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Adapted with kind permission from Fromont, G.; Chene, L.; Latil, A.; Bieche, I. Vidaud, M.; Vallancien, G.; Mangin, P.; Fournier, G.; Validire, P.; Cussenot, O. J. Urol. 2004, 172, 1382-1385. a Mean normal value was 1.

In addition to those listed by Fromont et a/.,12 other studies have shown that polymorphism of the TGFßl gene, which plays a significant role in cell proliferation and apoptosis, is associated with BPH. Using a sample of 221 BPH patients and 303 male controls, those with the codonlO polymorphism had a 1.51-fold increased risk of BPH. CYR61, a protein involved in BPH remodeling (see Section 6.24.3.4), also shows increased gene expression in patients with BPH. Figure 6 shows that the expression of CYR61 was higher in those patients with symptomatic BPH or comorbid prostate cancer than in normal controls.14 These findings suggest that abnormal expression of CYR61 may be a predisposing factor in the development of cancer. Other studies show that mutation of the SRD5A2 gene, which encodes for 5a-reductase, may be involved in the development of BPH. One longitudinal study of 510 men with BPH showed that those patients with polymorphism of this gene (referred to as LL/VL, AT/TT, and TA(0)/TA(0) genotypes) were considered high risk for BPH. These genotypes were also associated with larger prostate volumes.15

6.24.3.2 Cellular Changes

At the cellular level, BPH is characterized by a 're-awakening' of embryonic mesenchyme in the stroma and epithelium of the prostate periurethral zone; this induces proliferation of stromal smooth muscle cells, coupled with an increase in nonmuscle myosin heavy chain. This is followed by an increase in fibrous elements that can lead to the appearance of 'stromal BPH nodules.'16 The epithelium also changes; obstruction of ducts (possibly due to stromal growth and BPH nodules) may cause the luminal secretory epithelium to flatten, resulting in a dramatic increase in the intraluminal space. The basal epithelium becomes attenuated, which may be due to a loss of cellular adhesion molecule, a key marker involved in the maintenance of epithelial cell differentiation, and the density of neuroendocrine cells is reduced.16 This loss of normal prostate cell 'architecture' is characteristic of the histopathologic changes associated with BPH.

6.24.3.3 Changes in Proliferation, Apoptosis, and Senescence

BPH is associated with a change in the proliferation-to-apoptosis ratio, i.e., there is an increase in cell growth and a decline in cell death. The process by which cell proliferation increases during BPH development is largely unknown; however, there is evidence to suggest that local hypoxia in BPH tissue, caused by an excessive demand on oxygen supply from growing cells, may trigger an increase in growth factors such as FGF-7, IGF, and TGF and interleukins such

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