J. Kellogg Parsons

Effect of Selenium and Vitamin E on Risk of Prostate Cancer and Other Cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT)

CONTEXT Secondary analyses of 2 randomized controlled trials and supportive epidemiologic and preclinical data indicated the potential of selenium and vitamin E for preventing prostate cancer. OBJECTIVE To determine whether selenium, vitamin E, or both could prevent prostate cancer and other diseases with little or no toxicity in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS A randomized, placebo-controlled trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) of 35,533 men from 427 participating sites in the United States, Canada, and Puerto Rico randomly assigned to 4 groups (selenium, vitamin E, selenium + vitamin E, and placebo) in a double-blind fashion between August 22, 2001, and June 24, 2004. Baseline eligibility included age 50 years or older (African American men) or 55 years or older (all other men), a serum prostate-specific antigen level of 4 ng/mL or less, and a digital rectal examination not suspicious for prostate cancer. INTERVENTIONS Oral selenium (200 microg/d from L-selenomethionine) and matched vitamin E placebo, vitamin E (400 IU/d of all rac-alpha-tocopheryl acetate) and matched selenium placebo, selenium + vitamin E, or placebo + placebo for a planned follow-up of minimum of 7 years and a maximum of 12 years. MAIN OUTCOME MEASURES Prostate cancer and prespecified secondary outcomes, including lung, colorectal, and overall primary cancer. RESULTS As of October 23, 2008, median overall follow-up was 5.46 years (range, 4.17-7.33 years). Hazard ratios (99% confidence intervals [CIs]) for prostate cancer were 1.13 (99% CI, 0.95-1.35; n = 473) for vitamin E, 1.04 (99% CI, 0.87-1.24; n = 432) for selenium, and 1.05 (99% CI, 0.88-1.25; n = 437) for selenium + vitamin E vs 1.00 (n = 416) for placebo. There were no significant differences (all P>.15) in any other prespecified cancer end points. There were statistically nonsignificant increased risks of prostate cancer in the vitamin E group (P = .06) and type 2 diabetes mellitus in the selenium group (relative risk, 1.07; 99% CI, 0.94-1.22; P = .16) but not in the selenium + vitamin E group. CONCLUSION Selenium or vitamin E, alone or in combination at the doses and formulations used, did not prevent prostate cancer in this population of relatively healthy men. TRIAL REGISTRATION clinicaltrials.gov identifier: NCT00006392.

Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

CONTEXT The initial report of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) found no reduction in risk of prostate cancer with either selenium or vitamin E supplements but a statistically nonsignificant increase in prostate cancer risk with vitamin E. Longer follow-up and more prostate cancer events provide further insight into the relationship of vitamin E and prostate cancer. OBJECTIVE To determine the long-term effect of vitamin E and selenium on risk of prostate cancer in relatively healthy men. DESIGN, SETTING, AND PARTICIPANTS A total of 35,533 men from 427 study sites in the United States, Canada, and Puerto Rico were randomized between August 22, 2001, and June 24, 2004. Eligibility criteria included a prostate-specific antigen (PSA) of 4.0 ng/mL or less, a digital rectal examination not suspicious for prostate cancer, and age 50 years or older for black men and 55 years or older for all others. The primary analysis included 34,887 men who were randomly assigned to 1 of 4 treatment groups: 8752 to receive selenium; 8737, vitamin E; 8702, both agents, and 8696, placebo. Analysis reflect the final data collected by the study sites on their participants through July 5, 2011. INTERVENTIONS Oral selenium (200 μg/d from L-selenomethionine) with matched vitamin E placebo, vitamin E (400 IU/d of all rac-α-tocopheryl acetate) with matched selenium placebo, both agents, or both matched placebos for a planned follow-up of a minimum of 7 and maximum of 12 years. MAIN OUTCOME MEASURES Prostate cancer incidence. RESULTS This report includes 54,464 additional person-years of follow-up and 521 additional cases of prostate cancer since the primary report. Compared with the placebo (referent group) in which 529 men developed prostate cancer, 620 men in the vitamin E group developed prostate cancer (hazard ratio [HR], 1.17; 99% CI, 1.004-1.36, P = .008); as did 575 in the selenium group (HR, 1.09; 99% CI, 0.93-1.27; P = .18), and 555 in the selenium plus vitamin E group (HR, 1.05; 99% CI, 0.89-1.22, P = .46). Compared with placebo, the absolute increase in risk of prostate cancer per 1000 person-years was 1.6 for vitamin E, 0.8 for selenium, and 0.4 for the combination. CONCLUSION Dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00006392.

