Statin use linked with a decrease in the conversion from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer.

The roles of obesity, metabolic dysregulation and systemic inflammation to advance prostate carcinogenesis are unclear. This study investigates metabolic and inflammatory factors in the transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PC). We prospectively followed 160 men diagnosed with HGPIN at biopsy and therefore at high-risk and clinically monitored for PC. Analyses investigated body mass index (BMI), waist circumference, waist-hip ratio (WHR), height, fat mass, lean mass percent body fat, NSAIDs, statins, metformin, diabetes, hypertension, hypercholesterolemia representing metabolic dysregulation on the risk of a PC diagnosis during follow-up. Systemic inflammation was estimated through measurement of 13 plasma cytokine levels. Statin use was significantly linked with overall PC at follow-up [odds ratio (OR) = 0.45, (0.23, 0.91), P = 0.03], with a somewhat stronger link with high-grade [OR = 0.39, (0.15, 1.04), P = 0.06] PC compared with low-grade PC [OR = 0.50, (0.23, 1.12), P = 0.09]. Non-statin cholesterol-lowering medications, BMI, WHR, diabetes, hypertension and percent body fat were not significantly associated with PC. Although blood IL-12p70, IL-2 and IL-1ß levels were significantly lower among statin users, inflammatory markers were not significantly linked with PC and did not explain the observed relationship between statins and lower PC risk. In summary, this prospective study of HGPIN patients at high risk for PC finds that statin use was significantly associated with reduced risk of PC detection at follow-up. Systemic markers of inflammation did not mediate this association, suggesting that statins affect PC progression through alternative pathways.

Molecular correlates in urine for the obesity and prostatic inflammation of BPH/LUTS patients.

PURPOSE: Benign prostatic hyperplasia (BPH) is strongly associated with obesity and prostatic tissue inflammation, but the molecular underpinning of this relationship is not known. Here, we examined the association between urine levels of chemokines/adipokines with histological markers of prostate inflammation, obesity, and lower urinary tract symptoms LUTS in BPH patients. METHODS: Frozen urine specimens from 207 BPH/LUTS patients enrolled in Nashville Men's Health Study were sent for blinded analysis of 11 analytes, namely sIL-1RA, CXC chemokines (CXCL-1, CXCL-8, CXCL-10), CC chemokines (CCL2, CCL3, CCL5), PDGF-BB, interleukins IL-6, IL-17, and sCD40L using Luminex™ xMAP® technology. After adjusting for age and medication use, the urine levels of analytes were correlated with the scales of obesity, prostate inflammation grade, extent, and markers of lymphocytic infiltration (CD3 and CD20) using linear regression. RESULTS: sIL-1RA levels were significantly raised with higher BMI, waist circumference and waist-hip ratio in BPH patients after correction for multiple testing (P = 0.02). Men with greater overall extent of inflammatory infiltrates and maximal CD3 infiltration were marginally associated with CXCL-10 (P = 0.054) and CCL5 (P = 0.054), respectively. CCL3 in 15 patients with moderate to severe grade inflammation was marginally associated with maximal CD20 infiltration (P = 0.09), whereas CCL3 was undetectable in men with mild prostate tissue inflammation. There was marginal association of sCD40L with AUA-SI scores (P = 0.07). CONCLUSIONS: Strong association of sIL-1RA in urine with greater body size supports it as a major molecular correlate of obesity in the urine of BPH patients. Increased urine levels of CXCL-10, CCL5, and CCL3 were marginally associated with the scores for prostate tissue inflammation and lymphocytic infiltration. Overall, elevated urinary chemokines support that BPH is a metabolic disorder and suggest a molecular link between BPH/LUTS and prostatic inflammation.

Genetic Determinants of Metabolism and Benign Prostate Enlargement: Associations with Prostate Volume.

Prostate enlargement leading to clinical benign prostatic hyperplasia (BPH) is associated with metabolic dysregulation and obesity. The genetic basis of this association is unclear. Our objective was to evaluate whether single nucleotide polymorphisms (SNPs) previously associated with metabolic disorders are also associated with prostate volume (PV). Participants included 876 men referred for prostate biopsy and found to be prostate cancer free. PV was measured by transrectal ultrasound. Samples were genotyped using the Illumina Cardio-MetaboChip platform. Multivariable adjusted linear regression models were used to evaluate SNPs (additive coding) in relation to natural-log transformed (log) PV. We compared SNP-PV results from biopsy-negative men to 442 men with low-grade prostate cancer with similar levels of obesity and PV. Beta-coefficients from the discovery and replication samples were then aggregated with fixed effects inverse variance weighted meta-analysis. SNP rs11736129 (near the pseudo-gene LOC100131429) was significantly associated with log-PV (beta: 0.16, p-value 1.16x10(-8)) after adjusting for multiple testing. Other noteworthy SNPs that were nominally associated (p-value < 1x10(-4)) with log-PV included rs9583484 (intronic SNP in COL4A2), rs10146527 (intronic SNP in NRXN3), rs9909466 (SNP near RPL32P31), and rs2241606 (synonymous SNP in SLC12A7). We found several SNPs in metabolic loci associated with PV. Further studies are needed to confirm our results and elucidate the mechanism between these genetic loci, PV, and clinical BPH.

