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Protective effects of estrogen on ischemia/reperfusion–induced bladder dysfunction in female rabbits

Chuang, Shu-Mien PhD1; Long, Cheng-Yu MD, PhD2,3; Lin, Rong-Jyh PhD4,5; Liu, Keh-Min PhD6; Levin, Robert M. PhD7; Chang, Chao-Yuan MS8; Ho, Ya-Wen MS9; Wu, Wen-Jeng MD, PhD9,10; Chang, Wei-Chiao PhD11; Juan, Yung-Shun MD, PhD9,10,12

doi: 10.1097/GME.0b013e3182635bae
Original Articles

Objective The present study investigated the effects of ovarian hormone depletion and estrogen administration on ischemia/reperfusion (I/R)–induced bladder damage in female rabbits.

Methods Female New Zealand white rabbits were divided into five groups. A sham surgical procedure was performed on rabbits in group 1. In group 2, both vesical arteries were clamped for 2 hours and then released (I/R surgical procedure). In group 3, 17β-estradiol (100 μg/kg/d) was injected intramuscularly before I/R surgical procedure. In group 4, ovariectomies were performed before I/R surgical procedure. Group 5 had ovariectomy, recovered for 2 weeks, and then received 17β-estradiol for 2 weeks. I/R surgical procedure was performed thereafter. Rabbits were killed 7 days after I/R surgical procedure. Masson’s trichrome stain was used, and immunohistochemical experiments were performed to evaluate interstitial fibrosis and intramural nerve changes. Western immunoblots were examined to determine the expressions of markers for inflammation, fibrosis, and oxidative stress.

Results I/R surgical procedure decreased bladder contractile responses by 30% to 50%. Ovarian hormone depletion further reduced bladder contractile function by 45% to 55% compared with the I/R group members that retained their ovaries. Moreover, I/R surgical procedure significantly decreased intramural neurofilament staining by two thirds compared with the control group. Estrogen replacement after ovariectomy significantly increased the density of nerve terminals. In addition, the expression of transforming growth factor-β and fibronectin increased twofold and fivefold after I/R, respectively. Ovarian hormone depletion further increased the expression of these inflammatory and fibrosis markers. Ovariectomy significantly exacerbated oxidative damage, whereas estrogen replacement diminished oxidative stress to a level approaching that of the control group.

Conclusions I/R surgical procedure increases oxidative damage, enhances interstitial fibrosis, and results in bladder denervation. Ovarian hormone deficiency exacerbates this I/R–induced bladder damage, whereas estrogen therapy after ovariectomy attenuates this injury. These results reveal estrogen’s protective effects on bladders subjected to I/R injury and the potential benefits of estrogen therapy on I/R–induced bladder damage.

From the 1Yuh-Ing Junior College of Health Care and Management, Kaohsiung, Taiwan; 2Excellence for Environmental Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 3Department of Obstetrics and Gynecology, Kaohsiung Municipal Hsia-Kang Hospital, Kaohsiung, Taiwan; 4Department of Parasitology, College of Medicine, 5School of Pharmacy, College of Pharmacy, and 6Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 7Albany College of Pharmacy, Albany, NY; Departments of 8Physiology and 9Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 10Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan; 11Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taiwan; and 12Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.

Received March 10, 2012; revised and accepted June 6, 2012.

Funding/support: This study was supported, in part, by grants from the Department of Medical Research, National Science Council (NSC 98-2314-B-037-040-MY3), Kaohsiung Medical University Hospital (KMUH-100-0R44), and Kaohsiung Medical University (KMU-Q098015).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Yung-Shun Juan, MD, PhD, Department of Urology, College of Medicine, Kaohsiung Medical University, 100 Shih-Chuan First Road, Sanmin District, Kaohsiung City 807, Taiwan. E-mail:

© 2013 by The North American Menopause Society.