myofibroblasts that have increased secretory activities and contribute to extracellular matrix production.22 This 'reactive state' and the increased expression of extracellular matrix components may contribute to the development of angiogenesis (the formation and differentiation of blood vessels), cell invasion and tumorigenesis, which can permanently alter the prostate 'architecture.'

Increased expression of CYR61, an extracellular matrix signaling protein, is evident in BPH tissue and is believed to play a key role in cell adhesion, proliferation, angiogenesis, anti-apoptosis, and prostate enlargement. CYR61 messenger ribonucleic acid (mRNA), which is regulated by lysophosphatidic acid (an endogenous lipid growth factor), is increased in both the epithelium and stroma of BPH tissue; this in turn leads to an increased production of CYR61 protein. CYR61 exerts its hyperplastic and proliferation effects mainly via an effect on growth factors such as platelet-derived growth factor.14 This process may contribute to the development of prostate cancer. Androgen-Related Changes

The age-related changes in testosterone and DHT, and the implications for BPH development, have been discussed in Section However, a number of other androgen-related changes have also been shown to occur in BPH tissue; androgen receptor co-activators such as ARA54, ARA55, and SRCI are upregulated in BPH stroma whereas androgen receptor repressors such as DAX-1 are downregulated.16 This may, in part, explain why there is an increased conversion to DHT in BPH tissue, and is in addition to an increase in NADPH-sensitive 5a-reductase, which occurs as a consequence of age-related lipid peroxidation.

Further studies have shown that two isoenzymes of 5a-reductase exist in the prostate, known as type 1 and type 2; the type 1 isoenzyme predominates in epithelial cells and the type 2 isoenzyme is present in both epithelium and stroma. Both have a key role to play in prostatic enlargement. The expression of type 1 mRNA (and consequently type 1 isoenzyme activity) has been reported to be much higher than that of type 2; however, the clinical significance of this has yet to be established.24

In animal models, androgen-induced prostatic enlargement has been shown to have a direct effect on bladder obstruction. In a 28-day study, canines were given DHT 75mgday_ 1 and 17^-estradiol 0.75 mgday _ 1 (i.e., a realistic expression of BPH androgenic activity) via an implanted pump. Compared with controls, canines supplied with DHT and 17^-estradiol displayed obstructive micturition, increased detrusor pressure, lower urine-flow rate and a larger wet prostate weight. Furthermore, these changes were comparable to those observed in canines with natural BPH symptoms as shown in Figure 7.25 These researchers proposed that DHT induces obstruction by overstimulating

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