World J Mens Health.  2019 May;37(2):240-248. 10.5534/wjmh.180082.

Persistent Erectile Dysfunction after Discontinuation of 5-Alpha Reductase Inhibitor Therapy in Rats Depending on the Duration of Treatment

Affiliations
  • 1Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. drswlee@skku.edu
  • 2Department of Physiology and Biophysics, Seoul National University College of Medicine, Seoul, Korea.
  • 3Department of Urology, Chonbuk National University College of Medicine and Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute and Clinical Trial Center of Medical Device of Chonbuk National University, Jeonju, Korea.

Abstract

PURPOSE
The current study is aimed to assess whether a longer duration of 5α-reductase inhibitor (5α-RI) exposure was associated with higher rate of permanent erectile dysfunction (ED) in a rat model.
MATERIALS AND METHODS
Male Sprague-Dawley rats (n=76) were assigned to five groups: (i) normal control group; (ii) dutasteride (0.5 mg/rat/d) for 4-weeks group; (iii) dutasteride for 4-weeks plus 2-weeks of resting group; (iv) dutasteride for 8-weeks group; and (v) dutasteride for 8-weeks plus 2-weeks of resting group. In vivo erectile responses to electrical stimulation, and changes of fibrotic factors and smooth muscle/collagen contents in the corpus cavernosum were evaluated in each group.
RESULTS
Dutasteride administration for 4 and 8 weeks significantly decreased erectile parameters compared with the control group. Reduced erectile responses were recovered during 2 weeks of drug-free time in the 4-week treatment group, but were not in the 8-week group. Protein levels of fibrosis-related factors transforming growth factor (TGF)-β1, TGF-β2, and p-Smad/Smad (Smad 2/3) in the corpus cavernosum showed no significant change after 4 weeks of dutasteride oral administration, but were enhanced after 8 weeks. Dutasteride markedly decreased smooth muscle content and increased collagen after 4 and 8 weeks of use, but no nuclear size changes; however, neither group showed significant improvement in the smooth muscle to collagen ratio after the rest period.
CONCLUSIONS
Our study showed that recovery from ED depended on the duration of medication, and administration of dutasteride for more than 8-weeks in rats could result in irreversible ED even after discontinuation of medication.

Keyword

5-alpha reductase inhibitors; Dutasteride; Erectile dysfunction; Finasteride

MeSH Terms

5-alpha Reductase Inhibitors
Administration, Oral
Animals
Collagen
Dutasteride
Electric Stimulation
Erectile Dysfunction*
Finasteride
Humans
Male
Models, Animal
Muscle, Smooth
Oxidoreductases*
Rats*
Rats, Sprague-Dawley
Transforming Growth Factors
5-alpha Reductase Inhibitors
Collagen
Dutasteride
Finasteride
Oxidoreductases
Transforming Growth Factors

Figure

  • Fig. 1 In vivo erectile responses to serial electrical stimulation in the normal control, 4-week dutasteride group, and 4-week dutasteride with 2-week resting group. Duta: dutasteride, ICP: intracavernosal pressure, MAP: mean arterial pressure, AUC: area under curve. MBP: mean blood pressure, BP: blood pressure. ap<0.05 vs. Normal, bp<0.05 vs. Dutasteride 4-week group.

  • Fig. 2 In vivo erectile responses to serial electrical stimulation in the normal control, 8-week dutasteride group, and 8-week dutasteride with 2-week resting group. Duta: dutasteride, ICP: intracavernosal pressure, MAP: mean arterial pressure, AUC: area under curve. MBP: mean blood pressure, BP: blood pressure. ap<0.05 vs. Normal, bp<0.05 vs. Dutasteride 8-week group

  • Fig. 3 (A) The changes in protein levels (protein: 40 µg) of fibrosis-related factors transforming growth factor (TGF)-β1, TGF-β2, and p-Smad/Smad (Smad 2/3) in the 4-week dutasteride group. (B) Changes in protein levels (protein: 40 µg) of fibrosis-related factors in the 8-week dutasteride group. N: normal control, D4: dutasteride 4 weeks, D4R2: dutasteride 4 weeks plus 2 weeks of rest, D8: dutasteride 8 weeks, D8R2: dutasteride 8 weeks plus 2 weeks of rest, nNOS: neuronal nitric oxide synthesis, iNOS: inducible nitric oxide synthase, eNOS: endothelial nitric oxide synthase, SMA: smooth muscle actin, Duta: dutasteride.

  • Fig. 4 The changes of immunohistochemical staining of smooth muscle (SM) (staining red) and collagen content (staining blue) in the corpus cavernosum of the rat model (Masson's trichrome staining, ×100). Duta: dutasteride. ap<0.05 compared with normal control.


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