a major pathway in BPH and PCa development and progression. In addition, we discuss the potential clinical implications of this evidence and suggest directions for future research.

2. Evidence acquisition

A National Center for Biotechnology Information (NCBI) PubMed search for relevant articles published between 1995 and September 2011 was performed by combining the following Patient population, Intervention, Comparison, Outcome (PICO) terms: male, metabolic syndrome, prostate, benign prostatic hyperplasia, prostate cancer, prevention, diagnosis, treatment, and prognosis. Only articles published in the English language were selected. In addition, sources in the reference sections of the identified publications were added to the list. Evidence was not limited to human data; data from animal studies were also included in the review. Each article title and abstract were reviewed for their appropriateness with regard to the diagnosis of MetS, and relevance was graded using the Oxford Centre for Evidence-based Medicine Levels of Evidence, including only those references with levels between 1 and 3. Details of the selected references are summarised in Table 1 and Table 2. References relating the diagnosis of BPH and PCa with individual components of MetS were not considered to evaluate the association between MetS and prostatic disease. All selected references were obtained as full-text PDF files. The initial list of selected papers was further enriched by individual suggestions from an expert panel of international opinion leaders on the topic (Fig. 1).

Table 1 Relevant clinical studies of the relationship between metabolic syndrome and benign prostatic hyperplasia

Authors, yr Study design Country Population Time period Age, yr (range or mean±SD) Cohort size MetS criteria Outcome/comments Level of Evidence
Rohrmann et al., 2005 [27] Cross-sectional United States NHANES III 1988–1994 >60 2372 Four of the following:

WC >102cm, HDL <1.03 nmol/l, triglycerides ≥1.69 mmol/l, systolic blood pressure ≥130mmHg, fasting glucose ≥6.1 mol/l
MetS was associated with LUTS (OR: 1.8; 95% CI, 1.1–2.94) 2b
Hammarsten et al., 1998 [32] Cohort Sweden Consecutive LUTS patients 1998 45–82 158 Not defined Median annual prostate growth rate was higher in patients with MetS (1.019 ml/yr vs 0.699 ml/yr) 3b
Ozden et al., 2007 [33] Cohort Turkey Consecutive BPH patients with LUTS 2004 50–83 78 NCEP-ATP-III Median annual prostate growth rate was higher in patients with MetS (1.0 ml/yr vs 0.64 ml/yr) 3b
Kupelian et al., 2009 [34] Cohort United States BACH 2002–2005 30–79 1899 NCEP-ATP-III MetS was associated with a symptom score ≥8 (OR: 1.85; 95% CI, 1.19–2.86; p<0.05) and a voiding score ≥5 (OR: 1.73; 95% CI, 1.03–2.44; p<0.05) 2b
Hammarsten et al., 2001 [38] Cohort Sweden Consecutive LUTS patients 2001 45–82 307 Not defined Direct relationship (<0.001) 3b
Temml et al., 2009 [39] Cross-sectional Austria Health screening project 6 mo 30–69 2371 IDF No relationship (13.8% of patients with LUTS) 2b
Hong et al., 2010 [40] Cohort Korea General Health Examination Programme 2008–2009 48.8±6.8 538 NCEP-ATP-III No relationship (mean IPSS in MetS patients was 5.03±0.46 vs 5.4±0.27; p=0.399) 3b
Gupta et al., 2006 [41] Retrospective data registry United States Vietnam War Veterans 1982–2004 35–50 1206 NCEP-ATP-III No relationship (RR: 1.01; 95% CI, 0.76–1.33; p=0.97) 2b
Park et al., 2008 [42] Cohort Korea KLoSHA 2005–2006 74±8.1 348 Three or more of the following:

WC >90cm or BMI >25 kg/m2, HDL<40 mg/dl, triglycerides >150 mg/dl,

systolic blood pressure >130mmHg, fasting glucose >110 mg/dl
No relationship (mean IPSS in MetS patients was 11.1±8.2 vs 12.3±8.8; p=0.575) 3b
Gao et al., 2011 [43] Cohort China FAMHES 2009 28–44 3103 Three or more of the following:

