The Effects of Chronic 5-Alpha-Reductase Inhibitor (Dutasteride) Treatment on Rat Erectile Function

Abstract

Introduction Numerous clinical series have reported an association between 5-alpha-reductase inhibitors (5ARIs) and sexual dysfunction, but there are limited preclinical data available. Aim To further investigate the mechanisms of erectile dysfunction (ED) related to 5ARI therapy using a rat model. Main Outcome Measures Outcome measures include serum dihydrotestosterone (DHT), relaxant and contractile properties of cavernosal muscle, and nitric oxide synthase expression. Methods Twenty adult male Sprague-Dawley rats were randomized into control (N = 10) and dutasteride (0.5 mg/rat/day, in drinking water, N = 10) groups. Serum samples were obtained at baseline, from which DHT was measured after 30 days of treatment via radioimmunoassay (Beckman Coulter, Fullerton, CA, USA). Before the terminal blood draw, erectile response was measured using cavernosal nerve stimulation. The relaxant and contractile properties of cavernosal muscle strips were evaluated in tissue baths, and immunohistochemical (IHC) staining for nitric oxide synthase (NOS) and collagen deposition was performed. Results Mean serum DHT was suppressed by 86.5% (range 64.2–94.8%) after 30 days of 5ARI treatment and was statistically significant (P = 0.0024). In vivo erectile response in the dutasteride treated group decreased significantly compared with control (P < 0.001). While electrical field stimulation (EFS)-induced and acetylcholine-induced relaxation was decreased, EFS-induced and phenlyephrine-induced adrenergic contraction was significantly enhanced in the dutasteride group (P < 0.01). IHC studies demonstrated increased collagen deposition in the treatment arm as well as altered expression of neuronal NOS (nNOS) and inducible NOS (iNOS). Conclusions The 5ARIs, as demonstrated in these rat cavernosal smooth muscle studies, have a detrimental effect on erectile function. Enhanced iNOS expression may protect penile smooth muscle from fibrosis. The effect of 5ARIs on human sexual function warrants further investigation.

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…An editorial following the report by Belknap [89] has highlighted the need to re-think the safety of these drugs [90]. The following section summarizes preclinical and clinical evidence documenting how finasteride and dutasteride may impair sexual function, including sexual desire, erectile, ejaculation and orgasmic function [23,[91][92][93][94][95].…”

“…Öztekin et al, [95] and Pinsky et al, [94] demonstrated that treatment of mature animals with dutasteride resulted in reduced serum 5α-DHT levels by~86.5 % after 30 days. A significant decrease in the intracavernosal pressure (ICP) was recorded in animals treated with dutasteride.…”

“…Thus, these drugs are likely to contribute to erectile dysfunction (ED) via well-established and characterized mechanisms [94,95].…”

Mirabegron causes relaxation of human and rat corpus cavernosum: could it be a potential therapy for erectile dysfunction?

“…CC strips with one end attached to a holder and the other to a wire connected to a force transducer, were allowed to equilibrate for 60 min, and the bath medium was changed at 15 min intervals [25].…”

Sindrome post-finasteride: tra mito e realtà

“…Tale dato potrebbe spiegare le segnalazioni di fibrosi del corpo cavernoso post-finasteride [8]. In tale ambito, altri studi basici e in vitro risulterebbero necessari per determinare quali isoforme di 5AR sono presenti nei tessuti dei corpi cavernosi [3].…”