Bruce Bracken

The effect of finasteride in men with benign prostatic hyperplasia

Background Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. Methods In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. Results As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. Conclusions The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

The Effect of Finasteride in Men with Benign Prostatic Hyperplasia

BACKGROUND Benign prostatic hyperplasia is a progressive, androgen-dependent disease resulting in enlargement of the prostate gland and urinary obstruction. Preventing the conversion of testosterone to its tissue-active form, dihydrotestosterone, by inhibiting the enzyme 5 alpha-reductase could decrease the action of androgens in their target tissues; in the prostate the result might be a decrease in prostatic hyperplasia and therefore in symptoms of urinary obstruction. METHODS In a double-blind study, we evaluated the effect of two doses of finasteride (1 mg and 5 mg) and placebo, each given once daily for 12 months, in 895 men with prostatic hyperplasia. Urinary symptoms, urinary flow, prostatic volume, and serum concentrations of dihydrotestosterone and prostate-specific antigen were determined periodically during the treatment period. RESULTS As compared with the men in the placebo group, the men treated with 5 mg of finasteride per day had a significant decrease in total urinary-symptom scores (P less than 0.001), an increase of 1.6 ml per second (22 percent, P less than 0.001) in the maximal urinary-flow rate, and a 19 percent decrease in prostatic volume (P less than 0.001). The men treated with 1 mg of finasteride per day did not have a significant decrease in total urinary-symptom scores, but had an increase of 1.4 ml per second (23 percent) in the maximal urinary-flow rate, and an 18 percent decrease in prostatic volume. The men given placebo had no changes in total urinary-symptom scores, an increase of 0.2 ml per second (8 percent) in the maximal urinary-flow rate, and a 3 percent decrease in prostatic volume. The frequency of adverse effects in the three groups was similar, except for a higher incidence of decreased libido, impotence, and ejaculatory disorders in the finasteride-treated groups. CONCLUSIONS The treatment of benign prostatic hyperplasia with 5 mg of finasteride per day results in a significant decrease in symptoms of obstruction, an increase in urinary flow, and a decrease in prostatic volume, but at a slightly increased risk of sexual dysfunction.

Long-term (7 to 8-year) experience with finasteride in men with benign prostatic hyperplasia

OBJECTIVES To evaluate the effects of finasteride, a specific type II 5-alpha-reductase inhibitor, on symptoms of benign prostatic hyperplasia, prostate volume, and urinary flow during a 7 to 8-year period. METHODS A total of 190 men with symptomatic benign prostatic hyperplasia and enlarged prostates entered one of two Phase II double-blind 3 to 6-month studies. Of these, 156 patients continued taking open-label finasteride, and more than 70 patients completed 7 to 8 years of treatment. The symptoms were scored using a patient self-administered modified Boyarsky symptom questionnaire. Prostate volume was measured by magnetic resonance imaging or ultrasonography, and the maximal urinary flow rate was assessed noninvasively. RESULTS Treatment with finasteride for 7 to 8 years led to sustained improvement in symptoms, reduction in prostate volume (28% from baseline), and increased urinary flow (median 2.5 mL/s from baseline). Decreases in dihydrotestosterone (86%) and prostate-specific antigen (54%) levels were also maintained. Long-term finasteride treatment was safe and generally well tolerated. CONCLUSIONS Long-term treatment with finasteride was well tolerated and resulted in durable symptom relief and improvement in prostate volume and urinary flow.