WC ≥90cm, HDL<1.03 mmol/l, triglycerides ≥1.7 mmol/l, systolic blood pressure ≥130mmHg, fasting glucose ≥5.6 mmol/l
No relationship (OR: 0.97; 95% CI, 0.67–1.39; p>0.05) 2b
Ohgaki et al., 2011 [44] Cohort Japan General Health check-up 2008–2009 57±8.7 900 WC >85cm plus any two of the following: HDL<40 mg/dl,

triglycerides >150 mg/dl,

systolic blood pressure >130mmHg, fasting glucose ≥110 mg/dl
No relationship 2b

SD=standard deviation; MetS=metabolic syndrome; NHANES III=Third National Health Center Nutrition Examination Survey; WC=waist circumference; HDL=high-density lipoprotein; LUTS=lower urinary tract symptoms; OR=odds ratio; CI=confidence interval; BPH=benign prostatic hyperplasia; NCEP-ATP-III=National Cholesterol Education Program Adult Treatment Panel III; BACH=Boston Area Community Health Survey; IDF=International Diabetes Federation; IPSS=International Prostate Symptom Score; RR=risk ratio; KLoSHA=Korean Longitudinal Study on Health and Aging; BMI=body mass index; FAMHES=Fangchenggang Area Male Healthy and Examination Survey.

Table 2 Relevant clinical studies of the relationship between metabolic syndrome and prostate cancer

Authors, yr Study design Country Population Time period Age, yr (range or mean±SD) Cohort size Exposure assessment: MetS criteria No. of cases Results/comments (outcome: PCa) Level of evidence
Laukkanem et al., 2004 [49] Longitudinal cohort study Finland Kuopio communities 1984–2001 42–62 1880 (white) WHO 56 Risk increase (RR: 1.94; 95% CI, 1.06–3.53) 3b
Lund Haheim et al., 2006 [50] Longitudinal cohort study Norway Oslo study 1972–1998 40–49 15 933 (white) Upper quartile levels ATP-III criteria 507 Risk increase (RR: 1.56; 95% CI, 1.21–2.0) 2b
Martin et al., 2009 [51] Longitudinal cohort study Norway HUNT 2 1996–2005 48±16.4 29 364 (white) NCEP-ATP-III 687 No association (HR: 0.91; 95% CI, 0.877–1.09) 2b
Beebe-Dimmer et al., 2009 [52] Case-control study United States GECAP 2001–2004 62±10.4 881 (56% white; 44% African American) NCEP-ATP-III 637 Risk increase in African American population (OR: 1.71; 95% CI, 0.97–3.01) 3b
Tande et al., 2006 [53] Longitudinal cohort study United States ARIC 1987–2000 45–64 6429 (49% white; 61% African American) NCEP-ATP-III 385 Risk reduction (RR: 0.77; 95% CI, 0.51–1.05) 2b
De Nunzio et al., 2011 [54] Cohort study Italy Prostate biopsy cohort study 2009–2010 47–83 195 (white) NCEP-ATP-III 102 No association (OR: 0.97; 95% CI, 0.48–1.95); increased risk for Gleason score ≥7 in patients with PCa (OR: 3.82; 95% CI, 1.33–10.9) 3b
Wallner et al., 2011 [56] Cohort study United States Olmsted County 1990–2005 49–79 2445 (white) WHO 206 HR: 0.81; 95% CI, 0.2–3.3 (2 patients with PCa out of 28 patients with MetS) 3b

SD=standard deviation; MetS=metabolic syndrome; PCa=prostate cancer; WHO=World Health Organisation; RR=risk ratio; CI=confidence interval; NCEP-ATP-III=National Cholesterol Education Program Adult Treatment Panel III; HUNT 2=Nord-Trondelang Health Study; GECAP=Gene Environment and Prostate Cancer Study; OR=odds ratio; ARIC=Atherosclerosis Risk in Communities.


Fig. 1 Flow diagram of the search results.

