TY - JOUR
T1 - Effects of a selective androgen receptor modulator (SARM), GSK2849466A, on stress urinary incontinence and bladder activity in rats with ovariectomy-induced oestrogen deficiency
AU - Kadekawa, Katsumi
AU - Kawamorita, Naoki
AU - Shimizu, Takahiro
AU - Kurobe, Masahiro
AU - Turnbull, Philip S.
AU - Chandra, Sundeep
AU - Kambara, Takahito
AU - Barton, Joanna C.
AU - Russell, Alan J.
AU - Yoshimura, Naoki
N1 - Funding Information:
This work was supported by a research grant from GlaxoSmithKline and a grant from National Institutes of Health (R01 DK107450).
Funding Information:
This work was supported by a research grant from GlaxoSmithKline and a grant from National Institutes of Health (R01 DK107450).
Publisher Copyright:
© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - ovariectomy
KW - selective androgen receptor modulators
KW - sneeze reflex
KW - stress
KW - urethra
KW - urinary incontinence
UR - http://www.scopus.com/inward/record.url?scp=85082857709&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85082857709&partnerID=8YFLogxK
U2 - 10.1111/bju.15022
DO - 10.1111/bju.15022
M3 - Article
C2 - 32011085
AN - SCOPUS:85082857709
VL - 125
SP - 911
EP - 919
JO - British Journal of Urology
JF - British Journal of Urology
SN - 1464-4096
IS - 6
ER -