Benign prostatic hyperplasia is a common disease of aged males. It is associated with low urinary tract syndrome and can result in serious complications including renal failure. The main pathophysiological factors, and consequently, therapeutic targets, are sex hormones and sympathetic activity. Testosterone, dihydrotestosterone, and estradiol play crucial roles, and their effects are influenced by several genetic factors.
The models of benign prostatic hyperplasia can be divided into in vivo and in vitro models. Animal models include spontaneous and hormonally or pharmacologically induced prostatic hyperplasia, as well as newly generated transgenic models. Cell cultures are simple and cost effective, but the research in vitro is difficult to interpret for human pathology.
The number of various models indicates that an ideal model of benign prostatic hyperplasia does not exist. Thus, further improvements are awaited to enhance the biomedical research with clinical outcome on this entity.
Male aging is accompanied by several prostate diseases including prostate cancer and prostatitis. However, by far the highest incidence and prevalence is reached by benign prostatic hyperplasia (BPH). Despite huge scientific and clinical effort, this entity is still an important biomedical problem, as neither the understanding of pathophysiology nor the currently applied therapy are satisfying. Research focused on BPH, thus, clearly is needed and should be supported by appropriate models of BPH. Nevertheless, the wide spectrum of models indicates that there is no clear winner of the race—no ideal model of BPH.
Although the existence of a female prostate is more or less accepted (Zaviacic and Ablin, 1998, 2000), this chapter will focus on male prostate hyperplasia, as the incidence of diseases of female prostate seems to be low and no specific animal or cell culture models exist for research on female prostate.
The contemporary view on the pathophysiology of BPH is presented, as it implies several different internal as well as external factors that influence prostate growth. This divergence can also explain the number of different available BPH models and the related problems regarding the interpretation of the results of various studies, both clinical and experimental. There is a need for further development of new models that would be closer to human pathology.
About 50% of men over 60 years have a pathologically increased prostate (see Figure 52.1).
The huge prevalence of BPH in men over the age of 80 years of more than 90% makes BPH ''an inescapable phenomenon'' for the male population if taking into account the contemporary rise of life expectancy in the developed world (Berry et al., 1984; Lepor, 2005). The volume and weight of prostate tissue is increasing from 20 g in 40 years to 60 g in 80 years of age (Oesterling et al., 1993). The hyperplasia of the prostate is not a life-threatening condition per se; however, BPH causes serious and dangerous complications. These include acute urinary retention as the most frequent complication, recurrent infections, chronic urinary retention, and even renal failure (Thorpe and Neal, 2003).
Most patients with BPH are asymptomatic and undiag-nosed. The most prominent complication is so-called LUTS—low urinary tract syndrome (see Table 52.1). LUTS and bladder outlet obstruction bring the patient to the clinician, but although the prevalence of LUTS also increases with age, the relationship between BPH and LUTS is complex (see Figures 52.2 and 52.3).
The severity of LUTS, for example, does not depend linearly on prostate size, although further research is needed (Girman, 1998). To distinguish between BPH, obstruction syndrome, and LUTS is difficult in epidemio-logic studies because the borders are unclear. However, this clinical feature is mostly not a part of the BPH models for research.
The mortality from BPH decreases steadily during the last 50 years. Bias caused by better diagnostics and differences in the inclusion criteria cannot be excluded. However, the increase in mortality in Eastern Europe and some other parts of the world is a warning signal that should not be overlooked (Levi et al., 2003).
TABLE 52.1 Low urinary tract syndrome—LUTS symptoms
Prolonged urination Post-micturation dribbling Poor urinary flow Incomplete bladder emptying Delay in onset of micturation Storage
Urge incontinence Nocturia
There are many factors influencing the so-called aging male. Androgens and other sex hormones that decrease in elderly men definitely belong to these factors; this condition is called PADAM—partial androgen deficiency of the aging male (Schulman and Lunenfeld, 2002). The role of androgens in the pathogenesis of BPH is common to their role in the prostatic carcinogenesis (Parnes et al., 2005). The relationship between prostate cancer and BPH is a matter of debate, which is out of scope of this chapter. Nevertheless, it should be noted that the BPH does not represent a clear premalignancy and the pathogenesis of both entities is divergent, although androgens play an important role in both pathologies.
Androgens affect the static part of BPH pathophysiol-ogy—the size of the prostate. The other group of factors is related to the dynamic tension of prostatic smooth muscles (see Figure 52.4).
In general, currently used therapy of BPH involves antiandrogenic treatment (reducing the prostate size) and alpha adrenergic blockade (relaxing of smooth muscle inside the prostate). The finding that alpha adrenergic blockade improves the symptoms of patients three-fold in comparison to antiandrogenic treatment does not ultimately mean that the adrenergic stimulation is more important in the pathogenesis of BPH. Other studies have shown the opposite, if longer observation periods were chosen. Moreover, many clinically important symptoms might be caused by conditions other than BPH, including functional denervation or detrusor dysfunctions, and these conditions might be affected by the alpha adrenergic blockade (Skolarikos et al., 2004).
The hormonal influence on the pathogenesis of BPH is undoubted. Castrated males do not develop BPH. Sex hormones have been shown to be a major factor in normal physiological development of prostate, but also in the pathological hyperplasia. However, the detailed mechanism of their effects is not clear (Roberts et al., 2004).
Besides androgens, recently the role of estrogens in prostate growth is also discussed, although previously, estrogens were thought to act protectively against BPH.
