MP65-02 EFFECTS OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR, GSK2849466A AND TESTOSTERONE ON STRESS URINARY INCONTINENCE IN OVARIECTOMIZED RATS

Abstract

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Female Incontinence: Therapy II1 Apr 2016MP65-02 EFFECTS OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR, GSK2849466A AND TESTOSTERONE ON STRESS URINARY INCONTINENCE IN OVARIECTOMIZED RATS Takahiro Shimizu, Katsumi Kadekawa, Naoki Kawamorita, Philip Turnbull, Alan Russell, and Naoki Yoshimura Takahiro ShimizuTakahiro Shimizu More articles by this author , Katsumi KadekawaKatsumi Kadekawa More articles by this author , Naoki KawamoritaNaoki Kawamorita More articles by this author , Philip TurnbullPhilip Turnbull More articles by this author , Alan RussellAlan Russell More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.1213AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Stress urinary incontinence (SUI) is common in post-menopausal women, indicating that estrogen deficiency is one of the major causes of SUI that induces atrophic and degenerative changes in urethral and pelvic floor muscles. Selective androgen receptor modulators (SARMs) selectively stimulate anabolic pathway of the androgen receptor (AR) in muscle and bone while sparing the androgenic effects. In this study, we examined effects of a SARM (GSK2849466A, GSK) and dihydrotestosterone (DHT) on urethral continence function in a bilateral ovariectomy (OVX)-induced rat SUI model. METHODS Female nulliparous Sprague-Dawley rats with bilateral OVX were used. Rats were divided into 5 groups; sham operated (S), vehicle-treated OVX (O-V), GSK-treated OVX (0.005 or 0.03 mg/kg/day, po, O-L or O-H, respectively), and DHT-treated OVX (1 mg/kg/day, sc, O-D) groups. At 2 or 3 weeks after OVX, GSK (or vehicle) or DHT treatment was started. Six weeks after OVX, rats were subjected to the evaluation of sneeze-induced continence reflex and sneeze-induced leak point pressure (SLPP) measurements, followed by histological analyses of urethral tissues. RESULTS Urethral baseline pressure (UBP) and the amplitude of urethral responses during sneezing (AURS) were significantly reduced in O-V rats (n=11) by 46% and 38%, compared to S rats (n=8). Compared to the O-V, UBP was significantly increased in the O-L (n=6) and O-H (n=9) by 123% and 86%, and AURS was significantly increased in the O-H and O-D (n=10) by 106% and 60%. Fluid leakage was observed during sneezing in all O-V rats (n=8, SLPP=59.9 ± 9.5 cmH2O) whereas sham rats (n=8) did not leak. The leakage was also observed in O-L (7 of 9 rats, SLPP=67.4 ± 3.0 cmH2O), O-H (1 of 8 rats, SLPP=82.9 cmH2O) and O-D rats (3 of 8 rats, SLPP=73.2 ± 12.8 cmH2O). O-H rats showed hypertrophy/reversal of atrophy of striated (ST) and smooth (SM) muscles in urethral transverse sections, compared to O-V rats. CONCLUSIONS These results indicate that OVX significantly impairs urethral continence function after 6 weeks, and that GSK dose-dependently restores the reductions in UBP, AURS and SLPP accompanied with urethral muscle hypertrophy, leading to the prevention of SUI. Based on our previous studies, UBP and AURS predominantly reflect urethral SM and ST activity in rats. Considering that DHT restores the reduction in AURS without affecting reduced UBP and partially prevents SUI in OVX rats, SARMs could be more effective for the treatment of SUI by enhancing both SM and ST-mediated urethral function under stress conditions such as sneezing. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e864 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Takahiro Shimizu More articles by this author Katsumi Kadekawa More articles by this author Naoki Kawamorita More articles by this author Philip Turnbull More articles by this author Alan Russell More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...