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Objective To investigate the use of 5α-reductase inhibitors (5ARIs) and α-blockers among men with benign prostatic hyperplasia (BPH) in relation to prostate cancer (PCa) incidence, severity and mortality. Patients and methods A retrospective 20-year cohort study in men residing in Saskatchewan, aged 40-89 years, with a BPH-coded medical claim between 1995 and 2014, was conducted. Cox proportional hazards regression was used to compare incidence of PCa diagnosis, metastatic PCa, Gleason score 8-10 PCa, and PCa mortality among 5ARI users (n = 4 571), α-blocker users (n = 7 764) and non-users (n = 11 677). Results In comparison with both non-users and α-blocker users, 5ARI users had a ~40% lower risk of a PCa diagnosis (11.0% and 11.4% vs 5.8%, respectively), and α-blocker users had an 11% lower risk of a PCa diagnosis compared with non-users. Overall, the incidence of metastatic PCa and PCa mortality was not significantly different among 5ARI or α-blocker users compared with non-users (adjusted hazard ratios [HR] of metastatic PCa: 1.12 and 1.13, respectively, and PCa mortality: 1.11 and 1.18, respectively, P > 0.05 for both drugs), but both 5ARI and a-blocker users had ~30% higher risk of Gleason score 8-10 cancer, adjusted HR 1.37, 95% confidence interval [CI] 1.03-1.82, P = 0.03, and adjusted HR 1.28, 95% CI 1.03-1.59, P = 0.02, respectively compared with non-users. Conclusion The use of 5ARIs was associated with lower risk of PCa diagnosis, regardless of comparison group. Risk of high grade PCa was higher among both 5ARI users and α-blocker users compared with non-users; however, this did not translate into higher risk of PCa mortality.

OBJECTIVES To determine the clinical performance of the urinary prostate cancer antigen 3 (PCA3) test to predict the risk of Gleason grade re-classification amongst men receiving a 5α-reductase inhibitor (5ARI) during active surveillance (AS) for prostate cancer. PATIENTS AND METHODS Patients with low-risk prostate cancer were enrolled in a prospective Phase II study of AS complemented with prescription of a 5ARI. A repeat biopsy was taken within the first year and annually according to physician and patient preference. In all, 90 patients had urine collected after digital rectal examination of the prostate before the first repeat biopsy. The PCA3 test was performed in a blinded manner at a central laboratory. RESULTS Using a PCA3-test score threshold of 35, there was a significant difference (P < 0.001) in the risk of being diagnosed with Gleason ≥7 cancer during a median of 7 years of follow-up. Adjusted Cox regression and Kaplan-Meier analyses also showed a significantly higher risk of upgrading to Gleason ≥7 during follow-up for those with a higher PCA3-test score. CONCLUSION The urinary PCA3 test predicted Gleason grade re-classification amongst patients receiving a 5ARI during AS for low-risk prostate cancer.

Objective To evaluate the associations of non-steroidal anti-inflammatory drug (NSAID) use with risk of erectile dysfunction (ED), considering the indications for NSAID use. Patients and Methods We analysed data from 4 726 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) without evidence of ED at baseline. Incident ED was defined as mild/moderate (decrease in normal function) or severe (absence of function). Proportional hazards models were used to estimate the covariate-adjusted associations of NSAID-related medical conditions and time-dependent NSAID use with ED risk. Results Arthritis (hazard ratio [HR] 1.56), chronic musculoskeletal pain (HR 1.35), general musculoskeletal complaints (HR 1.36), headaches (HR 1.44), sciatica (HR 1.50) and atherosclerotic disease (HR 1.60) were all significantly associated with an increased risk of mild/moderate ED, while only general musculoskeletal complaints (HR 1.22), headaches (HR 1.47) and atherosclerotic disease (HR 1.60) were associated with an increased risk of severe ED. Non-aspirin NSAID use was associated with an increased risk of mild/moderate ED (HR 1.16; P = 0.02) and aspirin use was associated with an increased risk of severe ED (HR 1.16; P = 0.03, respectively). The associations of NSAID use with ED risk were attenuated after controlling for indications for NSAID use. Conclusions The modest associations of NSAID use with ED risk in the present cohort were probably attributable to confounding indications for NSAID use. NSAID use was not associated with ED risk.

