5-alpha reductase inhibitors (5ARIs) have been reported to increase the risk of erectile dysfunction (ED), depression, gynecomastia, and breast cancer (BrCa) in patients treated for benign prostatic hyperplasia (BPH). We conducted cohort studies with nested case-control analyses using the United Kingdom’s Clinical Practice Research Datalink to estimate the risk of ED, depression, gynecomastia, and BrCa in men prescribed 5ARIs for the treatment of BPH over the 20 year study period (1992-2011).
We identified men with BPH who received at least one prescription for a 5ARI or an alpha blocker (AB). We identified separate cohorts for each study outcome. In the ED (N=71,849) and depression (N=77,732) studies, exposure was defined as use of 5ARI only, 5ARI+AB, or AB Only. In the gynecomastia and BrCa studies (N=94,701) exposure was defined as use of 5ARIs (alone or in combination with AB), AB Only, or unexposed to either. ED cases were men who had a first ED diagnosis or treatment, depression cases were men who had a first depression diagnosis and received a prescription for an antidepressant within 90 days of the diagnosis, and gynecomastia and BrCa cases were men with a first such diagnosis during follow-up. We calculated incidence rates (IRs) and adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs). We also conducted nested case-control analyses to control for major confounders and calculated adjusted odds ratios (ORs) with 95% CIs.
The risk of ED was not elevated in users of 5ARI only (IRR=0.92, 95%CI 0.85-0.99) or 5ARI+AB (IRR=1.09, 95%CI 0.99-1.21) in comparison with AB only. The risk of depression was not increased with use of 5ARI Only (IRR=0.94, 95%CI 0.85-1.04) or 5ARI+ABs (IRR=1.04, 95%CI 0.89-1.21) compared to use of AB Only. Compared to no exposure, gynecomastsia risk was elevated for users of 5ARIs (IRR=3.55, 95%CI 3.05-4.14) but was null for users of AB Only. In the nested case-control analyses, ORs for ED and depression remained null, while the ORs for gynecomastia remained elevated regardless of number of prescriptions or exposure timing. The risk of ED and depression increased with longer duration of BPH, independent of exposure. 5ARI users did not have an increased risk of BrCa compared to unexposed men (OR=1.52, 95%CI 0.61-3.80).
In a large, 20 year, real world observational study, 5ARI therapy for BPH did not significantly increase the risk of clinically meaningful incident ED or depression compared to treatment with ABs only. Risk of ED and depression increased with longer duration of BPH. Use of 5ARIs increased the risk of gynecomastia, but not BrCa, compared to AB use and no exposure.
