Info

PdetmaxQmax (cm water)

PdetmaxQmax (cm water)

Prostate weight (g)

Figure 7 Androgen- and benign prostatic hyperplasia (BPH)-induced urinary problems (i.e., increased detrusor pressure and prostate volume and lower urine flow) compared with controls in canines. DHT, dihydrotestosterone; E, 17p-estradiol; PdetmaxQmax, maximum detrusor pressure at maximum urine flow rate; Qmax, maximum urine flow rate. (Reproduced from Yokota, T.; Honda, K.; Tsuruya, Y.; Nomiya, M.; Yamaguchi, O.; Gotanda, K.; Constantinou, C. E. Prostate 2004, 58, 156-163, copyright © 2004 Wiley-Liss, Inc., A Wiley Company, with permission of John Wiley & Sons, Inc.)

muscarinic cholinergic receptors leading to a supersensitive effect on the detrusor muscle, and the magnitude of urethral constriction observed (and consequently low urine-flow rate) may depend on the duration of excessive DHT exposure. Although these findings are not directly comparable to the age-related effects of DHT in human males, they are still a useful hormonal-urodynamic model of BPH.

6.24.3.6 Inflammation

A number of inflammatory markers are associated with the cell proliferation and differentiation changes observed in BPH. It has been suggested that elevated numbers of T lymphocytes and macrophages leads to an increased secretion of various proinflammatory factors such as IL1, IL6, tumor necrosis factor alpha (TNF-a), and VEGF, resulting in chronic inflammation, clogged epithelial ducts, and disruption of glandular epithelium in BPH tissue.21 Many of these factors are also responsible for the upregulation of COX-2, a key marker involved in the age-related decline in testosterone biosynthesis (see Section 6.24.1.1). Not surprisingly, COX-2 concentrations increase in epithelial areas where there are high levels of T lymphocyte and macrophage infiltration (as shown in Figure 8). COX-2 overexpression may also be linked to increased proliferation, cell death inhibition, prevention of oxy-radical defense systems in BPH tissue, and the development of prostate cancer.26 Macrophages are also a source of ROS such as hydrogen peroxide, mainly via an effect on NADPH oxidase. Macrophage-induced ROS can lead to oxidative stress and tissue injury in areas where these cells have accumulated.21

6.24.3.7 Impact on Bladder Pathophysiology

Although BPH is largely confined to prostate abnormalities, a number of degenerative changes can take place in the bladder. It is thought that prostate hyperplasia can result in partial bladder outlet obstruction (PBOO), which increases urethral resistance to urine flow and causes acute bladder distension. The bladder responds to distension by inducing bladder wall growth (i.e., bladder hypertrophy) and angiogenesis, a compensation process that is designed to improve the bladder's ability to void. This is rapidly followed by a period of decompensation, where these growth mechanisms are switched off, possibly via genetic signals. Nevertheless, voiding-induced ischemia and tissue hypoxia are still features of the stabilized, hypertrophic bladder, and can have an effect on urinary retention. Marked remodeling of the bladder wall due to denervation, loss of smooth muscle and compliance, and increased fibrosis also remains, and is likely to have a significant long-term effect on bladder emptying and the development and expression of LUTS. Obstructed bladder dysfunction, secondary to BPH, is a chronic and progressive aspect of the disease, which may eventually result in renal damage.27 The development of bladder dysfunction as a consequence of unrelieved PBOO is outlined in Figure 9.

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