Objective To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study. Patients and Methods CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV

Objectives To evaluate hyaluronan-mediated motility receptor (RHAMM) expression in normal, hyperplasic and neoplastic prostate tissue after various types and durations of androgen-deprivation therapy (ADT). Clinical and oncological data from men with localised prostate adenocarcinoma were also assessed and compared with RHAMM expression data. Patients and Methods Data from 367 men who underwent histological evaluation of the prostate were retrospectively evaluated under six conditions: (i) benign prostatic hyperplasia (BPH), (ii) BPH treated with finasteride, (iii) prostate cancer without ADT, (iv) prostate cancer treated with neoadjuvant ADT before prostatectomy (cyproterone 200 mg/day), (v) castration-resistant prostate cancer (CRPC), and (vi) normal peritumoral prostate tissue. Tissue microarrays were constructed and 1354 cores were evaluated for immunohistochemical RHAMM expression. Results There was no RHAMM expression in any tissue from normal patients or those with BPH or prostate cancer without ADT. There was RHAMM expression in 39.4% of prostate cancer tissues treated with ADT and in 46.2% of CRPC samples (P = 0.001). There was a significant increase in RHAMM expression with increased ADT duration in group 4, with a marked increase in RHAMM expression after 6–12 months of ADT (P = 0.04). No prognostic or clinical factors related to prostate cancer were associated with RHAMM expression. Conclusions RHAMM expression in prostate cancer is directly associated with ADT. Significant RHAMM expression occurs as early as after 1 month of ADT and progressively increases with ADT duration. When prostate cancer becomes CRPC, RHAMM expression is higher. RHAMM expression was not associated with prostate cancer prognostic factors. RHAMM overexpression may contribute to the development of hormonal resistance in prostate cancer.

What's known on the subject? and What does the study add? Cerebral lateralization/specialization is a neurophysiological feature that has been documented regarding somatic, psychological and sexual functioning and that may be manifested in differences in hand preference, cognitive style, gonadal hormonal effects and possibly even sexual orientation. In this study we investigated a possible cerebral lateralization effect on sexual response for dihydrotestosterone, using finasteride as a hormone-blocking compound. The results of this study differ substantially from other studies examining the effects of finasteride on sexual response, presumably due to the greater restrictions we placed on defining relevant sexual activity, to our alerting patients to both positive and negative sexual effects and to the fact that we assessed the effects separately in right-handed vs left-handed patients. Handedness, as a proxy for cognitive style and possible lateralization of effect/function, appears to be a relevant factor when considering the sexual effects of specific gonadal hormones. OBJECTIVE • To investigate the relationships between pharmacologically induced deprivation of dihydrotestosterone, sexual arousal, libido and hand preference, by comparing the self-reported sexual response prior to and during reception of the anti-androgen finasteride in men undergoing treatment for male pattern baldness. PATIENTS AND METHOD • In total, 33 sexually healthy Romanian men participated in this study. • Patients prospectively provided information regarding their sexual functioning (over 4 weeks), as measured by the International Index of Erectile Function (IIEF) prior to and after commencing treatment with 1 mg finasteride for male pattern baldness. RESULTS • Overall IIEF scores as well as the erectile function, orgasmic function, sexual desire and overall satisfaction subscales showed group, treatment and group by treatment effects. • The intercourse satisfaction subscale showed group and group by treatment effects. • On most subscales, right-handed men showed no effect or lower sexual function whereas left-handed men reported no effect or improved sexual function, primarily. CONCLUSIONS • These results suggest that the sexual effects of dihydrotestosterone deprivation may depend on handedness – a proxy variable that may represent cognitive style – which lends further support to the idea of two distinct neuroendocrine psychosexual axes. • They further suggest that detection of such sexual effects may be enhanced by using research methodologies and communication strategies that increase patients' sensitization to such effects.

UNLABELLED What's known on the subject? and What does the study add? Finasteride (Proscar) and dutasteride (Avodart) are 5-α reductase inhibitors (5-ARIs) used to treat LUTS in men with benign prostatic enlargement. Because these drugs suppress androgens, the theory has been put forward that 5-ARIs might prevent the development of prostate cancer. Careful analysis of two randomized controlled trials, however, showed that, in the clinical setting, this was not the case, and that these drugs can increase the occurrence of more aggressive high-grade disease. Because of this, the U.S. Food and Drug Administration did not approve 5-ARIs for the primary prevention of prostate cancer and notified healthcare professionals about a change in the 'Warnings and Precautions' for these drugs. Interest remains among some for using 5-ARIs in men diagnosed with very low-risk prostate cancer to delay the progression from clinically indolent disease to clinically significant disease requiring treatment. The present study investigated whether 5-ARI use among men with very low-risk prostate cancer in an active surveillance (AS) programme would reduce the number of cancers reclassified to clinically significant disease on surveillance biopsy. Our results do not support the use of 5-ARIs for slowing or preventing cancer progression in men with low-risk prostate cancer, but do suggest that men with very low-risk prostate cancer who take 5-ARIs for LUTS are unlikely to be at increased risk for the development of high grade disease during AS. OBJECTIVE To determine whether 5-α reductase inhibitor (5-ARI) use delays cancer reclassification in an active surveillance (AS) cohort. PATIENTS AND METHODS We performed a retrospective study of 587 men enrolled in an AS programme, who had no history of 5-ARI use. Chi-squared and t-tests were used to compare characteristics of 5-ARI users and non-users. Univariable and multivariable proportional hazards models, treating 5-ARI use as a time-dependent covariate, were used to evaluate the influence of 5-ARIs on the risk of a subsequent biopsy no longer meeting criteria for continued AS (i.e. reclassification). RESULTS 5-ARI use was initiated in 47 men while on AS. Men using 5-ARIs had larger prostates and higher PSA levels at diagnosis. During 5-ARI use, PSA levels and prostate volume deceased by mean values of 47% and 11%, respectively. Men using 5-ARIs had a mean of 2.5 surveillance biopsies while on the drug. Reclassification occurred in 17% of 5-ARI users compared with 31% of non-users (P = 0.04). Multivariable models (adjusting for age, α-blocker use, PSA level, %free PSA, PSA density, prostate volume and number/percent biopsy core involvement at diagnosis) showed nonsignificant risk reductions for reclassification in 5-ARI users as determined by either tumour extent (hazard ratio [HR] = 0.37 (95% confidence interval [CI] 0.12 to 1.13), P = 0.08) or grade (HR = 0.8 (95% CI 0.25-2.59), P = 0.7). CONCLUSION Treatment with 5-ARIs did not significantly alter the outcome of biopsy reclassification by grade in men with very low-risk prostate cancer.