3. Evidence synthesis

3.1. Metabolic syndrome

3.1.1. Definition and epidemiology

Historically, in 1987, Gerald Reaven gave his famous Banning Lecture and introduced the concept of “syndrome X” as an aggregation of atherosclerosis risk factors, including insulin resistance and hyperinsulinemia, hypertension, hypertriglyceridemia, and depressed high-density lipoprotein (HDL) cholesterol. Reaven also suggested that the combination of insulin resistance and hyperinsulinemia instead of obesity should be considered the underlying factor that determines the other aspects of the syndrome [14], [15], and [16]. Since then, numerous international organisations and expert groups have endeavoured to include all the different parameters describe in syndrome X to define MetS (Table 3) [2], [17], [18], [19], and [20].

Table 3 Diagnostic criteria for metabolic syndrome in the male population

WHO (1998) EGIR (1999) AACE (2003) AHA/NHLBI (2004) NCEP-ATP-III (2005) IDF (2005) JSSO (2005) IDF and AHA/NHLBI (2009)
Absolute required Insulin resistance (impaired fasting glucose or impaired glucose tolerance) Hyperinsulinemia (plasma insulin >75th percentile) Insulin resistance (impaired glucose tolerance) None None Central obesity (WC >94 cm) Central obesity (WC >85 cm) None
Criteria Insulin resistance or DMT2 plus two of the following Hyperinsulinemia plus two of the following Insulin resistance plus two of the following Any three of the following Any three of the following Obesity plus two of the following Obesity plus two of the following Any three of the following
Obesity BMI >30 kg/m2

W/H >0.9
WC >94 cm BMI ≥25 kg/m2 WC ≥102 cm WC >102 cm Already required Already required Elevated WC according to country-specific definition
Hyperglycemia Already required Already required Already required Fasting glucose ≥100 mg/dl Fasting glucose ≥110 mg/dl Fasting glucose ≥100 mg/dl Fasting glucose ≥100 mg/dl Fasting glucose ≥100 mg/dl
Dyslipidemia TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <39 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
TG ≥150 mg/dl

HDL <40 mg/dl
Hypertension BP ≥140/90mm Hg BP ≥140/90mm Hg or antihypertensive drugs BP ≥130/85mm Hg BP ≥130/85mm Hg BP ≥130/85mm Hg BP ≥130/85mm Hg BP ≥130/85mm Hg or antihypertensive drugs BP ≥130/85mm Hg
Other criteria Microalbuminuria (≥20μg/min)

WHO=World Health Organisation; EGIR=European Group for the Study of Insulin Resistance; AACE=American Association of Clinical Endocrinology; AHA/NHLBI=American Heart Association/National Heart, Lung and Blood Institute; NCEP-ATP-III=National Cholesterol Educational Program Adult Treatment Panel III; IDF=International Diabetes Federation; JSSO=Japan Society for the Study of Obesity; WC=waist circumference; DMT2=diabetes mellitus type 2; BMI=body mass index; W/H=waist-to-hip ratio; TG=triglycerides; HDL=high-density lipoprotein; BP=blood pressure.

Currently, the two most widely used definitions are those proposed by the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and the International Diabetes Federation (IDF) focusing on abdominal obesity measured by waist circumference. In contrast, the World Health Organisation (WHO) and the European Group for the Study of Insulin Resistance (EGIR) definitions are principally focused on insulin resistance [2]. Notwithstanding all attempts made to correctly define MetS, a major problem related to most definitions remains their applicability to different ethnic groups—in particular, for the definition of different obesity cut-offs [2].

It is evident that the prevalence of MetS depends on the different criteria used in various definitions as well as other factors such as the age, gender, race, and ethnicity of the population. Prevalence increases linearly from the 20 yr of age until 50 yr of age, when it plateaus and affects >40% of the population in the United States and nearly 30% in Europe [14] and [21]. According to the National Health and Examination Study (NHANES) 2003–2006, a cross-sectional survey of the adults in the United States, approximately 34% of people had MetS according to the NCEP-ATP-III criteria [22]. Similar to Western countries, the prevalence of MetS is rapidly increasing in developing countries, ranging from 9.8% in males from urban north India to 16.3% in Morocco to 25.4% in urban Brasil to 33.5% in South Africa and 33.7% in Iran [2] and [14]. This increase is observed independently of the criteria used to define MetS and reflects the worldwide transition from a traditional to a Western-like lifestyle.

