Peripheral serotonin contributes to testosterone and estradiol induced urinary voiding dysfunction in adult male mice.

OBJECTIVE

Millions of aging men are diagnosed with lower urinary tract dysfunction (LUTD) each year. Alpha adrenergic receptor blockers relax prostatic, urethral, and bladder smooth muscle to relieve LUTD symptoms and are often, but not always, effective. Serotonin is proposed to cause contractions in the female urethra, as well as in the lungs and bowel. This study tests that serotonin synthesized in the periphery, outside of the central nervous system, contributes to the development of LUTD induced in mice by subcutaneous implants of testosterone (T) and estradiol (E2), mimicking the hormone milieu of aging men.

METHODS

Immunofluorescent staining of male human and mouse urethra was used to confirm the presence of neuroendocrine cells and interstitial cells of Cajal, which contribute to serotonin-induced contractions in the female mouse urethra. Wild type and tryptophan hydroxylase 1 null (Tph1-/- ) mice, which are deficient in the rate-limiting enzyme in peripheral serotonin synthesis, were given sham surgery or T+E2 implants. Voiding behavior was measured with the void spot assay one day before surgery and two weeks post-surgery. Four weeks after surgery, bladders were exteriorized and measured to calculate volume, and anesthetized cystometry was performed to assess bladder activity.

RESULTS

Serotonin-positive neuroendocrine cells and serotonin receptor positive interstitial cells of Cajal were detected in the prostatic urethra of humans and mice. Two weeks after T+E2 implantation surgery, a baseline level of urinary retention occurred in both wild type and Tph1-/- mice. However, wild type mice treated with T+E2 had increased frequent small voids (P<0.01) and decreased bladder activity (P<0.005) when compared to wild type mice with sham treatment and Tph1-/- mice with T+E2 treatment.

CONCLUSIONS

Wild type mice developed a more severe voiding dysfunction phenotype than Tph1-/- mice when treated with T+E2, indicating that peripheral serotonin plays a role in T+E2-mediated LUTD. Because the urinary dysfunction observed in mice mimics that of human men, future studies to understand and exploit the role of serotonin may provide a treatment option for a subset of LUTD.