Metabolic syndrome increases the risk of aggressive prostate cancer detection
What's known on the subject? and What does the study add?
- Metabolic syndrome can identify patients at high risk of cardiovascular disease. The prevalence of metabolic syndrome is increasing worldwide and is associated with increased age, obesity and hypogonadism. The association between metabolic syndrome and prostate cancer development has not been studied comprehensively, and published studies report divergent results.
- This study indicates that tumours detected in men with metabolic syndrome are more aggressive than those detected in men without this condition.
- To further examine the association between metabolic syndrome (MS), prostate cancer (PC) detection risk and tumour aggressiveness.
Patients and Methods
- From 2006 to 2010, 2408 men not receiving 5α-reductase inhibitors were scheduled for prostatic biopsy due to PSA above 4 ng/mL and/or abnormal digital rectal examination.
- MS was evaluated according to the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III definition.
- Tumour aggressiveness was evaluated through biopsy Gleason score, clinical stage and risk of biochemical recurrence after primary treatment.
- The rates of PC detection were 34.5% and 36.4% respectively in men with and without MS, P = 0.185. High grade PC rates (Gleason score 8–10) were 35.9% and 23.9% respectively, P < 0.001. The advanced disease rates (cT3–4 N0–1 M0–1) were 17% and 12.7% respectively, P = 0.841.
- The high risk PC rates (cT2c–4 or Gleason score 8–10 or PSA > 20) were 38.5% and 33.0% respectively, P = 0.581.
- Multivariate analysis confirmed that MS was not associated with the risk of PC detection but it was associated with an increased risk of high grade tumours (odds ratio 1.75, 95% CI 1.26–2.41), P < 0.001.
- MS seems not be associated with an increased risk of PC detection but it is associated with an increased risk of more aggressive tumours.
body mass index
Prostate cancer (PC) is the most commonly diagnosed malignancy in men from industrialized countries . The main risk factors for PC development are age, race and family history. However, large geographical variations in PC incidence suggest that lifestyle factors such as physical activity and diet play a significant role in its pathogenesis . Thus, altered metabolic pathways could be important in prostatic carcinogenesis and possible therapeutic targets could be considered .
Metabolic syndrome (MS) is an entity characterized by clinical and serological parameters (obesity, hypertension, insulin resistance and dyslipidaemia) that identify patients at high risk of cardiovascular disease . The prevalence of MS is increasing worldwide and is associated with increased age, obesity and hypogonadism .
The association between MS and PC development has not been studied comprehensively, and published studies report divergent results. Moreover, few studies have considered MS rather than some of its components. Among the studies that have considered MS, some have found a positive association in Scandinavians [6, 7] and Afro-Americans [8, 9], whereas others have found an inverse association in a mixed population  or no relationship in Scandinavians  or whites in the USA .
The objective of this study was to analyse the relationship between MS and the risk of PC detection in men undergoing prostate biopsy, as well as the tumour aggressiveness.
From 2006 and 2010, 2408 consecutive men, not treated with 5α-reductase inhibitors, were scheduled for prostate biopsy for PSA > 4.0 ng/mL and/or an abnormal DRE after signing an informed consent. All men underwent physical examination including height, weight, waist circumference, resting blood pressure measurements and DRE. Treatments with hypolipidaemiants, antihypertensives and hypoglycaemiants were also registered. Fasting blood samples were drawn for coagulation tests between 7:00 and 9:00 and serum samples were analysed for glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, PSA and testosterone. In all, 1938 men (80.5%) had a PSA > 4.0 ng/mL and normal DRE, 45 men (1.9%) had an abnormal DRE and PSA < 4.1 ng/mL, and 425 men (17.6%) had a PSA > 4.0 ng/mL and suspicious DRE. Clinical characteristics of the men and diagnosed tumours are summarized in Table 1.