The Correlation Between Metabolic Syndrome and Prostatic Diseases

CONTEXT 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). OBJECTIVE 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. CONCLUSIONS 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.

p63 PROTEIN EXPRESSION IS RARE IN PROSTATE ADENOCARCINOMA: IMPLICATIONS FOR CANCER DIAGNOSIS AND CARCINOGENESIS

OBJECTIVES To examine the expression of the p63 protein in normal, preneoplastic, and neoplastic human prostatic tissue. The p63 gene, a member of the p53 gene family, is expressed in the basal epithelial cells of multiple organs. Irregularities in p63 expression have been associated with epithelial carcinogenesis. METHODS We performed immunohistochemistry with an anti-p63 antibody on specimens from radical prostatectomies, prostate needle biopsies, and metastatic prostate adenocarcinoma. We analyzed p63 expression in regions of normal prostate, benign prostatic hyperplasia, proliferative inflammatory atrophy (PIA), high-grade intraepithelial neoplasia, and adenocarcinoma. RESULTS Basal epithelial cells in normal, benign prostatic hyperplasia, and high-grade intraepithelial neoplasia tissue stained intensely for the p63 polypeptide, but the vast majority of adenocarcinoma specimens from 233 patients-66 (94%) of 70 radical prostatectomies, 132 (89%) of 148 prostate needle biopsies, and 14 (93%) of 15 metastases-did not. In tumors in which the adenocarcinoma cells were positive, the staining intensity was weak and occurred in less than 1% of the cells. Tumors that stained positive for p63 were more likely to be high grade than those that did not (P <0.0001). Basal cells in PIA expressed p63, but these cells were sparsely distributed relative to the basal cells in the normal glands. Luminal cells in PIA were, in general, negative for p63. CONCLUSIONS In contrast to normal and preneoplastic prostatic tissue, the vast majority of prostate adenocarcinomas do not express p63. Therefore, p63 immunohistochemistry represents a potential novel adjuvant method for facilitating the pathologic diagnosis of prostate cancer in prostate needle biopsies. The selective expression of p63 in normal basal cells, coupled with the finding that p63 null mice fail to develop prostates, provides strong evidence that the basal cells represent prostatic epithelial stem cells. In addition, these findings suggest that p63 may protect prostatic epithelial cells against neoplastic transformation and support the hypothesis that intermediately differentiated cells in the luminal epithelium of PIA are the targets of neoplastic transformation in the prostate.

Serum Testosterone and the Risk of Prostate Cancer: Potential Implications for Testosterone Therapy

Objective: A potential risk of testosterone replacement therapy is an increase in the incidence of prostate cancer, but it is unclear whether higher levels of serum testosterone are associated with a higher risk of prostate cancer. We prospectively evaluated serum androgen concentrations and prostate cancer risk. Method: Included were 794 members of the Baltimore Longitudinal Study of Aging. We estimated the rate ratio (RR) of prostate cancer by entering serial measures of serum total testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin, calculated free testosterone, and free testosterone index (FTI) into a Cox proportional hazards regression model with simple updating. Results: Higher calculated free testosterone was associated with an increased age-adjusted risk of prostate cancer {RRs by quartile: 1.00, 1.52 [95% confidence interval (95% CI), 0.93-2.50], 1.16 (95% CI, 0.61-2.20), 2.59 (95% CI, 1.28-5.25); Ptrend = 0.03}, which persisted after excluding measures in men <45 years of age [RRs by quartile: 1.00, 1.33 (95% CI, 0.78-2.25), 1.26 (95% CI, 0.68-2.33), 1.89 (95% CI, 0.99-3.61); Ptrend = 0.03]. Compared to men with eugonadal FTI (≥0.153), men with hypogonadal FTI had a decreased risk of prostate cancer (RR, 0.51; 95% CI, 0.31-0.82). Conclusion: Higher levels of calculated serum free testosterone are associated with an increased risk of prostate cancer. These findings suggest that men receiving testosterone therapy should be regularly monitored for prostate cancer and underscore the need for prospective trials of testosterone therapy incorporating incidence of prostate cancer as a primary safety end point.

Benign Prostatic Hyperplasia and Male Lower Urinary Tract Symptoms: Epidemiology and Risk Factors

The epidemiology of benign prostatic hyperplasia (BPH) and male lower urinary tract symptoms (LUTS) has evolved considerably during the past several years. The term LUTS describes a distinct phenotype and allows for a broad epidemiologic description of urinary symptoms at a population level. Although it is becoming the preferred term for studying urinary symptoms in populations, LUTS remains interconnected with BPH in the literature. The incidence and prevalence of BPH and LUTS are increasing rapidly as the US population ages. BPH and LUTS are associated with serious medical morbidities, an increased risk of falls, depression, diminished health-related quality of life, and billions of dollars in annual health care costs. Although age and genetics play important roles in the etiology of BPH and LUTS, recent insights at the population level have revealed that modifiable risk factors are likely key components as well. Serum dihydrotestosterone, obesity, elevated fasting glucose, diabetes, fat and red meat intake, and inflammation increase the risk; vegetables, regular alcohol consumption, exercise, and NSAIDs decrease the risk.