3.1.2. Potential biologic mechanism

Although insulin resistance and obesity are considered at the core of the pathophysiology of MetS, a number of other factors, such as atherogenic dyslipidemia, deregulations of the hypothalamic–pituitary adrenal axis (HPA), proinflammatory state, and cellular oxidative stress, can also be involved in its pathogenesis and potential interactions [2] (Fig. 2). In most cases, MetS develops as a result of poor eating habits and/or sedentary lifestyles, which are associated with insulin resistance and obesity. Insulin resistance occurs when there is a decrease in the responsiveness of peripheral tissues (skeletal muscle, fat, and liver) to the effect of insulin, with a concomitant hyperinsulinemia responsible for insulinlike growth factor 1 (IGF-1) production in the liver [21]. IGF-1 is a potent mitogenic factor and apoptosis inhibitor that has be linked with PCa risk [23].


Fig. 2 Pathophysiology of metabolic syndrome.HPA=hypothalamic–pituitary adrenal axis; IGF-1=insulinlike growth factor 1; TNF-α=tumour necrosis factor 1; IL-6=interleukin-6; CRP=C-reactive protein; PAI-1=plasminogen activator inhibitor 1; HDL=high-density lipoprotein; LDL=low-density lipoprotein.

Central obesity is also considered an early step in the development and progression of MetS. Visceral adipose tissue secretes various bioactive substances known as adipocytokines, which can induce insulin resistance and have proinflammatory and proatherogenic effects. Circulating levels of cytokines, including resistin, leptin, tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, C-reactive protein (CRP), fibrinogen and plasminogen activator inhibitor 1 (PAI-1), are typically increased in obese patients and in patients with DMT2. In contrast, adiponectin, a circulating tissue-specific hormone, is lower in individuals with visceral fat accumulation [19] and [21]. Adiponectin stimulates glucose metabolism and fatty acid oxidation in the muscle, enhances insulin sensitivity in the liver, and inhibits macrophage transformation to foam cells within the vascular wall [19], [20], and [21].

MetS has also been associated with a state of chronic, low-grade inflammation. Several studies showed that patients with MetS were more likely than those without the syndrome to have elevated levels of a marker of inflammation such as CRP as well as proinflammatory cytokines such as TNF-α, IL-8, IL-6, and IL-1β[24], [25], and [26].

3.2. Association between metabolic syndrome and benign prostatic hyperplasia

3.2.1. Potential biologic mechanism

Several studies suggested that insulin resistance with secondary hyperinsulinemia is associated with prostatic enlargement [6] and [8]. Hyperinsulinemia is in turn associated with an increased sympathetic nervous system activity and may contribute to increased smooth muscle tone of the prostate, resulting in more severe LUTS independent of prostatic enlargement [27] and [28]. Hyperglycaemia may play a role by increasing cytosolic-free calcium in smooth muscle cells and neural tissue, leading to sympathetic nervous system activation. The IGF pathway may also contribute to the association between insulin resistance and BPH. Insulin presents a structural similarity to IGF-1 and can bind its receptor, which may activate a complex pathway influencing prostate cell growth and proliferation. Alternatively, as insulin increases, IGF-1 binding protein-1 decreases, thus increasing IGF bioavailability [28]. The hypothesis has been proposed regarding the fact that prostatic inflammation as observed in patients with MetS may play an important role in BPH development and progression. T-cell activity in prostate inflammatory infiltrates may result in stimulation of stromal and epithelial cell proliferation that is sustained by an autoimmune mechanism. Tissue damage and the subsequent chronic process of repetitive wound healing induced by inflammation may lead to the development of BPH nodules [5], [6], and [8].

The sex hormone milieu may further contribute to this association. Men with LUTS and BPH often present with relatively low androgen and high oestrogen levels. This condition, also observed in men with MetS, may play a role in BPH pathogenesis [3] and [29]. In classical studies on the effects of steroid hormones on canine prostate growth by the Johns Hopkins group, it was observed that oestrogen markedly synergises androgen effects, and this process induces a >4-fold increase in total prostate weight. This enhancement of prostate growth requires the combination of oestrogen with a 5α-reduced steroid like dihydrotestosterone or one of its metabolites [30]. Alternative hypotheses include pelvic atherosclerosis leading to chronic ischaemia of the bladder and the prostate, which may result in functional impairments clinically manifested as LUTS (Fig. 3).