Urine chemokines indicate pathogenic association of obesity with BPH/LUTS.

OBJECTIVES: High prevalence of lower urinary tract symptoms (LUTS) consistent with benign prostate hyperplasia (BPH) is associated with obesity and prostatic inflammation. Here, we investigated whether chemokines associated with obesity and prostatic inflammation can be measured in normally voided urine of BPH/LUTS patients to demonstrate the mechanistic association between obesity and BPH/LUTS. METHODS: Frozen urine specimens of BPH/LUTS patients enrolled in the Nashville Men's Health Study were sent for blinded analysis to University of Pittsburgh. Thirty patients were blocked by their AUA-SI (>7 or ≤7) and prostatic enlargement (<40, 40-60, >60 cc). Clinical parameters including age, prostate size, and medications were derived from chart review. CXC chemokines (CXCL-1, CXCL-8, and CXCL-10), CC chemokines (CCL2 and CCL3), and sIL-1ra were measured in thawed urine using Luminex™ xMAP(®) technology and ELISA for NGF. RESULTS: Urinary CCL2 levels were several fold higher compared with the other six proteins, of which CCL3 was detectable in less than one-fourth of patients. Urine levels of sIL-1ra and CXCL-8 were significantly associated with increasing BMI and waist circumference in BPH patients. CXCL-8 showed a marginal association with overall AUA-SI scores, as well as obstructive (p = 0.08) symptom subscores. Prostate volume was inversely and marginally associated with urinary CXCL-10 (p = 0.09). CONCLUSIONS: Urine levels of CXCL-8, CXCL-10, and sIL-1ra were associated with varying degrees with LUTS severity, prostate size, and obesity, respectively. These findings in urine are consistent with past studies of chemokine levels from expressed prostatic secretions and demonstrate the potential of noninvasively measured chemokine in urine to objectively classify BPH/LUTS patients.

Association between physical activity, lower urinary tract symptoms (LUTS) and prostate volume.

OBJECTIVES: To determine the association between lower urinary tract symptoms (LUTS) severity and physical activity (PA) across workplace, home, and leisure domains. To determine the mediating role of prostate enlargement on LUTS severity and PA. PATIENTS AND METHODS: The study included 405 men without prostate cancer or prostatic intraepithelial neoplasia. LUTS severity was ascertained using the American Urological Association Symptom Index and prostate size by ultrasonography. PA was assessed using validated questionnaires, with conversion to metabolic equivalent of task (MET)-h/week to estimate leisure-time PA energy expenditure. Analysis used multivariable linear regression, controlling for body mass index (BMI), age, race, and treatment for benign prostatic hyperplasia, cardiovascular disease and diabetes. RESULTS: Higher leisure-time PA energy expenditure and light housework activities were significantly associated with lower LUTS severity. Prostate volume was not significantly associated with PA in adjusted analyses, and controlling for prostate volume did not affect the association between LUTS severity and PA. Stratification by BMI showed a moderate interaction (P = 0.052), suggesting that PA was more strongly associated with LUTS severity among obese men. CONCLUSIONS: In this cross-sectional analysis, leisure-time and home-time PA was inversely associated with LUTS severity. The association between PA and LUTS severity was stronger for irritative symptoms and among obese men, and was not mediated through changes in prostate size. Our results indicate the need for further detailed investigation of PA and LUTS.

Obesity, body composition, and prostate cancer.