Proscar: five-year experience

We assessed the long-term safety and efficacy of finasteride, an orally active 5 alpha-reductase inhibitor, in 2 previously reported groups of patients with symptomatic benign prostatic hyperplasia (BPH). Prostate volume was measured by magnetic resonance imaging, and the maximum urinary flow rate was assessed noninvasively. Symptoms were scored utilizing a patient self-administered symptom score questionnaire. Total symptom scores ranged from 0 (or asymptomatic) to 35 (severely symptomatic). After an initial double-blind period, the patients in study 1 were treated with 10 mg finasteride for 1 year and then switched to 5 mg finasteride for an additional 4 years, whereas patients in study 2 were treated with 5 mg finasteride for the entire 5 years. A total of 190 patients were randomized in the double-blind studies, 156 entered year 1 of the open extension and 70 patients completed 5 years of finasteride therapy. In both studies prostate volume was reduced from baseline by 30%, dihydrotestosterone was reduced by 72%, and the maximum urinary flow rate improved by approximately 1.5 ml/s. Prostate-specific antigen was decreased by approximately 50%. Finasteride was well tolerated; approximately 10% of patients reported sexual adverse experiences during the 5-year study period, which were considered drug related by the investigators. The incidence in reporting sexual adverse experiences did not increase with the increased duration of treatment: findings consistent with previous reports. In summary treatment of BPH with finasteride for 5 years inhibits the progression of the disease with an excellent safety profile and represents a low-risk medical option for the treatment of symptomatic BPH.

A Duplex Quantitative Polymerase Chain Reaction Assay Based on Quantification of α-Methylacyl-CoA Racemase Transcripts and Prostate Cancer Antigen 3 in Urine Sediments Improved Diagnostic Accuracy for Prostate Cancer

PURPOSE Most men with increased serum prostate specific antigen and negative biopsy require repeat biopsy because of the lack of a sensitive and specific prostate cancer detection test. In this study we evaluated the diagnostic potential of a duplex assay for prostate cancer by quantifying transcript levels of alpha-methylacyl-CoA racemase and prostate cancer antigen 3 in urine sediments following prostatic massage. MATERIALS AND METHODS Urine sediments from 92 patients, 43 with and 49 without prostate cancer, were collected after digital rectal examination. Transcript levels of AMACR, PCA3 and PSA in total RNA isolated from these samples were determined by absolute quantitative real-time polymerase chain reaction. AMACR and PCA3 scores were obtained by normalizing the transcript level to that of prostate specific antigen for each sample and multiplying by 100. RESULTS AMACR (p = 0.006) and PCA3 (p = 0.014) scores, but not serum prostate specific antigen (p = 0.306), distinguished specimens from patients with prostate cancer from specimens from patients without prostate cancer, and ROC analysis established the diagnostic cutoff scores for the AMACR and PCA3 tests at 10.7 and 19.9, respectively. As determined from these cutoff scores the AMACR test had 70% (95% CI 56-83) sensitivity and 71% (95% CI 59-84) specificity, whereas the PCA3 test had 72% (95% CI 59-85) sensitivity and 59% (95% CI 45-73) specificity for prostate cancer detection. The combined use of AMACR and PCA3 scores in a dual marker test increased sensitivity to 81% (95% CI 70-93) and specificity to 84% (95% CI 73-94). CONCLUSIONS Urinary AMACR and PCA3 tests were superior to a serum prostate specific antigen test for detecting prostate cancer. Their combined use in a dual marker test further improved sensitivity and accuracy, and could serve as a surveillance test after repeat negative prostate biopsies.

Exposure to Bisphenol A Correlates with Early-Onset Prostate Cancer and Promotes Centrosome Amplification and Anchorage-Independent Growth In Vitro

Human exposure to bisphenol A (BPA) is ubiquitous. Animal studies found that BPA contributes to development of prostate cancer, but human data are scarce. Our study examined the association between urinary BPA levels and Prostate cancer and assessed the effects of BPA on induction of centrosome abnormalities as an underlying mechanism promoting prostate carcinogenesis. The study, involving 60 urology patients, found higher levels of urinary BPA (creatinine-adjusted) in Prostate cancer patients (5.74 µg/g [95% CI; 2.63, 12.51]) than in non-Prostate cancer patients (1.43 µg/g [95% CI; 0.70, 2.88]) (p = 0.012). The difference was even more significant in patients <65 years old. A trend toward a negative association between urinary BPA and serum PSA was observed in Prostate cancer patients but not in non-Prostate cancer patients. In vitro studies examined centrosomal abnormalities, microtubule nucleation, and anchorage-independent growth in four Prostate cancer cell lines (LNCaP, C4-2, 22Rv1, PC-3) and two immortalized normal prostate epithelial cell lines (NPrEC and RWPE-1). Exposure to low doses (0.01–100 nM) of BPA increased the percentage of cells with centrosome amplification two- to eight-fold. Dose responses either peaked or reached the plateaus with 0.1 nM BPA exposure. This low dose also promoted microtubule nucleation and regrowth at centrosomes in RWPE-1 and enhanced anchorage-independent growth in C4-2. These findings suggest that urinary BPA level is an independent prognostic marker in Prostate cancer and that BPA exposure may lower serum PSA levels in Prostate cancer patients. Moreover, disruption of the centrosome duplication cycle by low-dose BPA may contribute to neoplastic transformation of the prostate.

