Incomplete Recovery of Erectile Function in Rat After Discontinuation of Dual 5-Alpha Reductase Inhibitor Therapy

Abstract

Aim The association of 5-alpha reductase inhibitor (5ARI) therapy and sexual dysfunction has been reported. Some patients claim persistent erectile dysfunction despite long-term discontinuation of 5ARI treatment. The aim of this study was to assess erectile function after cessation of 5ARI therapy using a rat model. Methods Twenty-six adult male Sprague-Dawley rats were randomized into three groups: (i) control (N = 10); (ii) 8-week dutasteride treatment (0.5 mg/rat/day, in drinking water, N = 8); and (iii) 6-week dutasteride treatment followed by a 2-week washout period (N = 8). The experiments were performed after 8 weeks from the initiation of treatment in all groups. In vivo erectile activity and in vitro contractile and relaxant responses of cavernosal smooth muscle were investigated. Results In vivo erectile activity (intracavernosal pressure [ICP]/mean arterial pressure [MAP] and total ICP) in treatment groups were significantly decreased compared with controls (ICP/MAP: P < 0.001 for 2.5 v, 5 v, and 7.5 v; total ICP: P < 0.001 for 5 v and P < 0.01 for 7.5 v). Acetylcholine-induced relaxations were diminished in treatment groups (P < 0.05). Relaxant responses to electrical field stimulation (EFS) were decreased in the 8-week treatment group (P < 0.05) but were similar to controls in the washout group. Sodium nitroprusside (SNP)-induced endothelium-independent relaxations were reduced in the 8-week dutasteride treatment group (P < 0.01), while these responses were restored in the washout group. The contractile responses to the alpha1-adrenergic agonist phenylephrine were decreased in treatment groups compared with controls (P < 0.01). Direct neurogenic contractile responses in the dutasteride groups were significantly lower than controls between 1 and 15 Hz frequencies (but not at 20 Hz) and washout partially restored the responses at 10 and 15 Hz. Conclusion Discontinuation of dutasteride improved the relaxant responses to EFS and SNP, while cholinergic and adrenergic responses remained depressed. Our findings suggest a time-dependent detriment of dutasteride on erectile function. The withdrawal/washout effect of 5ARIs on parameters of 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].…”

Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia

“…Treatment of mature male animals with dutasteride produced significant reductions in the intracavernosal pressure (ICP) [40,41]. Electrical field stimulation (EFS) or acetylcholine-induced smooth muscle relaxation was significantly attenuated in corpus cavernousm tissues from dutasteride-treated animals [40,41].…”

“…Thus, it is conceivable that inhibition of 5α-Rs may result in serious sexual adverse effects during the treatment and even after cessation of the treatment due to the complex mechanism of these enzyme reactions [6][7][8]. Pre-clinical studies provided biochemical and physiological evidence for a role for 5α-dihydrotestosterone (5α-DHT) in erectile physiology [40][41][42]. A number of studies demonstrated that the effects of androgens on erectile physiology were likely mediated by the 5α-reduced metabolite, 5α-DHT [43][44][45][46][47][48][49][50].…”