Table 1. Demographics and patient characteristics in the overall series and according to the diagnosis of MS
|Men (number)||2408||1552 (64.5)||856 (35.5)||–|
|Age* (year)||68 (46–79)||68 (46–79)||68 (51–80)||0.756|
|Serum PSA* (ng/mL)||6.8 (0.7–1240)||6.7 (0.7–195)||7.2 (2.9–1240)||0.001|
|Positive DRE (%)||470 (19.5)||297 (19.1)||173 (20.2)||0.555|
|Serum testosterone* (ng/dL)||447 (127–1071)||460 (203–1071)||393 (127–870)||0.001|
|Prostate volume* (mL)||48 (20–170)||48 (20–121)||49 (36–170)||0.582|
|Body mass index* (kg/m2)||27.6 (18.4–46.0)||26.3 (18.4–46.0)||30.2 (19.0–45)||0.001|
|Hypolipidaemic treatment (%)||744 (30.9%)||416 (26.8)||328 (38.3%)||0.001|
|Antihypertensive treatment (%)||664 (27.6%)||352 (22.7)||312 (36.4%)||0.001|
|Hypoglycaemic treatment (%)||336 (14.0%)||136 (8.8)||200 (23.4)||0.001|
|Prostate cancer (%)||848 (35.2)||536 (34.5)||312 (36.4)||0.185|
|Advanced disease† (%)||121 (14.3)||68 (12.7)||53 (17.0)||0.053|
|High grade cancer (%)||240 (28.3)||128 (23.9)||112 (35.9)||0.001|
|High risk cancer‡ (%)||297 (35.0)||177 (33.0)||120 (38.5)||0.064|
MS was evaluated according to National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, Adult Treatment Panel III criteria . Patients with three or more of the following factors were classified as having MS: waist circumference >102 cm; triglycerides ≥150 mg/dL; HDL ≤ 40 mg/dL or hypolipidaemic treatment; fasting glucose ≥110 mg/dL or hypoglycaemic treatment; and blood pressure ≥130/85 mmHg or antihypertensive treatment.
PB was carried out under local anaesthesia. An end-fire ultrasound transducer (Falcon 2101, B-K Medical Inc.) and a 16-gauge automated biopsy needle (Bard Inc.) were used. A minimum of 10 cores were obtained, and one to eight additional cores were taken as determined by the age of the men and prostate volume, according to a modified Vienna nomogram .
Bone scan, CT or MRI was performed in patients with serum PSA > 20 ng/mL or Gleason score >7. Tumour aggressiveness was analysed according to clinical stage (localized tumour cT1–2 N0 M0 vs locally advanced or disseminated disease), Gleason score (high grade 8–10 vs low or intermediate grade) and risk of biochemical recurrence after primary treatment according to a modified D'Amico classification  (high risk T2c–4 N0–1 M0–1 or PSA > 20 or Gleason score >7 vs low or intermediate risk).
Quantitative variables were expressed as median (range) and qualitative variables as rates. Univariate analysis included the Mann–Whitney U test to compare quantitative variables, the chi-squared test to relate qualitative variables and the Cochrane test to analyse the strength of associations. Multivariate logistic regression analysis was performed to analyse predictors of PC risk and PC aggressiveness. SPSS software (V16) was used to carry out this analysis.
MS was diagnosed in 856 of the 2408 men included in this study (35.5%). The rate of PC was 36.4% in men with MS while it was 34.5% in men without MS, P = 0.185. Demographics and clinical characteristics of the population according to the presence of MS are summarized in Table 1. We emphasize a significant increase of the serum PSA level and the body mass index (BMI), as well as a significant decrease of the serum testosterone level, in those men diagnosed with MS. Moreover the rates of men on hypolipidaemiants, antihypertensives and hypoglycaemiants were significantly higher in men with MS. The characteristics related to tumour aggressiveness are also summarized in Table 1. The rate of high grade tumours was 35.9% in men with MS whereas it was 23.9% in men without MS, P < 0.001. Men with MS also had a non-significant increased rate of advanced disease and high risk of recurrence tumours.
PC was detected in 10 of 45 men (22.2%) with abnormal DRE and serum PSA < 4.1 ng/mL, in 620 of 1938 men (32.0%) with normal DRE and serum PSA > 4.0 ng/mL, and in 218 of 425 men (51.3%) with abnormal DRE and PSA > 4.0 ng/mL. Table 2 summarizes the characteristics of patients according to PC diagnosis. The rate of MS was 36.6% in patients with PC and 34.9% in men without PC, P = 0.185. We observed a significant increase of age, serum PSA level and the rate of abnormal DRE in men with PC, and a significant decrease of serum testosterone and prostate volume. With respect to drug consumption, a significant decrease of men on hypolipidaemiants and a significant increase of men on hypoglycaemiants were detected in men diagnosed with PC.