What's known on the subject? and What does the study add? The male steroid hormone metabolism is an important target in the treatment of prostatic diseases. However, present literature is inconsistent about intraprostatic concentrations of steroid hormones and the role of intraprostatic steroid hormones in the arise and the course of prostatic diseases is yet to be determined. Part II of this two-piece mini-review reviews the effect of medication that alters the male steroid hormone metabolism (i.e. 5-alpha reductase inhibitors, androgen deprivation therapy) on intraprostatic steroid hormone concentrations. Better knowledge of the intraprostatic steroid hormone concentrations might lead to more individualized treatment and even to new medical targets. Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.

Study Type – Prognostic (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Previous studies used the decrease in PSA after 6 months of dutasteride treatment as a new ‘baseline’ PSA value from which subsequent rises may serve as a warning for prostate cancer; however, PSA tends to continue to decrease as dutasteride treatment continues. By comparing positive biopsy rates in the REDUCE study using any rise from nadir in the dutasteride arm and standard PSA decision criteria (NCCN) in the placebo arm, we demonstrated that the ability to detect prostate cancer and high grade prostate cancer is maintained with dutasteride treatment. OBJECTIVES • To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. • To analyse whether the use of treatment-specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS • The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. • The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. • The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. • Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS • Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. • If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8–10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8–10 cancers would have been missed in the placebo group. • In both groups, the incidence of Gleason 7 and Gleason 8–10 cancers generally increased with greater rises in PSA. • Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7–10 cancers in men treated with dutasteride vs placebo. • Men with Gleason 7 and Gleason 8–10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION • Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. • The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8–10) or higher than (Gleason 7–10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.

Study Type – Therapy (RCT) Level of Evidence 1b What’s known on the subject? and What does the study add? Both dutasteride and finasteride inhibit type 2 5α-reductase, the dominant form of 5α-reductase in benign prostatic tissue, making these effective treatments for BPH. In comparison with finasteride, dutasteride has a longer half-life and leads to a greater and more consistent suppression of serum and intraprostatic DHT. EPICS is currently the only prospective, randomized, double-blind study of finasteride vs dutasteride for BPH endpoints conducted for longer than a few months. Over a one-year period, treatment with dutasteride and finasteride led to similar reductions in prostate volume, and improvements in peak urine flow and urinary symptoms associated with BPH in men with an enlarged prostate. Men treated with finasteride and dutasteride also experienced similar rates of adverse events over the course of one year, which suggests that inhibition of both type 1 and type 2 5α-reductase, resulting in greater DHT suppression than type 2 inhibition alone, does not confer an increase in adverse events. Given the long-term, progressive nature of BPH, the one-year duration of EPICS may limit the potential to observe major differences between dutasteride and finasteride treatment. OBJECTIVE • To assess the efficacy and safety of dutasteride compared with finasteride in treating men with symptomatic benign prostatic hyperplasia (BPH) for 12 months. PATIENTS AND METHODS • The Enlarged Prostate International Comparator Study was a multicentre, randomized, double-blind, 12-month, parallel-group study. • Men aged ≥50 years with a clinical diagnosis of BPH received once-daily treatment with dutasteride 0.5 mg (n= 813) or finasteride 5 mg (n= 817). After a 4-week placebo run-in period, patients were randomized to receive dutasteride or finasteride for 48 weeks, followed by an optional 24-month, open-label phase, during which patients received dutasteride 0.5 mg once daily. • The primary endpoint was change in prostate volume, and the secondary endpoints included improvement in American Urological Association Symptom Index (AUA-SI) scores, improvement in maximum urinary flow rate (Qmax) and long-term safety in the 24-month open-label phase. RESULTS • Both dutasteride and finasteride were effective at reducing prostate volume with no significant difference between the two treatments during the study. • Similar reductions in mean AUA-SI scores and Qmax were also observed for men in both treatment groups. • A similar percentage of adverse events was experienced by patients of both treatment groups, and no new adverse events were reported in the open-label phase. CONCLUSION • Dutasteride and finasteride, when administered for 12 months, were similarly effective in reducing prostate volume and improving Qmax and urinary symptoms associated with BPH in men with an enlarged prostate.