Fig. 3 Potential biologic mechanisms for lower urinary tract symptoms and benign prostatic hyperplasia in relation to metabolic syndrome.IGF-1=insulinlike growth factor 1; IL=interleukin, TGF-β=transforming growth factor-β; IFN-γ=interferon-γ; FGF-2=fibroblast growth factor 2; LUTS=lower urinary tract symptoms; BPH=benign prostatic hyperplasia.

3.2.2. Clinical evidence

MetS has been associated with an increased risk of LUTS and BPH in several observational studies [27], [32], [33], [34], [38], [39], [40], [41], [42], [43], and [44] (Table 1). Out of 2372 male participants in the NHANES III study, those with at least three components of MetS were at 80% increased risk for LUTS compared to those with no components [27] and [31]. Hammarsten et al. [32] examined 158 patients with LUTS secondary to BPH and found that men with individual components of MetS had significantly larger prostate volumes and faster annual BPH growth rates. In particular, the calculated annual growth rate was increased by 47%, 17%, 36%, 31%, and 28% in patients with DMT2, hypertension, obesity, low HDL cholesterol, and high fasting insulin, respectively. Ozden et al. [33] confirmed these findings in a Turkish population in which patients with MetS presented with a significantly higher median annual prostate growth rate than that of BPH patients without MetS (1.0ml/yr vs 0.64ml/yr, respectively; p=0.018).

Analysis of the Boston Area Community Health (BACH) survey [34] showed a trend in increasing MetS prevalence with increasing American Urological Association Symptom Index (AUA-SI) scores. The prevalence of MetS defined by using the NECP-ATP-III criteria was lowest (about 20%) for men reporting no symptoms or one symptom and increased with mild LUTS (AUA-SI 2–7) to approximately 40%, with no further increase with moderate to severe LUTS (AUA-SI ≥8). A statistically significant association was also observed between MetS and a voiding symptom score ≥5 (odds ratio [OR]: 1.73; 95% confidence interval [CI], 1.06–2.80) but not for a storage symptom score ≥4 (OR: 0.94; 95% CI, 0.66–1.33).

A recent review summarised a direct and significant relationship between some components of MetS (obesity, insulin resistance, and hypertension) and the BPH/LUTS complex [35]. In particular, in the Baltimore Longitudinal Study of Aging, each 1-kg/m2 increase in body mass index (BMI) corresponded with a 0.41-ml increase in prostate volume; obese patients had a 3.5-fold increased risk of an enlarged prostate compared to nonobese participants [4]. In a further analysis of >16 000 radical prostatectomies, it was confirmed that each 1-kg/m2 increase in preoperative BMI was associated with a 0.45-g (95% CI, 0.35–0.55g) increase in total prostate weight, with a 70% increased risk of prostate enlargement when comparing obese to nonobese patients [36]. Finally, the relationship between obesity and BPH/LUTS was observed in different races and ethnicities, indicating its generalisability [35].

A few studies do not support the association between MetS and LUTS. However, these negative outcomes are related to studies with weak data for their retrospective design or for suboptimal study populations with a limited number of patients with clinically important LUTS [37], [39], and [41]. Not all data from Asian populations [40], [42], [43], and [44] demonstrate a possible association between MetS and BPH/LUTS, either, although an association between obesity and LUTS/BPH was suggested in a recent review in these populations [35]. These data may be related to the different criteria used to define the presence of MetS or to the lower prevalence of MetS (14–29%) when compared to the United States or European series (29–31%), or they could reflect different cultural and lifestyle backgrounds.

It is important to emphasise that most available data on the possible association between MetS and BPH derive from observational studies often geographically limited to a specific area or population and consequently should be considered exploratory and serve primarily to develop and implement future clinical trials.

