Persistent erectile dysfunction after discontinuation of 5-alpha reductase inhibitor therapy in rats depending on the duration of treatment
Sung, HH1; Kang, SJ1; Chae, MR1; So, I2; Park, JK3; Lee, SW1
1: Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine; 2: Department of Physiology and Biophysics, Seoul National University College of Medicine; 3: Department of Urology, Chonbuk National University and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Clinical Trial Center of Medical Device of Chonbuk National University
Objectives: It is controversial that 5-alpha reductase inhibitors (5ARI) are related to permanent erectile dysfunction (ED) even after discontinuation. This study is to investigate the effects of dutasteride on the persistent ED after discontinuation of dutasteride in the rat model, depending on the duration of medication.
Materials and Methods: Male rats (n=76) were assigned to five groups: (i) normal control group; (ii) dutasteride (0.5mg/rat/day) 4-weeks group; (iii) dutasteride 4-weeks plus 2-weeks of resting group; (iv) dutasteride 8-weeks group; (v) a dutasteride 8-weeks plus 2-weeks of resting group. In vivo erectile responses to electrical stimulation were measured, and change of fibrotic factors and smooth muscle/collagen contents in the corpus cavernosum were evaluated in each group using Western blot and Masson’s trichrome staining.
Results: Dutasteride 4- and 8-weeks feeding groups significantly decreased erectile parameters compared with control group (p < 0.05). Reduced erectile responses were recovered through 2-weeks of drug-free interval in the 4-weeks group, but not in the 8-weeks group. There was no significant change of protein regarding fibrosis-related factors including TGFβ1, TGFβ2, and p-Smad/Smad in corpus cavernosum after 4-weeks of dutasteride feeding (p > 0.05), but enhanced in the 8-weeks groups (p < 0.05). Dutasteride markedly decreased smooth muscle contents, and increased collagen after 4- and 8-weeks of use (p < 0.05). Dutasteride administration markedly decreased smooth muscle content and increased collagen after 4 and 8 weeks of feeding (p < 0.05). There was no significant improvement in the smooth muscle to collagen ratio after the rest period in both the 4- and 8-week groups.
Conclusions: In a rat model, the reduction of DHT by dutasteride decreased erectile responses to electrical stimulation. This was accompanied by changes in protein levels and histological features, and resulted in increased fibrosis and decreased smooth muscle content in the corpus cavernosum. The current study demonstrated that recovery from ED depended on the duration of medication, and that administration of dutasteride for longer than a critical period could result in irreversible ED, even after discontinuation of dutasteride.
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