BACKGROUND: Established risk factors for prostate cancer have not translated to effective prevention or adjuvant care strategies. Several epidemiologic studies suggest greater body adiposity may be a modifiable risk factor for high-grade (Gleason 7, Gleason 8-10) prostate cancer and prostate cancer mortality. However, BMI only approximates body adiposity, and may be confounded by centralized fat deposition or lean body mass in older men. Our objective was to use bioelectric impedance analysis (BIA) to measure body composition and determine the association between prostate cancer and total body fat mass (FM) fat-free mass (FFM), and percent body fat (%BF), and which body composition measure mediated the association between BMI or waist circumference (WC) with prostate cancer. METHODS: The study used a multi-centered recruitment protocol targeting men scheduled for prostate biopsy. Men without prostate cancer at biopsy served as controls (n = 1057). Prostate cancer cases were classified as having Gleason 6 (n = 402), Gleason 7 (n = 272), or Gleason 8-10 (n = 135) cancer. BIA and body size measures were ascertained by trained staff prior to diagnosis, and clinical and comorbidity status were determined by chart review. Analyses utilized multivariable linear and logistic regression. RESULTS: Body size and composition measures were not significantly associated with low-grade (Gleason 6) prostate cancer. In contrast, BMI, WC, FM, and FFM were associated with an increased risk of Gleason 7 and Gleason 8-10 prostate cancer. Furthermore, BMI and WC were no longer associated with Gleason 8-10 (OR(BMI) = 1.039 (1.000, 1.081), OR(WC) = 1.016 (0.999, 1.033), continuous scales) with control for total body FFM (OR(BMI) = 0.998 (0.946, 1.052), OR(WC) = 0.995 (0.974, 1.017)). Furthermore, increasing FFM remained significantly associated with Gleason 7 (OR(FFM) = 1.030 (1.008, 1.052)) and Gleason 8-10 (OR(FFM) = 1.044 (1.014, 1.074)) after controlling for FM. CONCLUSIONS: Our results suggest that associations between BMI and WC with high-grade prostate cancer are mediated through the measurement of total body FFM. It is unlikely that FFM causes prostate cancer, but instead provides a marker of testosterone or IGF1 activities involved with retaining lean mass as men age.

Blood magnesium, and the interaction with calcium, on the risk of high-grade prostate cancer.

BACKGROUND: Ionized calcium (Ca) and magnesium (Mg) compete as essential messengers to regulate cell proliferation and inflammation. We hypothesized that inadequate Mg levels, perhaps relative to Ca levels (e.g. a high Ca/Mg ratio) are associated with greater prostate cancer risk. STUDY DESIGN: In this biomarker sub-study of the Nashville Men's Health Study (NMHS), we included 494 NMHS participants, consisting of 98 high-grade (Gleason≥7) and 100 low-grade cancer cases, 133 prostate intraepithelial neoplasia (PIN) cases, and 163 controls without cancer or PIN at biopsy. Linear and logistic regression were used to determine associations between blood Ca, Mg, and the Ca/Mg ratio across controls and case groups while adjusting for potential confounding factors. RESULTS: Serum Mg levels were significantly lower, while the Ca/Mg ratio was significantly higher, among high-grade cases vs. controls (p = 0.04, p = 0.01, respectively). Elevated Mg was significantly associated with a lower risk of high-grade prostate cancer (OR = 0.26 (0.09, 0.85)). An elevated Ca/Mg ratio was also associated with an increased risk of high-grade prostate cancer (OR = 2.81 (1.24, 6.36) adjusted for serum Ca and Mg). In contrast, blood Ca levels were not significantly associated with prostate cancer or PIN.Mg, Ca, or Ca/Mg levels were not associated with low-grade cancer, PIN, PSA levels, prostate volume, or BPH treatment. CONCLUSION: Low blood Mg levels and a high Ca/Mg ratio were significantly associated with high-grade prostate cancer. These findings suggest Mg affects prostate cancer risk perhaps through interacting with Ca.

The associations between statin use and prostate cancer screening, prostate size, high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer.

OBJECTIVE: Prior studies report statins may reduce the risk of advanced prostate cancer. This study investigates the association between statin use and the likelihood of having a PSA or DRE test, blood PSA levels, prostate volume, and the severity of lower urinary tract symptoms. We also describe the association between statin use and prostate cancer and high-grade prostatic intraepithelial neoplasia (PIN) before and after controlling for prostate cancer screening indices associated with statin use. METHODS: The Nashville Men's Health Study used a multicenter, rapid recruitment protocol to collect clinical, biologic, behavioral, and body measurement data from 2,148 men 40 years or older scheduled for diagnostic prostate biopsy. Medication use and other data were ascertained by research survey, clinical interview, and chart review. RESULTS: Approximately 37% of participants were taking a statin. Statin use was significantly associated with a 12% lower PSA levels and 8% smaller prostate volume after controlling for age, race, BMI, WHR, aspirin use, and other comorbidity. Simvastatin was more strongly associated with prostate volume, while atorvastatin was associated with PSA. Statin use was marginally associated with increasing PSA test frequency among men with undiagnosed cancer. Statin use was not associated with the frequency or results of digital rectal exams, lower urinary tract symptom severity, high-grade (Gleason > 6) prostate cancer (OR = 0.95 (0.73, 1.24)), low-grade (Gleason = 6) prostate cancer (OR = 1.11 (0.86, 1.42)) or PIN (OR = 0.82, (0.57, 1.17)). Additional control for the number of prior PSA tests, PSA levels, and prostate volume did not alter these results. CONCLUSION: These results suggest selective referral for biopsy associated with statin use is an essential element to address in further understanding the potential for statins to prevent prostate cancer.

Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume.

PURPOSE: Nonsteroidal anti-inflammatory drugs such as aspirin prevent cardiovascular disease and several prior studies suggest that nonsteroidal anti-inflammatory drugs also decrease prostate inflammation and prostate cancer risk. We investigated the association between nonsteroidal anti-inflammatory drug use, prostate specific antigen and prostate volume, hypothesizing that there would be lower prostate specific antigen and prostate volume with nonsteroidal anti-inflammatory drug use. MATERIALS AND METHODS: The Nashville Men's Health Study uses a multicenter, rapid recruitment protocol to collect clinical, biological, behavioral and body measurement data on 1,277 men older than 40 years who are scheduled for diagnostic prostate biopsy. Nonsteroidal anti-inflammatory drug use was ascertained by survey and clinical interview. Medical charts were reviewed to ascertain current prostate specific antigen, prostate volume and clinical diagnoses following biopsy. RESULTS: Approximately 46% of patients reported receiving nonsteroidal anti-inflammatory drugs, primarily aspirin (37%). After adjusting for age, race and other factors prostate volume was similar between aspirin users and nonusers (47.6 vs 46.0 ml, p = 0.16). In contrast, prostate specific antigen was significantly lower in aspirin users (7.3 vs 8.0 ng/ml, p = 0.01). The association between prostate specific antigen and aspirin was significant in men with latent prostate cancer (6.1 vs 7.3 ng/ml, p <0.01), marginal in patients with high grade prostatic intraepithelial neoplasia (5.0 vs 5.9 ng/ml, p = 0.09) and nonsignificant in those with a negative biopsy (5.6 vs 5.7 ng/ml, p = 0.64). The strongest prostate specific antigen-aspirin association was in men with cancer and a prostate volume of 60 ml or more (7.3 vs 12.7 ng/ml, p <0.01). CONCLUSIONS: Prostate specific antigen was significantly lower in aspirin users with latent cancer. Prostate volume was not associated with nonsteroidal anti-inflammatory drug use. Results suggest that aspirin may affect prostate cancer detection, suggesting a potential detection bias to address in future studies of nonsteroidal anti-inflammatory drugs and prostate cancer prevention.

Prostate volume modifies the association between obesity and prostate cancer or high-grade prostatic intraepithelial neoplasia.

The relationship between obesity and prostate cancer remains unclear. We investigated the effect of prostate volume on the obesity and prostate cancer association. With a multi-centered, rapid-recruitment protocol, weight and body size measurements were collected prior to diagnosis, and medical charts were reviewed for pathology results (n = 420 controls, 119 high-grade prostatic intraepithelial neoplasia (PIN) cases, and 286 cancer cases (41% Gleason > 6). In multivariable logistic regression models adjusting for age, PSA levels and history, DRE results, and number of cores at biopsy, the association between BMI and cancer was restricted to men with a smaller prostate volume (volume < 40 cm(3): OR(BMI > or = 30) = 2.17 (1.09, 4.32), p (trend) = 0.02; volume > or = 40 cm(3): OR(BMI > or = 30) = 0.77 (0.34, 1.77), p (trend) = 0.17; p (interaction) = 0.03). Similarly, the WHR and PIN association was significantly modified by prostate volume (volume < 40 cm(3): OR((WHR: Tertile 3 vs. T1)) = 3.76 (1.54, 9.21) (p (trend) < 0.01); volume > or = 40 m(3): OR((WHR: T3 vs. T1)) = 0.63 (0.32, 1.23) (p (trend) = 0.17); p (interaction) < 0.01). In conclusion, prostate volume acts as a modifier, and BMI and WHR are significantly associated with prostate cancer or PIN, respectively, in the absence of biopsy sampling error derived from obesity-related prostate enlargement.