Cancer Epidemiol Biomarkers Prev 2010; 19: 2164 –2171. Background: The knowledge about and use of chemopreventive agents for prostate cancer by physicians has not been described. The Prostate Cancer Prevention Trial (PCPT) showed that finasteride was effective in reducing the incidence of prostate cancer. We examined the influence of the PCPT on finasteride prescribing within the Veterans Health Administration (VHA). Methods: We assessed trends on monthly new and total prescriptions for finasteride filled within the VHA from January 2000 to December 2005. Additionally, all VHA urologists and a random sample of VHA primary care physicians (PCP) were surveyed about their use of finasteride. Results: The number of men starting finasteride grew over the study period. Publication of the PCPT was not significantly associated with any change in this pattern (P 0.45). Fifty-seven percent of urologists and 40% of PCPs endorsed prescribing finasteride more frequently in 2006 than 5 years prior. However, among those who reported changing prescribing patterns, fewer than 2% reported being influenced by the PCPT. Sixty-four percent of urologists and 80% of PCPs never prescribe finasteride for prostate cancer chemoprevention; 55% of urologists cited concerns of inducing high-grade tumors, whereas 52% of PCPs did not know it could be used for chemoprevention. Conclusions: The number of men starting finasteride in the VHA increased over time, but the change did not seem to be due to increased use of finasteride for chemoprevention. Publication of the PCPT seemed to have little influence over the study period. Editorial Comment: The analysis of the Veterans Health Administration drives home 2 key points. Despite publication of the PCPT in 2003, the medical community did not immediately embrace finasteride chemoprevention for prostate cancer. Given the recent Food and Drug Administration decision not to give dutasteride a chemoprevention indication, it is probably a good thing that doctors did not increase the use of finasteride for prostate cancer chemoprevention. The second and somewhat more interesting point is the gradual increase in use of finasteride throughout the study period. I suspect this increase may be related to the findings of the MTOPS (Medical Therapy of Prostatic Symptoms) trial, which concluded at roughly the same time. MTOPS was much less controversial and was consistent with the labeled indication for finasteride. I suspect it was this study that was responsible for the gradual increase in use of finasteride seen in the Veterans Administration.

Prostate cancer is among the most common causes of death from cancer in men, and accounts for 10% of all new male cancers worldwide. The diagnosis and treatment of prostate cancer place a substantial physical and emotional burden on patients and their families, and have considerable financial implications for healthcare providers and society. Given that the risk of prostate cancer continues to increase with age, the burden of the disease is likely to increase in line with population life-expectancy. Reducing the risk of prostate cancer has gained increasing coverage in recent years, with proof of principle shown in the Prostate Cancer Prevention Trial with the type 2 5 alpha-reductase (5AR) inhibitor, finasteride. The long latency period, high disease prevalence, and significant associated morbidity and mortality make prostate cancer a suitable target for a risk-reduction approach. Several agents are under investigation for reducing the risk of prostate cancer, including selenium/vitamin E and selective oestrogen receptors modulators (e.g. toremifene). In addition, the Reduction by Dutasteride of Prostate Cancer Events trial, involving > 8000 men, is evaluating the effect of the dual 5AR inhibitor, dutasteride, on the risk of developing prostate cancer. A successful risk-reduction strategy might decrease the incidence of the disease, as well as the anxiety, cost and morbidity associated with its diagnosis and treatment.

Objective To determine the effect of combined finasteride and flutamide therapy on haemoglobin and haematocrit values in men with advanced prostate cancer. Patients and methods Nineteen men, previously untreated by hormone therapy, with histologically confirmed adenocarcinoma of the prostate and clinical evidence of advanced disease, were treated with combined finasteride (5 mg/day) and flutamide (750 mg/day) for at least 6 months. Complete blood counts were performed before initiation and after 6 months of therapy. Results After 6 months of finasteride and flutamide therapy both haemoglobin levels and haematocrit decreased in all men, with a mean (sd, range) decrease of 16 (10, 3–42) g/L and 4.6 (2.7, 0.8–9.9)%, respectively. Conclusion Combined finasteride and flutamide therapy significantly lowers haemoglobin and haematocrit levels in men with advanced prostate cancer, and further study of this effect is warranted.