Table 2. Demographics and patient characteristics according to the diagnosis of PC
|Men (number)||1560 (64.8)||848 (35.2)||–|
|Age* (year)||67 (46–80)||70 (521–80)||0.001|
|Serum PSA* (ng/mL)||6.9 (0.7–43.7)||7.3 (2.8–1240)||0.001|
|Positive DRE (%)||242 (15.5)||228 (26.9)||0.021|
|Serum testosterone* (ng/dL)||459 (127–1071)||422 (148–926)||0.001|
|Prostate volume* (mL)||53 (36–170)||42 (20–116)||0.001|
|Body mass index* (kg/m2)||27.8 (18.7–45.0)||27.7 (19.0–46)||0.524|
|Metabolic syndrome (%)||544 (34.9)||312 (36.6)||0.185|
|Hypolipidaemic treatment (%)||512 (32.8)||232 (27.4%)||0.003|
|Antihypertensive treatment||432 (27.7)||232 (27.4%)||0.450|
|Hypoglycaemic treatment||136 (8.8)||200 (23.4)||0.001|
Table 3 summarizes the characteristics of patients according to the Gleason score distribution. The rate of MS in patients with high grade PC (Gleason score 8–10) was 40.4% while it was 34.8% in patients with low or intermediate grade (Gleason score 2–7), P = 0.013. We also observed a significant increase of age, serum PSA level and BMI in men with high grade PC, and a significant decrease in prostate volume. With respect to drug consumption an increased rate of men treated with hypolipidaemiants was detected in the subset of those diagnosed with high grade PC.
Table 3. Demographics and patient characteristics according to biopsy Gleason score
|Men (number)||608 (71.7)||240 (28.3)||–|
|Age* (year)||69 (52–80)||74 (53–80)||0.001|
|Serum PSA* (ng/mL)||6.1 (2.8–17.4)||14.2 (3.0–1240)||0.001|
|Positive DRE (%)||71 (11.7)||157 (65.4)||0.001|
|Serum testosterone* (ng/dL)||419 (148–745)||439 (206–926)||0.879|
|Prostate volume* (mL)||43 (24–116)||39 (20–78)||0.043|
|Body mass index* (kg/m2)||26.7 (20.7–46.0)||27.8 (19.0–34.8)||0.005|
|Metabolic syndrome (%)||192 (34.8)||120 (40.4)||0.013|
|Hypolipidaemic treatment (%)||135 (24.5)||97 (32.7%)||0.007|
|Antihypertensive treatment||151 (27.4)||81 (27.3%)||0.517|
|Hypoglycaemic treatment||71 (8.4)||41 (4.8)||0.391|
A logistic regression analysis was done in order to find independent predictors of PC risk and high grade tumour risk (Table 4). The presence of MS did not predict the risk of PC detection. The risk of PC detection increased with higher age and serum PSA, as well as with positive DRE. However, the risk of PC detection increased with lower serum testosterone and lower prostate volume. We also observed that hypolipidaemic treatment predicts a decreased risk of PC detection. The risk of high grade PC detection increased in men with MS with an odds ratio of 1.750 and 95% CI 1.260–2.414, P < 0.001. Higher serum PSA level and positive DRE also predicted higher risk of high grade PC detection.
Table 4. Multivariate analysis of predictors to prostate cancer risk (PCR) and to high grade prostate cancer risk (HGPCR)
|Age||1.068 (1.050–1.087)||0.001||1.128 (1.091–1.167)||0.001|
|Serum PSA||1.021 (1.005–1.038)||0.011||1.190 (1.142–1.240)||0.001|
|DRE (positive vs negative)||1.621 (1.012–3.023)||0.023||1.841 (1.217–4.654)||0.001|
|Serum testosterone||0.998 (0.997–0.999)||0.001||1.001 (0.999–1.002)||0.425|
|Prostate volume||0.972 (0.945–0.997)||0.001||0.991 (0.964–1.016)||0.394|
|Body mass index||1.004 (0.974–1.036)||0.785||0.983 (0.938–1.030||0.475|
|Metabolic syndrome (yes vs no)||0.974 (0.809–1.173)||0.785||1.750 (1.260–2.414)||0.001|
|Hypolipidaemic treatment (yes vs no)||0.717 (0.579–0.889)||0.002||1.242 (0.852–1.812)||0.260|
|Antihypertensive (yes vs no)||1.076 (0.883–1.312)||0.465||0.947 (0.667–1.345)||0.762|
|Hypoglycaemic treatment (yes vs no)||0.983 (0.752–1.286)||0.902||0.748 (0.456–1.227)||0.250|
MS is considered the main threat to public health in the 21st century and it is associated with an increased risk of cardiovascular disease . Obesity and physical inactivity are risk factors for the development of MS , and it is well known that obese individuals are more likely to develop insulin resistance than are non-obese individuals. Insulin resistance predisposes these individuals to metabolic risk factors such as elevated serum triglycerides, reduced HDL levels, elevated fasting glucose levels and high blood pressure . MS does not manifest itself uniformly in all populations. It is highly variable among ethnicities, and lifestyle, age and sex also affect the associated risk of its development . In our study we observed a 35.5% prevalence of MS which is in the range of the prevalence observed in the aging male population and almost the same prevalence as observed in a similar study of 195 men at risk of PC scheduled for prostate biopsy . The association between age-related androgen deficiency and MS is well established . As expected, we also found a lower level of serum testosterone and higher BMI in men with MS .