3.3. Association between metabolic syndrome and prostate cancer

3.3.1. Potential biologic mechanism

Although conflicting results exist, several studies found that serum insulin, fasting glucose level, and insulin resistance or DNA polymorphisms in the insulin gene itself are associated with an increased PCa risk [13], [45], and [46]. Moreover, the relative risk of PCa was found to decrease significantly with increasing time from DMT2 diagnosis, suggesting the importance of insulin because of the fact that insulin levels decline with longer-standing DMT2 as a result of beta cell burnout [47]. In addition to insulin, IGF-1, which is significantly elevated in patients with insulin resistance, is known to stimulate growth of both androgen-sensitive and androgen-independent human PCa cell lines in vitro, and elevated IGF-1 serum levels are associated with an increased PCa risk in humans [13] and [45].

Another possible mechanism involved is a change in the sex steroid pathway. MetS is associated with increased serum estradiol levels, decreased sex hormone–binding globulin (SHBG) concentration, and decreased free testosterone levels. Although the exact role of androgen and oestrogen in PCa development and progressions is still unclear, it has been suggested that testosterone may exert a differentiating effect on PCa and that only partially aggressive androgen-insensitive cancer can grow in a low-androgen–hostile environment [13] and [45]. Animal and experimental studies also suggest that elevated oestrogen levels may promote testosterone-induced carcinogenesis and result in larger and more aggressive PCa [10], [13], and [45].

Chronic prostatic inflammation as observed in patients with MetS is associated with a milieu rich in proinflammatory cytokines, inflammatory mediators, and growth factors, which may lead to an uncontrolled proliferative response with rapidly dividing cells that are more likely to undergo mutation, as observed in cancer [6] and [10]. Circulating levels of cytokines as leptin and adiponectin have been preliminarily associated with PCa carcinogenesis. Leptin stimulates the in vitro growth of androgen-insensitive PCa cells, and increased serum leptin levels were associated with larger, high-grade, and more advanced tumours. Adiponectin showed antitumour activity via inhibition of angiogenesis, and lower adiponectin serum levels were associated with high-grade and more advanced PCa [13], [45], and [48] (Fig. 4).


Fig. 4 Biologic hypothesis for prostate cancer aggressiveness in relation to metabolic syndrome.IL=interleukin; TGF-α=transforming growth factor-α; IGF-1=insulinlike growth factor 1; SHBG=sex hormone–binding globulin; PCa=prostate cancer.

3.3.2. Clinical evidence

Data on the association between MetS and PCa risk are conflicting, with studies mostly performed in northern Europe [49], [50], and [51] or in the United States [52] and [53] (Table 3). Data from studies in Finland [49], [50], and [51] indicated a positive association between MetS and PCa, with one study [50] of 507 PCa cases showing a 56% increased risk for patients with at least three metabolic factors and a second study [49] showing a 94% excess risk among those with MetS [12]. In contrast, an inverse relationship between MetS and PCa risk was reported in a large cohort of men participating in the Atherosclerosis Risk in the USA communities study [53]. These investigators observed an inverse association between MetS and PCa risk: Men who had MetS showed a 23% reduction in risk, with no racial difference in the magnitude of relation, although this inverse association was not confirmed among African American men participating in the Genes Environment Prostate Cancer (GECAP) study [52]. MetS was associated with an increased PCa risk in African American men (OR: 1.71; 95% CI, 0.97–3.01) but not in white men (OR: 1.02; 95% CI, 0.64–1.62). A recent study evaluating the association between MetS and PCa risk among Italian men with an elevated prostate-specific antigen (PSA) level or an abnormal digital rectal examination scheduled for a prostatic biopsy found that MetS was highly prevalent (44%); it was not associated with an increased risk of PCa but was associated with an increased risk (OR: 3.8; 95% CI, 1.33–10.9) of Gleason score ≥7 in patients with PCa at biopsy [54].

Still, from a methodologic standpoint, analyses of MetS and PCa are problematic, as comparisons are likely influenced by differences in race, obesity, and MetS prevalence; PCa and aggressive PCa prevalence; and variable clinical criteria for MetS [55]. The Italian cohort, for example, was composed entirely of Caucasians, with no Hispanics or Africans, as is typical in many American cohorts. Looking at studies performed in the Scandinavian population [12], patient cohorts are again not comparable, because their patients tend to be slimmer (12–15% obese population), with a lower prevalence of MetS (19–22%) compared to Italian (44%) or American cohorts (24–40%) [2].