OBJECTIVE To assess the potential problem that different tools for predicting a positive outcome of prostate biopsy can produce divergent outcomes in the same man, by comparing the risk calculators based on the Prostate Cancer Prevention Trial (PCPT) and the European Randomized Study of Screening for Prostate Cancer (ERSPC). MATERIALS AND METHODS In the prostate-specific antigen (PSA) range of 0.2-30.0 ng/mL, the prediction curves of 'virtual' standard study participants were evaluated using both prediction tools. The effects of prostate volume, digital rectal examination, transrectal ultrasonography (TRUS), previous negative biopsy, family history, race, and age were also assessed. RESULTS Important differences in underlying study design and populations between the PCPT and ERSPC cause an essential discrepancy between the risk calculators. In the PCPT there were few biopsies in the higher PSA ranges, and in the ERSPC in the lower PSA ranges. Both risk indicators have incorporated some variables that are not used in the other, because they were insignificant in multivariate analysis. TRUS and especially prostate volume (not available in the PCPT) have a considerably larger effect on predictions in comparable PSA ranges than race, age, family history of prostate cancer, and previous negative biopsy (indicators that were excluded in ERSPC). CONCLUSIONS Before using risk calculators users must consider the properties of the underlying populations and what are the included or unavailable risk factors, and compare these to the patient. When these prerequisites are disregarded, dissimilarities will result in grossly inaccurate predictions for individual patients.

Objective To clarify the effects of androgens (testosterone and dihydrotestosterone, DHT) and ageing on gene expression of vasoactive intestinal polypeptide (VIP), assessed as the expression of VIP mRNA, in rat corpus cavernosum. Materials and methods The study comprised 160 male Sprague Dawley rats divided into group A (56 rats, 5 weeks old), group B (50 rats, 10 weeks old) and group C (54 rats, 58 weeks old). Groups A–C were subdivided, respectively, into subgroups 1 (intact controls), 2 (castrated), 3 (castrated but given testosterone undecanoate 25 mg/kg per month by intramuscular injection), 4 (castrated with testosterone undecanoate 50 mg/kg per month) and 5 (treated with finasteride 4.5 mg/kg per day, orally). At 4 and 10 weeks after these treatments half the rats were killed. Serum samples were taken for the measurement of total and free testosterone and DHT, using a radioimmunoassay. Penile samples (corpus cavernosum) were frozen in liquid nitrogen and stored at −80°C. VIP mRNA was estimated using a semi-quantitative reverse-transcription polymerase chain reaction. Results There was no significant difference in VIP mRNA in rat corpus cavernosum between intact control and castrated subgroups, or subgroups treated with finasteride, in groups A–C, including both the 4- and 10-week old animals (P > 0.05). Penile VIP mRNA was unchanged at any dose of testosterone in the castrated subgroups in all groups (P > 0.05). There was no significant relationship between penile VIP mRNA and ageing (P > 0.05). Conclusions The gene expression of VIP in rat corpus cavernosum is independent of androgens (testosterone and DHT) and ageing. Androgens probably induce penile erection by pathways other than VIP; ageing may have little effect on penile VIP mRNA.

Author(s): Breyer, Benjamin N; Huang, Wen-Yi; Rabkin, Charles S; Alderete, John F; Pakpahan, Ratna; Beason, Tracey S; Kenfield, Stacey A; Mabie, Jerome; Ragard, Lawrence; Wolin, Kathleen Y; Grubb, Robert L; Andriole, Gerald L; Sutcliffe, Siobhan | Abstract: ObjectiveTo examine whether a history of sexually transmitted infections (STIs) or positive STI serology is associated with prevalent and incident benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS)-related outcomes in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.MethodsSelf-reported history of STIs (gonorrhoea, syphilis) was ascertained at baseline, and serological evidence of STIs (Chlamydia trachomatis, Trichomonas vaginalis, human papillomavirus (HPV)-16, HPV-18, herpes simplex virus type 2, human herpesvirus type 8 and cytomegalovirus) was detected in baseline serum specimens. We used data collected on the baseline questionnaire, as well as results from the baseline prostate-specific antigen (PSA) test and digital rectal examination (DRE), to define prevalent BPH/LUTS-related outcomes as evidence of LUTS (self-reported diagnosis of an enlarged prostate/BPH, BPH surgery or nocturia [waking ≥2 times/night to urinate]) and evidence of prostate enlargement (PSA g 1.4 ng/mL or prostate volume ≥30 mL) in men without prostate cancer. We created a similar definition of incident BPH using data from the follow-up questionnaire completed 5-13 years after enrolment (self-reported diagnosis of an enlarged prostate/BPH or nocturia), data on finasteride use during follow-up, and results from the follow-up PSA tests and DREs. We used Poisson regression with robust variance estimation to calculate prevalence ratios (PRs) in our cross-sectional analysis of self-reported (n = 32 900) and serologically detected STIs (n = 1 143) with prevalent BPH/LUTS, and risk ratios in our prospective analysis of self-reported STIs with incident BPH/LUTS (n = 5 226).ResultsGenerally null results were observed for associations of a self-reported history of STIs and positive STI serologies with prevalent and incident BPH/LUTS-related outcomes, with the possible exception of T. vaginalis infection. This STI was positively associated with prevalent nocturia (PR 1.36, 95% confidence interval (CI) 1.18-1.65), prevalent large prostate volume (PR 1.21 95% CI 1.02-1.43), and any prevalent BPH/LUTS (PR 1.32 95% CI 1.09-1.61); too few men had information on both STI serologies and incident BPH/LUTS to investigate the associations between T. vaginalis infection and incident BPH/LUTS-related outcomes.ConclusionsOur findings do not support associations of several known STIs with BPH/LUTS-related outcomes, although T. vaginalis infection may warrant further study.