In the present study we did not observe an association between MS and the risk of PC detection. Data on the association between MS and PC are controversial, with studies mostly performed in Scandinavian countries [6, 7, 11], in the USA [8-10] and recently in Italy . The results from the Finland and Italy studies [6, 7, 22] suggest that men with MS have at least a 50% higher risk of being diagnosed with PC. However, the studies performed in the USA [8, 9] reveal an inverse association between MS and PC risk. In fact men diagnosed with MS had a 23% reduction in PC risk, although this inverse association was not confirmed in another study among African-American men. In a recent study, based on 195 men scheduled for prostate biopsy, no relationship between MS and the risk of PC detection was observed . From our point of view, a critical aspect in investigating the association between MS and PC risk is to consider the influence of drug treatments related to the compounds of MS on prostate carcinogenesis. To our knowledge this aspect has never been considered in studies that analyse the association between MS and PC. However, we have observed a lower probability of PC detection in men on hypolipidaemiants. We remember that most of the hypolipidaemic treatments are statins and their influence in prostate carcinogenesis is also under debate .
The relationship of MS and tumour aggressiveness has not been studied previously. To analyse this aspect using our own information we decided to establish as dependent variables the clinical stage, the Gleason score and the risk of biochemical recurrence after primary treatment. In men with MS we observed a tendency to detect more advanced tumours as well as a higher rate of patients with a high risk of biochemical recurrence after the primary treatment and a significant increase of high grade tumours (Gleason score 8–10). DeNunzio et al.  have suggested that MS could be associated with more aggressive tumours based on their analysis. They found a greater risk of high grade tumours, defined by a Gleason score ≥7. Unfortunately they could not associate MS with Gleason score 8–10 because of the limited number of patients. Our results support the hypothesis that MS is associated with a significant increase of high grade tumours. In our population, the probability of being diagnosed with high grade PC was 1.7 higher in men with MS compared with men without MS.
According to the results of the present study it appears that MS does not increase the risk of PC detection but it increases the risk of high grade tumour detection. However, we find some limitations in our study. It only reflects the findings in a cohort of Mediterranean men at risk of PC, and therefore these results cannot be extrapolated to the overall population. We have no information about the incidence of PC in men who were not scheduled for prostrate biopsy. Although the influence of MS on PSA levels is unknown, some treatments like statins may reduce serum PSA levels . Therefore an unknown number of men on statins will not be scheduled for prostate biopsy because of a normal serum PSA. The conclusion that MS is associated with more aggressive tumours also has many limitations. We observed higher PSA levels in men with MS as well as a relationship between PSA and high grade tumours; therefore this association could be a bias in the interpretation that MS is associated with high grade tumours. Although we have observed an increase in the rate of high grade tumours in men with MS, this finding should be confirmed in radical prostatectomy specimens. Again, the influence of statins could mask the results that would support this conclusion . Finally, any analysis should consider the influence of many factors such as lifestyle, toxic habits, diet and treatments that can influence prostate carcinogenesis. Because MS is associated with age-related hypogonadism, it will be difficult to clarify whether these findings reflect the association between testosterone levels and PC. Perhaps a practical consequence for urologists is to consider that men with MS have greater risk of harbouring aggressive tumours.
In summary, MS is a frequent disorder in men at risk of PC detection. MS seems not be associated with an increase in the risk of PC detection in men scheduled for prostate biopsy; however, MS seems to increase the risk of more aggressive tumour detection.
Conflict of Interest