α-Methylacyl-CoA Racemase Spliced Variants and Their Expression in Normal and Malignant Prostate Tissues

OBJECTIVES To evaluate the possibility of using α-methylacyl-CoA racemase (AMACR) variants to improve the specificity of prostate cancer (CaP) detection. AMACR has been used as a diagnostic biomarker for CaP and is now a standard biomarker for needle biopsy specimens with ambiguous lesions. METHODS We used in silico analysis and molecular cloning to discover new AMACR variants and quantitative reverse transcription-polymerase chain reaction (RT-PCR) to measure the transcript levels of AMACR and its variants in 4 prostate cell lines and in 23 pairs of CaP and adjacent normal tissue. RESULTS We found 4 novel variants, IAs, IBL, IBLd, and IBLi. Transcript levels of most AMACR variants were significantly upregulated in CaP compared with its adjacent normal counterparts. A variants, the functional variants based on bioinformatic analysis, showed levels of transcript expression in CaP in this order: IA≫IAd=IIA≫IIAs>IAs. In contrast, the expression of the B variants, which appear to be nonfunctional due to the absence of exon 3, was lower than that of the A variants. IB was the most abundant form of B variant; and expression of IIB was negligible. More important, the difference between levels of variant IA, IAd, IIA, IIAs, IB, and IBLi in CaP and normal tissue was significantly higher than the difference in levels of total AMACR. CONCLUSIONS Our data suggest that AMACR variants have better power than total AMACR in discriminating between CaP and adjacent normal tissue. These findings may be useful for the development of future diagnostic assays.

Impact of Oxidative Stress Biomarkers and Carboxymethyllysine (an Advanced Glycation End Product) on Prostate Cancer: A Prospective Study

OBJECTIVE Biomarkers of oxidative stress and advanced glycation end products (AGE) have been linked to the development of prostate cancer, but evidence from human studies is scarce or controversial. METHODS We conducted a prospective nested case-control study among 48 men (24 prostate cancer cases and 24 controls) aged 48 to 76 years at baseline. The participants of our study were a part of the Fernald Community Cohort. Prostate cancer cases and controls were matched individually on age (± 3 years) with a 1:1 ratio. Biomarkers included urine F2-isoprostanes (markers of lipid oxidation), plasma fluorescent oxidation products (markers of global oxidation), and carboxymethyllysine (CML) (a major end-stage AGE). RESULTS At baseline, cases had similar age, body mass index, proportion of family history of prostate cancer, history of benign prostatic hyperplasia, history of hypertension, history of diabetes, number of smokers, and plasma glucose levels compared with controls. Levels of plasma CML were significantly higher in cases than in controls (182 vs. 152 μg/mL, P < .05). In the conditional logistic regression model, an increase in CML equivalent to 1 standard deviation was associated with an increased risk of incident prostate cancer (relative risk, 1.79; 95% confidence interval, 1.00-3.21) and accounted for approximately 8% variance of prostate cancer liability. Urine F2-isoprostanes and plasma fluorescent oxidation products were not associated with prostate cancer incidence. CONCLUSIONS Higher levels of plasma CML were associated with increased risk of prostate cancer. This suggests a potential new pathway for prostate cancer prediction and treatment.