OBJECTIVE To measure expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in the prostates of men after transurethral resection of the prostate (TURP) following 2 weeks of treatment with finasteride. PATIENTS AND METHODS Sixty-four men scheduled to undergo TURP were randomized to receive 5 mg of finasteride or placebo daily for 2 weeks before surgery. Sections of prostatic urothelium were stained for VEGF expression and for CD31 to assess MVD. Ten consecutive, non-overlapping high-power fields were analysed in a blinded fashion. RESULTS In all, 31 men received finasteride and 33 placebo; the groups were similar in patient age, resected prostate weight, preoperative catheterization, prostate-specific antigen level, aspirin use, spinal anaesthesia and postoperative diagnosis of prostate cancer. The mean (95% confidence interval) MVD was significantly lower in the finasteride group (60, 55–65) than in the placebo group (71, 64–78; P

In a study from Madrid, patients from one centre were retrospectively reviewed, comparing those who had surgery for BPH in the first half of 1992 to that of 2002. The authors concluded that surgery was currently less common in older patients, and in patients who had received medical treatment for longer. They also found that open surgery was more common in those who required surgery, perhaps because the increase in prostate size was not suppressed by the medical therapy predominantly prescribed in the decade in question. OBJECTIVES To compare the clinical profile (age, comorbidities, symptom severity, and incidence of acute urinary retention, AUR), the type and duration of medical treatment, and indications for surgery of patients undergoing surgery for benign prostatic hyperplasia (BPH) in 1992 and 2002 at one centre. PATIENTS AND METHODS In this single-centre, retrospective, cross-sectional observational study, the medical history of all patients who had surgery for BPH in the first semester of 1992 (85) and 2002 (70) was reviewed. The preoperative clinical profile was determined by assessing age, main comorbidities, prostatic volume, maximum urinary flow rate and symptom severity. The type and duration of pharmacology for BPH was evaluated from the medical history and telephone contact with the patients. Indications for surgery, the method of operation and the weight of removed tissue (open adenectomy) or the volume of the resected tissue (transurethral resection) were obtained from the patients’ records and compared. Surgical complications in both groups were assessed, as was the average stay in hospital. RESULTS In our institution, surgery for BPH decreased by 17.6% in the decade, with patients having surgery when older, at a mean (sd) of 69.1 (8.57) vs 72.3 (7.59) years, i.e. 3.1 years older (P = 0.028), but with similar comorbidities. Reasons for surgery in 1992/2002, respectively, were AUR in 41/37%, and symptoms worsening in 48/51%. The few cases of haematuria and bladder stone were similarly distributed in both groups. Pharmacology for BPH was prescribed in 46% of patients in 1992, phytotherapy being the most common (89%), whereas in 2002, 82% (P

In the first of these mini-reviews the selection of therapy for the maintenance of sexual function in patients with BPH is outlined, along with an explanation of how altered regulation of neurotransmitters, especially noradrenaline, may underlie the syndrome of LUTS and sexual dysfunction. Other mini-reviews outline the current status of robotic surgery to treat renal and adrenal disorders, and its future applications, and the potential use of the nitric oxide/cGMP pathway as a potential target to treat BOO associated with benign prostatic enlargement. Finally, the capacity to be creative in academic departments is extolled as a core property of academicians, and its surfacing described as having the potential to revitalize individuals and departments.

The therapeutic goal of treating benign prostatic hyperplasia (BPH) through early detection and effective therapy is to relieve the symptoms, improve patients' quality of life, decrease postvoid residual urine volume, and prevent the associated morbidity when the condition remains untreated. Alpha1-adrenoreceptor antagonists, e.g. doxazosin, terazosin, tamsulosin and alfuzosin, relax the bladder outlet to improve urinary flow, by reducing prostatic smooth muscle tone through the blockade of sympathetic adrenergic receptors. Doxazosin gastrointestinal therapeutic system (GITS) is a controlled-release formulation developed to enhance the pharmacokinetic profile of the drug while simultaneously minimizing possible adverse effects and reducing the need for dose titration. While both doxazosin standard and GITS are indicated for hypertension, they are also useful in the pharmacologically or naturally normotensive patient with BPH. In a cross-over trial comparing doxazosin GITS and tamsulosin, doxazosin gave a significantly greater improvement from baseline in symptoms. Results from recent trials (e.g. Medical Therapy of Prostatic Symptoms, MTOPS) showed that doxazosin was significantly more effective than the 5alpha-reductase inhibitor finasteride in relieving lower urinary tract symptoms, irrespective of prostate volume. The MTOPS trial showed clearly that over the long term, the combination of doxazosin and finasteride was more effective than either agent alone in significantly improving symptoms and reducing the clinical progression of BPH. Both doxazosin standard and GITS are well-tolerated, long-term therapies that are equally effective in younger and older men, and not associated with causing sexual dysfunction.

