While the direct effects of

While the direct effects of 5-ARI lead to a dramatic Paprotrain in serum DHT levels, other laboratory values are also affected by 5-ARI use. Serum testosterone elevations are known to occur with both finasteride and dutasteride use, but values will typically remain within the normal laboratory range [18]. Additionally, given the intended effect of 5-ARI causing the involution of prostatic epithelial tissue, which is the main source of intraprostatic as well as serum PSA, the inhibition of DHT by 5-ARI indirectly results in a decrease in PSA. For example, the use of finasteride for 12 months duration has been found to lower serum PSA by approximately 50% [21].
Clinical efficacy of 5-ARIs
Tolerability of 5-ARIs Finasteride was demonstrated to be well tolerated in PLESS, with the number of withdrawals from treatment due to side effects similar in the finasteride and placebo groups (11.5% vs. 10.9%). The side effects more frequently encountered in the finasteride group as compared to placebo were decreased libido, impotence, decreased ejaculate volume, ejaculation disorders, breast enlargement, breast tenderness, and general rash [24]. Similar tolerability profiles were found in PCPT, with sexual side effects and gynecomastia more common with finasteride treatment compared to placebo [27]. In the studies of dutasteride, the drug-related adverse event rate was similar between dutasteride and placebo (19% vs. 14%). The same proportion of men withdrew from the dutasteride and placebo groups due to side effects (8.9% in both groups) [25]. With dutasteride use for 4 years, the rate of newly reported sexual side effects generally decreased with time; however, gynecomastia had a relatively constant rate of incidence (1.3% in year 1 and 2, 1.8% in year 3, and 0.7% in year 4) [26]. In the MTOPS and CombAT trials, combination therapy with 5-ARIs and alpha blockers appear to be well tolerated with a similar side effect profile to the individual monotherapies used in combination [8,31].
Clinical guidelines for 5-ARIs Given the numerous studies demonstrating the clinical efficacy of 5-ARIs in the treatment of BPH, both the European Association of Urology (EAU) and the American Urologic Association (AUA) include 5-ARIs prominently in their guidelines for management of BPH. The EAU gives a grade A recommendation for the use of 5-ARIs for patients with moderate to severe LUTS and enlarged prostates (>40 g) and a grade A recommendation for the use of 5-ARIs in combination with alpha blockers for men likely to develop disease progression (e.g., larger prostate volume, reduced Qmax) [34]. Similarly, the AUA guidelines for management of BPH discuss 5-ARIs as an option for combination therapy with alpha blockers in men with demonstrable prostatic enlargement, noting the prevention of BPH progression noted with 5-ARI use (e.g., risk of AUR and need for BPH-related surgery). Additionally, the AUA guidelines specifically recommend against the use of 5-ARIs in men without prostatic enlargement [35]. Given the results of the PCPT and the REDUCE trial, clinicians must keep in mind the associations between 5-ARI use and prostate cancer. In the PCPT, patients randomized to finasteride had a roughly 25% lower incidence of prostate cancer as compared to placebo, but an increased proportion of prostate cancer diagnoses were high grade (37% vs. 22%) [27]. Similarly in the REDUCE trial, the prostate cancer incidence was 23% lower for men randomized to dutasteride, but the incidence of the highest grades of prostate cancer (e.g., Gleason score 8–10) was greater than placebo (0.9% vs. 0.6%, p = 0.15) [28]. Many subsequent studies have demonstrated seminiferous tubules the higher rate of high grade prostate cancer found with 5-ARI treatment was a result of selective inhibition of low grade cancers and decreased prostate volume resulting in improved biopsy yield [36,37]. However, the Food and Drug Administration has added a black box warning to 5-ARIs concerning the increased risk of developing high grade prostate cancer.