Effect of Late Androgen Replacement Therapy on Erectile Function Through Structural Changes in Castrated Rats

Abstract

Background: Because androgen replacement therapy (ART) is not performed immediately after the onset of androgen deficiency, the treatment is considered to be late.

Aim: To investigate the effects of late ART, starting 4 weeks after castration of rats, on erectile function and structural changes in the corpus cavernosum.

Methods: Rats were subjected to ART for 4 (Late-ART [4w]) or 8 (Late-ART [8w]) weeks. In either case, rats were assigned to the following groups: castrated (Cast), castrated with subcutaneous administration of testosterone (3 mg/kg/day; Cast+T), and sham (Sham). Cast + T rats received daily subcutaneous doses of testosterone starting 4 weeks after castration for 4 or 8 weeks whereas Sham and Cast rats received only the vehicle.

Outcomes: Erectile function was assessed by evaluating intracavernosal pressure (ICP) and mean arterial pressure (MAP) after electrical stimulation of the cavernous nerve, corporal veno-occlusive function using dynamic infusion cavernosometry, and histology using Masson's trichrome staining.

Results: No increase in the ICP was observed in Cast+T rats in the Late-ART (4w) group (0.47 ± 0.02, P > .05), whereas, in Cast+T rats in the Late-ART (8w) group, there was a significant increase in the ICP/MAP ratio (0.60 ± 0.02, P < .05), drop rate, and smooth muscle/collagen ratio.

Clinical translation: The present study provides scientific evidence for the effect of late ART on erectile function.

Strengths and limitations: This study provides insights into the influence of late ART on erectile function through improvements in the structure of corpus cavernosum. The major limitation of this study is the difference in the time required for healing between the humans and rats, which might have a bearing on the translational relevenace of the results.

Conclusions: Late ART could improve erectile function. However, as improvement requires a considerable time period, it is necessary to persist with therapy patiently for optimal results. Kataoka T, Hotta Y, Yamamoto Y, et al. Effect of Late Androgen Replacement Therapy on Erectile Function Through Structural Changes in Castrated Rats. Sex Med 2021;XX:XX-XXX.

Keywords: Corporal veno-occlusive function; Erectile dysfunction; Histological change; Testosterone.

Figure 1

Experimental design. Two intervention periods were set—Late-ART (4w) and Late-ART (8w; Figure 1). For each period, rats were assigned to the following groups: castrated (Cast), castrated with subcutaneous testosterone (3 mg/kg/day) (Cast+T), and sham (Sham). Sham rats underwent sham laparotomies and the incision was sutured. In the Cast+T group, rats received daily subcutaneous doses of testosterone (3 mg/kg/day) starting 4 weeks after the operation for 4 (Late-ART [4w]) or 8 weeks (Late-ART [8w]). At the end of these periods, rats were subjected to erectile function testing in vivo and in vitro.

Figure 2

Androgen receptor (AR) mRNA expression in the corpus cavernosum of rats. A. In the late-ART (4w) group; B. In the late-ART (8w) group. Target gene expression was quantified relative to the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using the comparative CT method. Data are reported as means ± standard error of the mean (n = 4 per group). N.S. means not significant using Bonferroni's multiple t-test.

Figure 3

(A-B) Representative tracings of changes in the intracavernous pressure (ICP) and arterial pressure during electrical stimulation of the cavernous nerve in Sham, Cast, and Cast+T rats in the Late-ART (4w) and Late-ART (8w) groups. (C-D) Evaluation of the erectile function based on the ICP/mean arterial pressure (MAP) ratio. Data are reported as means ± standard error of the mean (n = 7–10 per group). *P < .05, ^⁎⁎P < .01 vs each group as determined using analysis of variance and Bonferroni's multiple t-test.

Figure 4

(A-B) Corporal veno-occlusive function as determined using the drop rate in dynamic infusion cavernosometry (DIC). Data are reported as means ± standard error of the mean (n = 7 per group). *P < .05, ^⁎⁎P < .01 vs each group using analysis of variance and Bonferroni's multiple t-test.

Figure 5

Masson's trichrome staining of rat penile tissue. (A-B) Representative specimens stained with Masson's trichrome stain. (C-D) Histological evaluation of the corpus cavernosum used to calculate the area ratios of the smooth muscle (SM) and collagen fiber by computerized image analysis. Data are means ± standard error of the mean (n = 6 per group). ^⁎⁎P < .01 vs each group using analysis of variance and Bonferroni's multiple t-test.