The first paper in this section is a systematic review of the efficacy and adverse effects of doxazosin for treating LUTS compatible with benign prostatic obstruction. The criteria for inclusion were met by 13 studies involving 6033 men. The authors found evidence that doxazosin was effective and well tolerated in patients with LUTS. Combined therapy was superior to doxazosin alone in reducing the risk of clinical progression and other long-term complications of this condition. Authors from the UK reviewed the long-term results they achieved with an endourethral stent for treating BPH; quite a large proportion of patients had either died from unrelated causes or had had the stent removed. They stressed the necessity for careful case selection, but showed that it was a safe treatment for BPH in poor-risk patients. OBJECTIVE To evaluate the efficacy and adverse effects of doxazosin for treating lower urinary tract symptoms (LUTS) compatible with benign prostatic obstruction (BPO). METHODS Randomized controlled trials were included in the meta-analysis if: the study duration was ≥ 1 month; the study involved men with symptomatic BPO; and doxazosin was compared with placebo or active controls. Study and patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. RESULTS Thirteen studies involving 6033 men with (mean age 64 years) met the inclusion criteria; 10 were placebo-controlled, including two with combined doxazosin/finasteride therapy and finasteride monotherapy arms. Three trials were a comparison with other α-blockers. The study duration was 1–54 months. The mean baseline symptom scores and peak urinary flow (PUF) rates were indicative of moderate BPO. Doxazosin gave significant improvements in LUTS, assessed by symptom scores, vs placebo and finasteride in the short- to long-term. Two long-term studies (1 and 4 years) reported mean changes from baseline for the International Prostate Symptom Score of − 8.3 and − 6.6 points (−49% and − 39%) for doxazosin and − 5.7 and − 4.9 points (−33% and − 29%) for placebo, respectively. Doxazosin significantly increased PUF rates vs placebo. In pooled results from three studies, the weighted mean difference in the mean change from baseline vs placebo was 1.6 mL/s (95% confidence interval 1.2–2.1). Efficacy was comparable with other α1–blockers. In the long-term (>4 years) doxazosin was no better then finasteride in improving PUF. Combined doxazosin and finasteride significantly reduced the risk of overall clinical progression of BPO vs each drug separately in men followed for >4 years. Absolute risk reductions vs placebo were 11.3%, 6.9% and 6.4% for combined therapy, doxazosin and finasteride, respectively (P

Less than 10 years ago surgery and watchful-waiting were the only widely accepted management options for lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH) and benign prostatic obstruction (BPO). There has been an enormous decline in the popularity of surgery and it is now apparent that medication is the most frequently used treatment for BPH/LUTS; this has arguably therefore been the most major change in urological clinical practice in the last decade. Currently alpha(1)-adrenoceptor antagonists are the commonest medical therapy, and are thought to act by relaxing prostatic smooth muscle, the neural or so-called 'dynamic' component of BPO. 5alpha-reductase inhibitors (finasteride, dutasteride) are another option for BPH/LUTS, which reduce prostatic mass and therefore the mechanical or 'static' component of BPO. In the last 10 years there have been four direct comparative studies between alpha(1)-adrenoceptor antagonists and finasteride, including their combination, the results of which, and their implications for therapy, are discussed. Another group of agents are the phytotherapeutic extracts, which act via various mechanisms, many as yet poorly defined. This review critically assesses existing publications relating to the medical management of BPH/LUTS.

As my Comment in the first section of the journal suggested, the MTOPS results have offered the possibility to general practitioners of reducing the risk of side-effects of BPH, particularly urinary retention, by giving patients dual therapy with 5α-reductase inhibitor and alpha-adrenergic blocker. Authors from the UK present guidelines for the primary case management of male LUTS, which significantly fills this gap in the literature. Any help in the management of chronic nonbacterial prostatitis is welcome to clinicians; many treatments have been proposed after non-comparative trials, and so their value must be viewed cautiously. The authors from Canada and USA present the results of a randomized placebo-controlled study into the use of finasteride in such patients. The other papers in this section all deal with LUTS, e.g. frequency and nocturia, in a variety of situations. There is still great interest in the epidemiology of these symptoms, and in the various methods of grading their severity.

