Effects of a selective androgen receptor modulator (SARM), GSK2849466A, on stress urinary incontinence and bladder activity in rats with ovariectomy-induced oestrogen deficiency

Katsumi Kadekawa, Naoki Kawamorita, Takahiro Shimizu, Masahiro Kurobe, Philip S. Turnbull, Sundeep Chandra, Takahito Kambara, Joanna C. Barton, Alan J. Russell, Naoki Yoshimura

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Abstract

Objectives: To report the effect of a selective androgen receptor modulators (SARMs) on the urethral continence mechanisms in a rat model of stress urinary incontinence (SUI) induced by bilateral ovariectomy (OVX). Materials and methods: Female Sprague-Dawley rats with bilateral OVX were used. Rats were divided into five groups; sham operated, vehicle-treated OVX, low-dose SARM-treated OVX (GSK2849466A: 0.005 mg/kg/day, per os [p.o.]), high-dose SARM-treated OVX (GSK2849466A: 0.03 mg/kg/day, p.o.) and dihydrotestosterone (DHT)-treated OVX (1 mg/kg/day, subcutaneous) groups. After 4 weeks of SARM treatments or 3 weeks of DHT treatment (6 weeks after OVX), rats were subjected to evaluation of the sneeze-induced continence reflex using microtransducer-tipped catheter methods, sneeze-induced leak-point pressure, and continuous cystometry measurements, followed by histological analyses of urethral tissues. Results: (i) OVX significantly impaired urethral continence function after 6 weeks to induce SUI during sneezing. (ii) Low-dose SARM treatment restored urethral baseline pressure (UBP) without affecting the amplitude of urethral response during sneezing (A-URS), partially reversing OVX-induced SUI during sneezing. (iii) High-dose SARM treatment reversed decreases in both UBP and A-URS, more effectively preventing SUI during sneezing. (iv) DHT treatment only restored A-URS without affecting UBP, partially preventing OVX-induced SUI during sneezing. (v) The high-dose SARM treatment induced hypertrophy of the striated and smooth muscle around the urethra. (vi) SARM treatment did not affect bladder function in sham or OVX rats. Conclusion: Treatment with SARMs could be a more effective modality for the treatment of SUI than DHT, without affecting bladder function, by enhancing smooth- and striated muscle-mediated urethral function under stress conditions such as sneezing.

Original languageEnglish
Pages (from-to)911-919
Number of pages9
JournalBJU International
Volume125
Issue number6
DOIs
Publication statusPublished - 2020 Jun 1
Externally publishedYes

Keywords

  • ovariectomy
  • selective androgen receptor modulators
  • sneeze reflex
  • stress
  • urethra
  • urinary incontinence

ASJC Scopus subject areas

  • Urology

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