Obesity and Benign Prostatic Hyperplasia: Clinical Connections, Emerging Etiological Paradigms and Future Directions

PURPOSE Benign prostatic hyperplasia is a highly prevalent disease in older men with substantial adverse effects on public health. Classic etiological paradigms for benign prostatic hyperplasia focus on nonmodifiable risk factors. However, obesity also potentially promotes benign prostatic hyperplasia. MATERIALS AND METHODS We performed a structured, comprehensive literature review to identify studies of obesity, benign prostatic hyperplasia, lower urinary tract symptoms and physical activity. RESULTS A preponderance of published evidence suggests strong positive associations of obesity with benign prostatic hyperplasia and lower urinary tract symptoms. This evidence encompasses most established metrics of adiposity, including body mass index, waist circumference and waist-to-hip ratio, and falls under 3 general categories, including prostate volume, clinical benign prostatic hyperplasia and lower urinary tract symptoms. 1) Prior studies consistently showed that increased adiposity is positively associated with radiographically determined prostate volume and enlargement, suggesting that obesity promotes prostate growth. 2) Most studies revealed that obesity increases the risk of clinical benign prostatic hyperplasia by several measures, including the initiation of benign prostatic hyperplasia medical treatment, noncancer prostate surgery, physician diagnosed benign prostatic hyperplasia, histological diagnosis and urinary flow rate. 3) Prior studies demonstrated that obesity increases the risk of lower urinary tract symptoms, as measured by a validated questionnaire. Also, most studies showed that physical activity significantly decreases the risk of benign prostatic hyperplasia. CONCLUSIONS Obesity markedly increases the risk of benign prostatic hyperplasia. Since physical activity decreases the risk of benign prostatic hyperplasia, these observations support the development of novel prevention strategies and treatment targeted toward adiposity, weight loss and lifestyle.

Lower urinary tract symptoms increase the risk of falls in older men

To evaluate the association of lower urinary tract symptoms (LUTS) with the risk of falls in elderly community‐dwelling men.

Physical Activity, Benign Prostatic Hyperplasia, and Lower Urinary Tract Symptoms

BACKGROUND While some studies have indicated that physical activity may protect against benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS), others have not. OBJECTIVE To evaluate the association of physical activity with BPH and LUTS. DESIGN, SETTING, AND PARTICIPANTS Systematic review and meta-analysis using MEDLINE, the Cochrane Library, EMBASE, and abstracts from the Annual Meeting of the American Urological Association. We selected observational studies that provided empirical data and analyzed abstracted data with random effects models. MEASUREMENTS BPH, LUTS, and physical activity levels. RESULTS AND LIMITATIONS Eleven (n=43 083 men) studies met selection criteria. Eight studies observed inverse, 2 studies null, and 1 study equivocal associations of physical activity with BPH or LUTS. Eight studies (n=35675) were eligible for pooled analyses. We stratified physical activity levels into light, moderate, and vigorous categories, with a sedentary category for reference. Compared to the sedentary group, the pooled odds ratios for BPH or LUTS were 0.70 (95% CI 0.44-1.13, p=0.14), 0.74 (95% CI 0.60-0.92, p=0.005), and 0.74 (95% CI 0.59-0.92, p=0.006) for men engaging in light, moderate, and heavy physical activity, respectively. CONCLUSIONS Physical activity reduces the risks of BPH and LUTS. These findings are consistent with other studies demonstrating that the BPH/LUTS complex is associated with modifiable risk factors of cardiovascular disease and suggest that increased physical activity may prevent or attenuate these conditions.

Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome

OBJECTIVES To examine populations with diagnosed clinical interstitial cystitis (IC) and urethral syndrome and normal controls using the potassium sensitivity test (PST), to determine the incidence of PST-provoked pain and/or urgency, and to document the type and location of IC and urethral syndrome pain, association of pain with sexual intercourse, and family history of female urgency/frequency problems. METHODS The PST and a questionnaire were administered to 466 patients with clinical IC, 116 patients with urethral syndrome, and 42 controls. RESULTS The PST was positive in 78% of patients with clinical IC, in 55% of patients with urethral syndrome, and in 0% of the controls. Of the patients with clinical IC, 9% responded to the PST with pain only and 8% with urgency only. Patients with clinical IC reported the pain as dysuria (58%), urethral/vaginal (76%), above the pubic bone (53%), lower abdomen (47%), lower back (35%), vaginal (51%), and inguinal (28%). The results were similar for patients with urethral syndrome. Of the sexually active men and women, 71% with clinical IC and 59% with urethral syndrome reported pain associated with intercourse. Urgency/frequency problems in female relatives were reported by 35% of patients with IC and 33% of those with urethral syndrome. CONCLUSIONS The significant potassium sensitivity in both patients with clinical IC and those with urethral syndrome and the absence of potassium sensitivity in normal controls indicates that a positive PST suggests the presence of an abnormal bladder epithelium. The lower rate of positive PSTs in patients with urethral syndrome reflects the less severe, more intermittent, nature of the symptoms in urethral syndrome (early IC). Pelvic pain of bladder origin may occur anywhere in the pelvis. Finally, IC appears to have a genetic component.