Journal of Urology and Renal Diseases (ISSN: 2575-7903)

Article / review article

"Cyclical Estrogen as a Major Etiology of Interstitial Cystitis: A Theory and Review"

Robert M Levin1,2*, Catherine Schuler1, Robert E Leggett1 

1Stratton VA Medical Center, Albany, NY, USA

2Albany College of Pharmacy and Health Sciences, Albany, NY, USA

*Corresponding author: Robert M Levin, Senior Research Career Scientist, Stratton VA Medical Center, Albany, NY 12208, USA. Tel: +1-5183690173; Email:

Received Date: 20 September, 2018; Accepted Date: 05 October, 2018; Published Date: 10 October, 2018

1.            Abstract 

Interstitial Cystitis / Pelvic Bladder Syndrome (IC/PBS) is a lower urinary tract dysfunction characterized by urgency, frequency, and pain upon bladder distension. Although there is no widely accepted etiology of IC, most researchers and clinicians believe it involves the breakdown of the mucosal permeability barrier and the penetration of solutes from the urine into the bladder mucosa and muscle, causing sensory neuro-inflammation and other cellular and sub-cellular pathologies resulting in IC/PBS. Our hypothesis is: Cyclical Estrogen is a Major Etiological factor of Interstitial Cystitis / Pelvic Bladder Syndrome: The menstrual cycle is characterized by cyclical changes in circulating estrogen. We completed two rabbit studies in which circulating estrogen was cycled between low estrogen (following ovariectomy) and high estrogen (following implantation of slow-release estrogen tablet). Circulating estrogen concentrations were cycled at two-week intervals (mimicking the menstrual cycle) for 4 complete cycles; ending either after a low estrogen period or after a high estrogen period. These rabbit studies on the effect of cyclical estrogen demonstrate that during low estrogen periods, blood flow, PO2, and blood vessel density decrease; mucosa thickness decreases, mucosal and smooth muscle hypoxia increase; free radical generation and oxidative stress increase; and the volume fraction of smooth muscle / collagen decreases. During high estrogen periods all responses to low estrogen return back to or toward normal. This time frame would make it very likely that these same changes occur in women during the normal menstrual cycle; which provides direct support of our hypothesis. Additional support comes from several clinical papers that show: 1) Estrogen variations during the menstrual cycle significantly affect bladder pain in IC/PBS patients. 2) On a cellular level, estrogen directly modulates pain mechanisms. And 3) if one suppresses circulating estrogen, or increases circulating estrogen continually, IC/PBS pain symptoms are relieved but return when cyclical estrogen is restored.

Although the above studies provide direct support that cyclical estrogen has marked cyclical effects on bladder smooth muscle and mucosal blood flow, nerve density, oxidative stress, hypoxia, and structure (including hypertrophy, hyperplasia, apoptosis, and smooth muscle / collagen ratios). At this time there is no direct evidence that the pain associated with IC/PBS is directly related to either low or high estrogen periods.

2.            Keywords: Bladder; Estrogen; Interstitial Cystitis; Ischemia; Oxidative Stress; Painful Bladder Syndrom; Rabbits; Reperfusion

Figure 1: Schematic of the menstrual cycle showing the circulating estrogen, uteral hypertrophy, follicular and luteal phases, this figure is a modified free clip-art schematic


Figure 2: Effect of cyclic estrogen on compliance and volume fraction of smooth muscle: Each bar is the mean +/- SEM of 4 rabbits. Ovx = ovariectomy; Ovx + E = ovariectomy plus continuous estrogen; Cyclic – E = cyclical estrogen ending at the end of a low estrogen period. Cyclic + E = cyclical estrogen ending at the end of a high estrogen period. * = Significantly different from control; x = significantly different.

Figure 3: Effect of cyclic estrogen on blood flow and blood vessel density: Each bar is the mean +/- SEM of 4 rabbits. * = Significantly different from control; x = significantly different from Ovx; ** = significantly different from Ovx + E; xx = significantly different from Cyclic – E; p < 0.05.