Sexual Function There were 2 large RCTs that examined the side effects of 5-ARIs with 4-year follow-up.143, 174 The MTOPS trial, a multicenter, randomized, double-blinded, placebo controlled clinical trial comparing placebo, doxazosin, finasteride, and combined therapy reported an analysis of sexual function outcomes of 2,783 men at 4 years.143 They observed a gradual worsening of libido, erectile function, and ejaculatory function in all treatment groups including placebo with time. However, they observed a small but significant worsening of ejaculatory function in the finasteride group and worsening of both ejaculatory and erectile function in the combination group. The 4-year results of the CombAT trial, a multicenter, randomized, double-blinded trial comparing dutasteride, tamsulosin, and combined therapy in 4,844 men similarly noted a small worsening of ejaculatory and erectile function in the combination group, but did not comment on statistical significance.174 Gynecomastia The REDUCE trial found a small but statistically significant increase in gynecomastia in the dutasteride group (1.9% versus 1.0%).175 This rate did not appear to increase during the two-year observational extension study where no new cases of gynecomastia were reported.176 Dementia One observational study has reported a higher incidence of dementia in men taking 5-ARIs during the first 2 years of administration.177 However, it is thought these findings may represent coexistent cognitive impairment identified at the time of initial LUTS assessment, rather than a direct effect of the medication. Depression There is conflicting data about psychiatric adverse events of 5-ARIs. One large observational study found an increased risk of depression, but not suicide risk, in men taking 5-ARIs.47 Another large retrospective cohort study showed no increase in medically treated depression in men taking 5-ARIs when compared to ABs only, although there was an increase in treated depression with longer duration of BPH treatment, independent of drug exposure.178 Post-Finasteride Syndrome (PFS) PFS is a controversial and poorly-defined constellation of chronic 5-ARI-induced sexual, physical, and psychological symptoms that putatively persist after discontinuation of the 5-ARI.179 Current data on PFS draw primarily from anecdotal patient-reported outcomes mostly related to the use of finasteride to treat baldness in younger men.180 The adverse event reporting of available RCTs have not substantiated the clinical entity of PFS. Nevertheless, these concerns regarding PFS have prompted the FDA to amend the labels for 5-ARIs with a warning of its risks. Prostate Cancer Diagnosis The PCPT, a randomized, double-blinded, multicenter trial compared the use of finasteride to placebo for the reduction of prostate cancer risk in 18,882 men over 7 years. While there was an observed 24.8% reduction in the overall number of prostate cancers identified in the finasteride group, there was an increased rate of high-grade (≥Gleason Score 8) cancers (2.1% versus 1.1%).181 The REDUCE trial, a randomized, double-blinded, multicenter trial compared the use of dutasteride to placebo in 8,231 men for 4 years, showing similar findings with a 23% reduction in overall prostate cancer but also an increased risk of high-grade cancer (0.9% versus 0.6%).175 While these findings of an increased rate of high-grade prostate cancer raised concerns about the long-term impact of 5-ARI use, the 18 year follow-up of the PCPT showed no difference in overall survival between groups.182 Nevertheless, these findings prompted an FDA black box warning in 2011 stating that “healthcare professionals should be aware of this safety information and weigh the known benefits against the potential risks when deciding to start or continue treatment with 5-ARIs in men.”183  When prescribing 5-ARIs, clinicians should also bear in mind that typically there is an observable 50% reduction in PSA level at 3-6 months, including with the use of low-dose finasteride for alopecia.63, 64, 164 This expected reduction in PSA should be taken into account when calculating PSA kinetics for cancer detection.