signiﬁcance of the distinctions between ﬁnasteride and dutasteride on malignant prostate pathophysiology has been postulated (Andriole et al 2004), but has yet to be conﬁrmed in clinical trials. In the absence of prostate cancer, 5AR inhibition has a dramatic effect on serum PSA. An approximate 50% reduction in the PSA from baseline is to be expected after 6 months of continuous therapy with either ﬁnasteride or dutasteride (Gormley et al 1992; Roehrborn et al 2002). When patients on therapy with 5AR inhibitors for 6 months or greater undergo PSA based screening for prostate cancer, the measured PSA should be doubled before comparing it with reference values in consideration for prostate needle biopsy (Andriole et al 1998). After several years of therapy with 5AR inhibitors, the measured PSA must be increased by a factor of 2.5, to account for continued PSA decrease in treated men (Etzioni et al 2005). Prevention of prostate cancer with 5-alpha reductase inhibitors Men with congenital deﬁciency of 5AR have low levels of DHT, a diminutive prostate, and complete lack of prostatic glandular epithelium (Imperato-McGinley et al 1974, 1992) and are notable for a lack of reported cases of adenocarcinoma of the prostate. These ﬁndings, along with the well known androgen sensitive nature of prostate cancer prompted two large scale clinical trials investigating the possible role of 5AR inhibitors in the prevention of prostate cancer: the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) (Thompson et al 2003; Andriole et al 2004). The PCPT was a multicenter, randomized, double blind, placebo-controlled clinical trial comparing ﬁnasteride with placebo in the prevention of adenocarcinoma of the prostate. 18 882 men over the age of 55, with a PSA of 3.0 ng/ml or lower and a normal digital rectal examination (DRE) were randomized to receive 7 years of ﬁnasteride (5 mg) or placebo daily. The study participants were monitored with annual PSA (blindly adjusted in the finasteride group) and DRE. Transrectal ultrasound guided biopsies were performed for PSA greater than or equal to 4 ng/ml or for an abnormal DRE. Additionally, all men were recommended to undergo an end of study biopsy after the 7 years of treatment had elapsed (Thompson et al 2003). Of the 9060 men included in the ﬁnal statistical analysis, 18.4% of men in the ﬁnasteride group were diagnosed with adenocarcinoma of the prostate, compared with 24.4% in the placebo group; a 24.8% relative risk reduction (p<0.001). Clinical Interventions in Aging 2006:1(4) 5 alpha-reductase inhibitors in prostate cancer A signiﬁcant difference persisted across all subgroups analyzed and approximately 98% of cancers in both groups were organ conﬁned. Despite the impressive 24.8% relative risk reduction in the diagnosis of prostate cancer in the PCPT study population, several issues have prevented the widespread acceptance of ﬁnasteride as preventative therapy for prostate cancer. First and foremost, ﬁnasteride therapy was associated with an increased diagnosis rate of poorly differentiated prostate cancer compared with placebo (37.0% vs 22.2% of cancers diagnosed; 6.4% vs 5.1% overall) (Thompson et al 2003). Additionally, prostate cancer diagnosis rates were far higher than expected in both study groups (18.4% and 24.8% in this relatively low-risk group followed for 7 years vs lifetime prevalence of approximately 17%). Finally, nearly half of all positive cancer diagnoses were from end- of-study biopsies, tumors whose clinical signiﬁcance is unknown (Grover et al 2006). The PCPT was met with immediate skepticism by some investigators and clinicians, fueled by concerns that ﬁnasteride had selected for and accelerated the growth of high grade tumors (Scardino 2003). Subsequent analysis of PCPT data provide an alternative hypothesis to explain the slightly higher percentage of high grade tumors detected in the treatment group (Etzioni et al 2005; Thompson et al 2005, 2006). First, the greatest difference in the proportion of high versus low-grade cancers detected between the treatment and placebo groups was seen in those study subjects undergoing for-cause biopsies as opposed to end- of-study biopsies. The increased hazard ratio for detecting high grade prostate cancer in the treatment group did not increase over the course of the clinical trial. In fact, the number of men diagnosed with high grade prostate cancer during the end-of-study biopsies were similar across both study groups. A subsequent analysis found that ﬁnasteride inﬂuenced the characteristics of PSA as a screening test, increasing its sensitivity for all grades of prostate cancer in general, and high grade prostate cancer in particular (Thompson et al 2006). Additionally, PSA is more sensitive for high grade prostate cancer at various PSA cutoff levels ranging from 1.1 ng/ml to 10.1 ng/ml (Thompson et al 2005), decreasing the false negative rate and increasing the rate of diagnosis of high grade tumors. Therefore, the combination of cancer chemoprevention, PSA reduction (in benign disease), and increased sensitivity of PSA for high grade prostate cancer may have led to the increased rate of diagnosis of high grade prostate cancer in the ﬁnasteride group despite an overall reduction in the incidence of 427