Clinical treatment for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hypertrophy (BPH) in men is a significant cost to healthcare (>$4-billion/year), adversely affecting quality of life, and contribute to the mortality risk in men. The long term objectives of this project are to better understand the molecular and anatomical processes involved in manifestation of LUTS and to develop better methods for prevention and treatment of LUTS. Lower urinary tract dysfunction (LUTD), including bladder outlet obstruction (BOO), may occur through a number of physical obstructive events leading to physiological alteration of bladder function. Although bladder obstruction has typically been associated with nodular prostatic growth, the actual cause(s) of LUTS in men with clinical BPH remain unknown and may encompass several additional physiological/anatomical pathologies including bladder neck stricture, altered central nervous system function, and more recently prostatic fibrosis. Recent published and preliminary studies demonstrate that the tissue microenvironment of the prostate is permissive for ECM deposition and fibrosis. Such ?fibrosis?may increase prostate stiffness and promote urethral rigidity to produce an obstruction and hence lead to LUTS. The development and progression of LUTS has been clearly linked with fibrosis, yet it is not currently monitored or therapeutically targeted in men writhe with LUTD. Rather, medical approaches targeting smooth muscle contractility (e.g. alpha blockers), androgenic pathways [5-?-reductase inhibitors (5aRI)], or surgical methods [e.g. transurethral resection of the prostate (TURP)] are used to manage LUTS. Although these approaches may improve urinary flow a number of problems exist with this standard of care including: treatments are not effective in all men, elicit side-effects, and do not abolish the risk of disease progression. While the etiology of BPH remains largely unclear available data are consistent with the hypothesis that changing hormone levels, especially estradiol-17? (E2) and testosterone (T), are underlying causes of BPH/LUTS. Use of 5aRIs support this concept, because these therapies target the androgenic pathway. However, paradoxically androgen levels decrease as men age while E2 and E2:T ratios significantly increase. This posits that estrogens may be an important pathway in the etiology or persistence of BPH and associated LUTS. Estrogens primarily mediate their effects by binding two receptors;estrogen receptor (ER)-? and ER-?. ER transcription is further regulated by the capacity of the liganded receptor to homodimerize (ER-?/? or ER-?/?) or heterodimerize (ER-?/?). New unpublished data from our laboratory and others implicate E2 as a key mediator of LUTD. Our preliminary data implicate E2/ER-signaling via ER-?/? homodimerization as the key molecular mediator of LUTD. We hypothesize that abnormalities within the lower urogenital tract are mediated by inappropriate E2/ER-signaling that leads to urethral fibrosis and decreased urinary function. We further hypothesize that therapeutically targeting ERs will prevent the development of prostatic fibrosis and hence LUTD.

Public Health Relevance

During the aging process nearly all men experience some form of lower urinary tract symptoms (LUTS), often due to benign prostatic hyperplasia (BPH). In addition to morbidity and quality of life issues, LUTS also significantly affects mortality risk. The proposed research addresses an urgent need in the urological field by performing estrogen hormone action mechanistic studies that underpin molecular pathways involved in BPH/fibrosis. The expectation of these studies is to elucidate how fibrosis is associated with BPH/LUTS and develop therapeutic targets towards currently unknown pathways involved in BPH and hence prevent or treat this disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZDK1-GRB-7 (O2))
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University of Wisconsin Madison
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