It has recently been suggested that evaluating MetS as a single condition may be an inappropriate approach to investigating PCa risk. Specifically, combining all the multiple components of the syndrome into a single variable may confound or obscure the independent effects and interactions of these metabolic components on PCa risk [56]. Each of the primary components of MetS (DMT2, hypertension, obesity, and hyperlipidemia) has been individually observed to be directly associated with PCa risk. DMT2 has been associated with a reduction in PCa risk, probably in relation to the changing action of insulin over the course of diabetes progression [39] and [56]. The presence of hypertension may increase PCa risk, possibly in part through increased sympathetic nervous system activity, which can result in androgen-mediated stimulation of PCa cell growth [56]. Men with lower plasma cholesterol concentration were less likely to develop high-grade PCa than men with higher concentrations; this effect might be mediated by several pathways, including androgen metabolism and intracellular cholesterol-mediated signalling [57] and [58]. Most recent large studies suggest that obesity is associated with a decreased risk of low-grade disease but an increased risk of high-grade and advanced PCa [13]. It is evident that the evaluation of PCa risk in patients affected by MetS is complex, because the different combinations of the diverse metabolic abnormalities that define the presence of the syndrome may influence PCa risk differently. Therefore, further basic and clinical studies are needed to evaluate this association by investigating all these metabolic conditions as a whole.

3.4. Metabolic syndrome as a target for prevention and treatment

MetS management is considered a major challenge to global public health. Arguably, the most effective way to deal with MetS and its related consequences is primary prevention. The ATP-III panel recommended that obesity should be the primary target of intervention for MetS. Weight loss (weight loss of 7–10% during the first year of treatment) together with more regular or moderate physical activity (30min/d) lowers triglycerides and raises HDL cholesterol, lowers blood pressure, and reduces insulin resistance [17] and [18]. Antihypertensive drugs, statins, and metformin should be considered as second-line therapies in patients with persistent hypertension, dyslipidemia, or insulin resistance, respectively [17] and [18]. Considering the possible link between MetS, BPH, and PCa, it has been suggested that prevention and treatment of MetS through lifestyle interventions could have a positive effect on patients’ symptoms and disease progression [1].

Increased levels of physical activity have been associated with a decreased risk of BPH and LUTS in several large studies, although the mechanisms behind these observations are not completely understood. In the Massachusetts cohort, men reporting the highest levels of recreational physical activity were 50% less likely to report LUTS resulting from BPH than those in the bottom quartile [31] and [59]. In NHANES III, men who reported no engagement in leisure-time physical activity were twice as likely to have increased LUTS as those who engaged in physical activity [31] and [60]. These findings were confirmed in a recent meta-analysis showing that vigorous physical activity was associated with up to a 25% decrease in the risk of BPH or LUTS relative to a sedentary lifestyle, with the magnitude of the protective effect increasing with high levels of activity [36] and [61]. However, despite robust evidence from observational studies, there have been no randomised clinical trials (RCT) to explore whether lifestyle interventions may influence the natural history of these conditions.

The majority of data on the effect of diet and activity level interventions on PCa development and progression come from animal models. Multiple animal studies have revealed that diets that lower insulin levels (ie, low carbohydrate, low fat, and caloric restriction) decrease the development of PCa and slow tumour growth, supporting the importance of insulin as a stimulant for PCa growth, though other mechanisms have also been proposed [62], [63], [64], [65], and [66].

The most important data from clinical studies derive from the studies conducted by Ornish et al. [67], who conducted an RCT in men with PCa on active surveillance. The men were randomly assigned to a low fat vegetarian diet (12% dietary fat) supplemented with soy, vitamin E, fish oil, selenium, and vitamin C and combined with exercise (30min 6 d/wk) and a stress management program or control arm (no intervention). At the end of 1 yr, men on the intervention lost 4.5kg and experienced a 4% decline in PSA compared to a 6% rise in the control group. Two years after randomisation, more men in the control arm (13 patients) proceeded to PCa treatment than men on the intervention arm (2 patients; p=0.005) [63]. Two short-term prospective trials demonstrated that weight loss and dietary fat reduction reduced levels of growth factors in the serum stimulating PCa growth in an ex vivo bioassay, possibly through the IGF-axis, though the mechanisms remain undefined [68] and [69]. A recent meta-analysis [70] indicated that physical activity is associated with a small but significant PCa risk reduction. A relatively long-term period (>10 yr) might be required to observe this reduction. However, the specific biologic mechanisms linking MetS, physical activity, and PCa risk reduction remain unknown, although they are certainly an area for fertile research.