One of the sad reminders of advancing years is malepattern hair loss (MPHL). Not only is a highly reflective pate the source of many cruel jokes, but the condition is also associated with depression, suicide and a lack of selfesteem, as well as perceived discrimination [1,2]. Therefore it is hardly surprising that research into MPHL has been targeted by several pharmaceutical companies worldwide for many years, as a panacea for this condition would certainly be in great demand. Since early March 2002, finasteride 1 mg (PropeciaTM, Merck Sharp and Dohme) has been available in the UK to patients whose doctors are prepared to prescribe it privately. Predictably, this launch has achieved much media publicity. With the first 5-year study having recently appeared in a medical journal [3], encouraging results have been reported in treating MPHL and this is bound to further fuel the demand for finasteride 1 mg. Herein we discuss the possible implications of manipulating testosterone metabolism in MPHL in relation to prostate cancer.

Objective To study the influence of finasteride treatment on the molecular forms of prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH). Patients and methods Total PSA, free PSA and PSA complexed to α1-antichymotrypsin (PSA-α1ACT) were measured in plasma and serum from 40 men with BPH and a total PSA of

Objective To analyse the expression of the epidermal growth factor (EGF) system in prostate tissue and secretions obtained from patients with benign prostatic hyperplasia (BPH) treated with or without finasteride (which primarily targets the androgen-sensitive secretory epithelial cells in the prostate, with little effect on basal epithelial and stromal cells). Patients and methods The expression of the EGF system was evaluated by enzyme-linked immunosorbent assay and immunohistochemistry in samples of prostate tissue and secretions from patients with BPH randomized for treatment with finasteride or placebo for 3 months before surgery. Results Prostate tissue expressed the EGF receptor (HER1) and HER2, and the ligands EGF, transforming growth factor α (TGFα), heparin-binding (HB) EGF, betacellulin and amphiregulin. Treatment with finasteride produced greater concentrations of amphiregulin (P

Objective To determine the effect of various treatments for benign prostatic hyperplasia (BPH) on sexual function. Patients and methods In a longitudinal multicentre study carried out in the Netherlands, 670 consecutive patients with BPH (aged 50 years) were examined at baseline and 9 months after inclusion. All patients completed a questionnaire about symptomatology, bothersomeness and sexual function before and after treatment. Other diagnostic information was retrieved from the medical records. Results At baseline, 49–59% of the population (mean age 66 years) reported normal potency and 69% a normal libido. Outcomes at 9 months were stratified by type of treatment, i.e. surgery in 207, α-blockers in 43, finasteride in 47 and watchful waiting in 234 men. Patients with multiple or other treatments (131) or recent surgery (eight) were excluded from the analyses. For the four sexual items included, 84% of the patients reported no changes. All treatments showed both improvement and deterioration in 3–14% and 0–16% of the patients, respectively. Conclusion For sexual function, most patients remained stable after treatment for BPH, while positive and negative changes occurred in equal proportions for all treatments. These results question the previously reported high incidence of sexual adverse events, particularly after surgical intervention.

Objective To systematically review and evaluate the effectiveness and adverse effects of the α-antagonist, terazosin, for treating urinary symptoms associated with benign prostatic obstruction (BPO). Methods Studies were sought and included in the review if they were randomized trials of at least 1 month duration, involved men with symptomatic BPO and compared terazosin with placebo or active controls. The study, patient characteristics and outcome data were extracted in duplicate onto standardized forms using a prospectively developed protocol. Results Seventeen studies involving 5151 men met the inclusion criteria, i.e. placebo-controlled (10), α-blockers (seven), finasteride alone or combined with terazosin and placebo (one), and microwave therapy (one). The study duration was 4–52 weeks; the mean age of the men was 65 years and 82% were white. Baseline urological symptom scale scores and flow rates showed that men had moderate BPO. Efficacy outcomes were rarely reported in a way that allowed for data pooling, but indicated that terazosin improved symptom scores and flow rates more than did placebo or finasteride, and similarly to other α-antagonists. The pooled mean percentage improvement for the Boyarsky symptom score was 37% for terazosin and 15% for placebo (four studies). The mean percentage improvement for the American Urological Association symptom score was 38%, compared with 17% and 20% for placebo and finasteride, respectively (two studies). The pooled mean improvement in the International Prostate Symptom Score of 40% was similar to that with tamsulosin (43%). Peak urinary flow rates improved more with terazosin (22%) than with placebo (11%) and finasteride (15%), but did not differ significantly from the other α-antagonists. The percentage of men discontinuing terazosin was comparable with those receiving placebo and finasteride, but greater than with other α-antagonists. Adverse effects were greater than with placebo and included dizziness, asthenia, headache and postural hypotension. Conclusions The available evidence indicates that terazosin improves the symptoms and flow rates associated with BPO; it was more effective than placebo or finasteride and similar to other α-antagonists. Adverse effects were generally mild but more frequent than with other α-antagonists and associated with a two- to four-fold increase in treatment discontinuation.