Elsevier

Urology

Volume 146, December 2020, Pages 242-247
Urology

Reconstuctive Urology
Reversing Urethral Hypovascularity Through Testosterone and Estrogen Supplementation

https://doi.org/10.1016/j.urology.2020.06.103Get rights and content

Objective

To determine the ability of testosterone and estrogen to reverse urethral hypovascularity secondary to hypogonadism, we analyzed the effects of testosterone and estrogen supplementation on castrated Sprague Dawley rats.

Materials and Methods

Twenty four Sprague-Dawley rats were divided into 4 groups: (1) non-castrate (NC) controls; (2) castrate (C) unsupplemented rats; (3) castrate rats that received testosterone (T), or (4) castrate rats that received estradiol (E). With immunohistochemistry, we measured vessel density (endothelial cell marker CD31), expression levels of androgen receptor (AR), TIE-2, and estrogen receptors ER-alpha and GPER1.

Results

Urethral vascularity was significantly increased after both testosterone and estrogen supplementation (T: 8.92%, E: 7.66%, vs C: 3.62%; P <0.001 for both), surpassing that of NC (5.86%, P <0.001 for both). Testosterone restored AR expression to physiologic levels (T: 5.21%, NC: 4.54%, P =0.135), and upregulated expression of TIE-2 (T: 0.20%, NC: 0.43%, P <0.001), neither of which was expressed in the absence of testosterone. Expression levels of nuclear ER-alpha was nearly undetectable (0.06%-0.38%), while membrane-bound GPER1 expression was upregulated by estrogen (3.30%) compared to other groups (T: 2.01%, NC: 1.02%, C: 0.37%, P <0.01 for all). Increased vessel density was significantly associated with increased AR (r = 0.22, P = 0.019) and GPER1 expression (r = 0.25, P = 0.018) suggesting a mechanistic relationship.

Conclusion

Testosterone and estrogen exposure both restore periurethral vascularity in castrate (hypogonadal) rats via upregulation of AR/TIE-2 and GPER1 expression. Our results provide a foundation for testosterone or estrogen replacement in hypogonadal men to reverse atrophic effects of hypogonadism on the urethra.

Section snippets

Animals

This study was fully approved by the Institutional Animal Care and Use Committee of Northwestern University (Protocol #IS00004702). Six non-castrate and 18 castrate male Sprague-Dawley rats (7 weeks old, weight 175-225g) were acquired from Charles River Laboratories (Wilmington, MA). The rats were surgically castrated at 6.5 weeks to ensure that they had achieved sexual maturity prior to castration. The rats were divided into 4 groups: noncastrate (NC) control, castrate non-supplemented (C),

Periurethral Vascularity (CD31 Expression)

Detailed expression results for CD31, AR, TIE-2, ER-alpha, and GPER1 expression are listed in Table 1 and photographs of immunohistochemistry staining patterns are displayed in Figure 1. In order to quantify vessel density, we evaluated expression of the endothelial cell marker CD31. Castrated rats demonstrated the lowest levels of CD31 expression and vessel density (3.62%, Fig. 2A), reinforcing that testosterone deprivation is associated with decreased periurethral vascularity. CD31 expression

COMMENT

Because many AUS cuff erosions occur in hypogonadal men, we wondered whether hormonal supplementation with testosterone or estrogen might reverse atrophic changes seen from hypogonadism in a rat urethra model. As proof of concept, we confirmed that the rat urethra demonstrates significantly lower angiogenesis in the absence of androgen compared to the urethras of noncastrate control animals, analogous to the human urethra.3 TRT restored periurethral vascularity comparable to that of noncastrate

CONCLUSION

We found that testosterone supplementation as well as estrogen supplementation restored periurethral vascularity in castrated (hypogonadal) rats. Both hormone therapies were associated with equivalent, if not superior, periurethral vascularity compared to noncastrate control animals. These results provide a basis for employing testosterone or estrogen in order to reverse the effects of hypogonadism in men at risk for AUS complications due to urethral atrophy.

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Financial Disclosure: The authors declare that they have no relevant financial interests.

Histology services were provided by the Northwestern University Histology and Phenotyping Core Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.

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