Prostatic fibrosis, lower urinary tract symptoms, and BPH

Abstract

Lower urinary tract symptoms (LUTS)--constituting a spectrum disorder that encompasses weak stream, nocturia, and sensations of incomplete emptying and intermittent or hesitant urination--are indicative of lower urinary tract dysfunction (LUTD). LUTD is a progressive disease that can lead to bladder dysfunction if left untreated or treated ineffectively. Sequelae include urinary retention, recurrent UTI, bladder calculi, and, eventually, renal impairment. LUTD involving the prostate is associated with both ageing and inflammation. Tissue inflammation resulting from ageing, infection, or other inflammatory disease processes (for example, type 2 diabetes mellitus) is epidemiologically associated with the subsequent development of tissue fibrosis in multiple organ systems, including the prostate. Recent studies show that tissue fibrosis in the lower urinary tract is associated with LUTD, and suggest that fibrosis might be a previously unrecognized pathobiology that contributes to LUTD. Thus, antifibrotic therapeutic agents should be considered as a new approach to efficaciously treating men with LUTD, especially those who don't experience durable responses to 5α-reductase inhibitors or α-adrenergic receptor antagonists.

Figure 1

Prostatic pathobiologies that contribute towards lower urinary tract dysfunction. The prostate consists of ductal glands surrounded by fibromuscular stroma, which, in turn, surrounds the prostatic urethra. a | The ductal glands and fibromuscular stroma can separately or concurrently hyperproliferate, producing prostatic enlargement and urethral obstruction. BPH can be medically managed by 5α-reductase inhibitors, which prevent the conversion of testosterone to its active form, dihydrotestosterone, leading to reduced levels of available dihydrotestosterone and prostate tissue proliferation. b | Myofibroblast phenoconversion and accumulation—and consequent ECM deposition in periurethral prostatic tissue (and possibly also adjacent tissues)—causes tissue stiffness and reduced urethral compliance in men with lower urinary tract symptoms. c | Smooth muscle within the prostate can exhibit dysfunctional contractility with consequent urinary voiding dysfunction, which can be medically managed with α-adrenergic receptor antagonists (which relax smooth muscle). Abbreviation: ECM, extracellular matrix.

Figure 2

Contribution of inflammation and fibrosis to lower urinary tract dysfunction (LUTD). UTI, prostatitis, ageing, and type 2 diabetes mellitus are all sources of tissue inflammation that promotes fibrosis in the lower urinary tract. Periurethral tissue fibrosis, stromal or epithelial prostatic proliferation, and smooth muscle dysfunction can, alone or in combination, promote male LUTD. These three pathobiologies can occur concurrently in the same prostate gland.

Figure 3

Myofibroblast phenoconversion and the initiation of fibrosis in the prostate. a | Healthy prostate tissue is comprised of diverse cell types, including fibrocytes, fibroblasts, epithelial cells, and endothelial cells, as well as others not shown here (for example, neurons and leucocytes). b | Many of these cell types can act as precursor cells that undergo myofibroblast phenoconversion upon exposure to profibrotic stimuli. Myofibroblasts accumulate and deposit excessive ECM, which replaces normal tissue with stiff noncompliant fibrotic tissue. Abbreviation: ECM, extracellular matrix.