3. 5ARIs
5ARIs are recommended for the primary medical management of BPH, for prostates greater than 30 cc, in the 2022 CUA Guidelines.44 It has been shown to improve both symptoms and alter the natural course of disease progression, especially in combination with alpha-blockers.5,45
5-Alpha-reductase (5AR) converts testosterone to dihydrotestosterone. There are three isoenzymes: type I is mainly expressed in the skin and liver; type II is predominately expressed in the prostate, seminal vesicles, and epididymis; and type III is ubiquitously expressed.46 Dutasteride inhibits both types I and II,while finasteride inhibits only type I, although clinically major differences in outcomes have not been observed between these two 5ARIs. However, these medications do have side effects that can be significant and bothersome to patients and are in some cases irreversible (Table 2).
3.1. Sexual adverse effects
Sexual side effects are the most common and concerning for men on 5ARIs, ranging from 0.9% to 38% of patients.47,48 The rates are similar between dutasteride and finasteride 5,49 and not found to be different between normal and low-dose finasteride.50 The Proscar Long-Term Efficacy and Safety Study (PLESS) did show improvement in these adverse effects over time.51 However, some studies show possible sexual dysfunction even after treatment has been stopped.52
5ARIs are also associated with gynecomastia, with the risk being higher for dutasteride compared to finasteride.53 The Prostate Cancer Prevention Trial (PCPT) reported rates of gynecomastia in 4.5% of patients on finasteride compared to 2.8% placebo.54 The risk is present regardless of duration and timing.55 It is more commonly seen in patients undergoing androgen deprivation therapy in prostate cancer. Management is usually conservative but may involve tamoxifen, aromatase inhibitors,radiotherapy, and mastectomy. Medical therapy is typically reserved for symptomatic, acute, idiopathic gynecomastia.Tamoxifen, perhaps the most studied, in a randomized trial had a 78% complete resolution rate compared to 40% with danazol inpatients with idiopathic gynecomastia, however, with a higher relapse rate.56 Surgical options can be considered for chronic cases or concern for malignancy. There is no association between 5ARI and male breast cancer.57
3.2. Psychiatric adverse effects
Recently, psychiatric side effects are becoming more recognized and brought to the forefront. During the initial clinical trials, depression was rarely reported and was not listed on the initial medication packaging.58 Since then, post-finasteride syndrome has been used to describe prolonged and persistent sexual and psychological effects and reports of suicidality, even after discontinuing the medication.59 It is proposed that allopregnanolone, a neurosteroid produced by 5AR, is decreased in patients with depression and altered by 5ARIs.60 A review of VigiBase, the World Health Organization's global database of case safety reports, found increased signals of suicidality, depression, and anxiety in young patients, aged less than 45 years, taking low-dose finasteride.59 In 2011, a post-market report was sent to the FDA, and warnings have been added since then.59
