We propose what is to our knowledge a previously unexplored mechanism that might promote LUTS in men, namely prostate tissue stiffening consequent to fibrosis. Results demonstrate the feasibility of measuring prostate tissue stiffness, the association of high levels of tissue stiffness with collagen content and fibrosis, and the further association of these measures with LUTS. Such periurethral tissue fibrosis could decrease urethral flexibility and compromise the ability of the prostatic urethra to expand to accommodate urinary flow during micturition, which could manifest as obstructive symptoms.
A limitation of the current study was the inability to collect and examine transurethral resection of the prostate tissues procured after treatment for benign prostatic hyperplasia and prostatic enlargement. This inability was due to the current standard of care at our institution, which is based on laser ablation of prostate tissue. Although it is effective, this method does not permit tissue collection for research studies. Another limitation is the lack of information on LUTS in study patients other than preoperative AUASI scores. Since most patients are referred to our institution for prostatectomy after the prostate cancer diagnosis, information on a history of LUTS is not available. Also, it is unclear whether periurethral fibrosis reflects fibrosis only of the transitional zone of the prostate or whether it may indicate more widespread fibrosis including the peripheral zone and lower urinary tract. It is also unclear whether such more extensive fibrosis would impact urethral function. Furthermore, in 20 of the 28 men (70%) treated with prostatectomy ages clustered between 53 and 64 years. Thus, we could not adequately test the role of aging in the development of fibrotic changes in prostate tissue architecture. Despite these limitations we believe that our study clearly associates periurethral fibrosis with LUTS and provides the rationale for further study and perhaps therapeutic targeting of the mechanisms contributing to prostatic fibrosis.
Although to our knowledge it is novel in the setting of LUTS, aging associated fibrotic changes in tissue architecture contribute to dysfunction and disease in multiple organ systems.6
Fibrosis can generally be considered an errant wound healing process in response to chronic inflammation. Chronic inflammation has been noted in the prostate in the context of prostatitis and histological inflammatory infiltrate.6,8
Prostatitis is a common condition that accounts for almost 2 million ambulatory care visits annually in the United States.23
Epidemiological data reveal an association between chronic prostatic inflammation (ie prostatitis) and subsequent development of LUTS.24,25
Also, chronic inflammation has been noted in several histological studies of the prostate.25–29
Together these studies suggest that, as in other organ systems, inflammatory changes in the prostate consequent to aging or infection may promote progressive fibrosis and changes in tissue architecture, contributing to urinary obstructive symptoms.
Multiple cell types can differentiate or dedifferentiate into myofibroblasts ().30
Many if not all of these cell types comprise the prostatic tissue microenvironment, suggesting that dynamic changes in tissue composition may develop in the prostate due to aging and inflammatory processes. Our data suggest that fibrosis is one of these processes and it is associated with LUTS. Tissue fibrosis along with cellular proliferation/prostatic enlargement and smooth muscle hypercontractility may act independently or in combination to promote male LUTS (). Moreover, these 3 pathological processes likely overlap, in that the cell types involved in these processes can accumulate and transdifferentiate. If so, therapy targeting these 3 pathological processes may be needed to adequately alleviate the symptoms and pathobiology contributing to male LUTS.
Prostate fibrotic development and contribution to male LUTS. A, multiple cell types that can differentiate into myofibroblastic cells. B, 3 major pathobiological processes that can act alone or in combination to promote male LUTS.