The possibility of influencing BPH and PCa through therapies that alter cholesterol metabolism has also been investigated. A recent RCT evaluated men with LUTS and a serum low-density lipoprotein cholesterol between 100 and 190mg/dl. It showed no differences in International Prostate Symptom Score, prostate volume, urinary flow rate, or PSA among BPH patients treated for 6 mo with atorvastatin compared to controls [71]. The short-term follow-up used in the study has been proposed as a possible explanation for this null result; however, the hypothesis that cholesterol has no impact on BPH pathogenesis and progression should be considered.

Several observational studies and three meta-analyses on numerous RCTs of statin use observed no association between its use and overall PCa risk. However, there is growing evidence that statin use may preferentially reduce the risk of advanced PCa [57], although this hypothesis is not supported by dedicated PCa prevention trials.

Metformin, a biguanide derivate that blocks hepatic glucose production, reduces insulin resistance, and lowers insulin levels, inhibits human PCa cell proliferation and tumour growth through a decrease of the cyclin D1 level. Some ongoing studies have evaluated the safety and efficacy of metformin treatment in patients with PCa [72].

Although data on the effect of diet and lifestyle intervention on the natural histories of BPH and PCa require confirmation, it is reasonable to suggest that our patients exercise regularly, eat a balanced diet, and maintain a healthy weight [45] and [73] to prevent or reverse MetS. This advice will improve heart health and reduce the risk of cardiovascular disease, the most common cause of male mortality. In due time, these interventions may also be shown to influence the development and progression of BPH and PCa, improve clinical signs and symptoms, and maintain prostate health.

4. Conclusions

MetS is a complex and highly prevalent disorder in patients with BPH and PCa, and it is associated with several known and unknown biologic factors that may influence the prostate microenvironment. Although the molecular pathways of MetS as related to the prostate remain incompletely characterised, the cumulative evidence summarised in this report suggests an association between MetS and its mediators and the development of BPH and PCa. In clinical practice, it is fundamental that urologists recognise and manage (either directly or via referral to a primary care doctor) MetS for the benefit of their patients. In academic practice, knowledge of MetS should be included in the core curriculum of urologic training. In clinical research, a better understanding of the MetS pathway may identify new therapeutic targets and open novel strategies to reduce the risk of benign and malignant prostate tumours.

Author contributions: Cosimo De Nunzio had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: De Nunzio, Aronson, Freedland, Giovannucci, Parsons.

Acquisition of data: De Nunzio.

Analysis and interpretation of data: De Nunzio.

Drafting of the manuscript: De Nunzio.

Critical revision of the manuscript for important intellectual content: De Nunzio, Aronson, Freedland, Giovannucci, Parsons.

Statistical analysis: De Nunzio.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Aronson, Freedland, Giovannucci, Parsons.

Other (specify): None.

Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None.

Funding/Support and role of the sponsor: None.

Acknowledgment statement: The authors acknowledge Kimberlee Manzi from the University “La Tuscia,” Viterbo, Italy, who provided English editing support.


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a Department of Urology, Sant’Andrea Hospital, University “La Sapienza,” Rome, Italy

b Department of Urology, University of California, Los Angeles, School of Medicine, Los Angeles, CA, USA

c Division of Urologic Surgery, Duke Prostate Cancer Center, Duke School of Medicine, Durham, NC, USA

d Departments of Nutrition and Epidemiology, Harvard School of Public Health and Channing Laboratory, Boston, MA, USA

e Division of Urologic Oncology, Moores Comprehensive Cancer Center, University of California, San Diego, School of Medicine, San Diego, CA, USA

lowast Corresponding author. Department of Urology, Sant’Andrea Hospital, “La Sapienza” University, Via di Grottarossa 1035-00189, Rome, Italy. Tel. +39 0633777716; Fax: +39 0633775059. Please visit to read and answer questions on-line. The EU-ACME credits will then be attributed automatically.