A common precursor of steroids is cholesterol, and the specific precursor of androgens is dehydroepiandro-sterone (Celec and Starka, 2003). The main metabolic pathways of androgens are shown in Figure 52.5.
Nevertheless, testosterone and dihydrotestosterone (DHT) seem to be of major importance. Both steroids are recognized by the intracellular androgen receptor, but the activation of this transcription factor via DHT is stronger by a factor of 10 in comparison to testosterone. The production of DHT from testosterone is mediated by the enzyme 5-alpha reductase. Inhibiting this catalytic activity pharmacologically is one of the major therapeutical approaches currently used in the treatment of BPH. The levels of testosterone slightly increase due to the inhibition of 5-alpha reductase, but the clinical outcome is clearly a reduction of prostate size, so it seems that testosterone plays a secondary role in BPH pathogenesis. It may be explained by the fact that only 1% of testosterone is bioavailable for the activation of androgen receptors. The rest is bound to plasma proteins, specifically to sex hormone binding globulin (SHBG), and nonspecifically to albumin. As the concentrations of SHBG rise with age, the proportion of bioavailable free
testosterone decreases. Moreover, the production of testosterone in Leydig cells in testes also decreases; thus, the absolute concentration of free testosterone decreases considerably. However, there are other receptors for testosterone than androgen receptor; some of them are membrane bound, and some of them even recognize testosterone bound to SHBG. Their role in prostate growth is currently unknown and is expected to be of less importance, but future research will make this clear.
An interesting question is the role of estrogens in the pathogenesis of BPH. Estradiol is produced from testosterone, and this one step-one direction reaction is catalyzed by aromatase (see Figure 52.6).
Although the presence of aromatase in the prostate tissue is a matter of discussion, and the results of molecular studies are divergent and puzzling, the production of estradiol affects prostate growth independently from the site of its production (Risbridger et al., 2003). Estradiol increases the production of SHBG and thus decreases the free fraction of plasma testosterone available for the DHT production by 5-alpha reductase. This fact would explain a protective role of estrogens in BPH, but the last decade of research has shown that estrogens play the opposite role—they stimulate the growth of prostate tissue, particularly in a highly
Figure 52.6 Aromatase catalyzes the aromatization of testosterone to estradiol.
Figure 52.6 Aromatase catalyzes the aromatization of testosterone to estradiol.
androgenic environment (Roberts et al., 2004). The molecular aspects of estrogen action include the upregula-tion of androgen receptor expression. Thus, the sensitivity of the tissue to androgens is increased and the response to testosterone and also to DHT is enhanced. The effects of estradiol on prostate growth are age- and dose-dependent. The most prominent influence has been shown for low-dose estradiol during fetal life (vom Saal et al., 1997). Interestingly, estrogens and androgens act synergistically in BPH pathogenesis (see Figure 52.7), even if some effects are contradictory if these hormones are applied alone (Fujimoto et al., 2004).
There are several genetic factors that affect the actions of sex hormones in the prostate. The androgen receptor undergoes alternative splicing, and a longer version of the protein is more sensitive to DHT. Various polymorphisms have been associated with altered function of the androgen receptor. A CAG repeat in the first exon is the best described short tandem repeat (STR) in the androgen receptor gene. Normal number repeats is 10 to 40; a higher number is associated with a rare neurodegenerative Kennedy disease, and the activation of androgen receptor is weaker. Lower number of repeats is related to increased androgenity—increased response to androgens, and this condition is clinically associated with an increased risk of Alzheimer's, breast and prostate cancer, and BPH.
Similarly, the gene encoding 5-alpha reductase includes several polymorphisms important for the activity of the enzyme; best studied is the A49T polymorphism that increases the activity of 5-alpha reductase five-fold. Aromatase is encoded by a gene with a single nucleotide polymorphism C1558T and several STRs. Besides sex hormone receptors and metabolic enzymes, other genes and their polymorphisms are associated with BPH in humans, but their role in the etiology of BPH is unclear. It has been reported that the expression of a potential tumor suppressor protein p27Kip1 is very low or undetect-able in BPH tissue in contrast to control prostate tissue (Cordon-Cardo et al., 1998).
Although the prostate is an exocrine gland, BPH is caused mainly by proliferative changes of the fibro-muscular stroma. The histological classification distinguishes stromal and epithelial origin of BPH. The stromal BPH accounts for cca 80% and is further divided into proliferative processes of the fibrous tissue (40%) and smooth muscle (40%). Cell culture studies have provided evidence for the hypothesis that on a molecular level an important role in the pathogenesis of BPH is played by several growth factors (see Figure 52.8).
These growth factors include fibroblast growth factors (FGF) 2 and 9, insulin-like growth factors (IGF) I and II, and also transforming growth factor beta 1 (TGF), although the latter affects stromal cells of the prostate differentially according to its concentrations— stimulatory at lower and inhibitory in higher concentrations (Eaton, 2003). The effects of TGF are especially interesting as it induces apoptosis in epithelial cells but the opposite in stromal cells. The influence of growth factors on prostate is dependent on the presence of appropriate receptors at the surface of cell membranes as well as on the intracellular response pathway. Molecular biology and its modern methodological improvements like microarray experiments will facilitate the detailed understanding of BPH pathophysiology (Prakash et al., 2002).
Best described and widely used in vivo models include rodent, canine, and primate models (see Table 52.2). These can be either spontaneous or induced using various hormonal application regimes. Modern genetic technologies allow the production of several new transgenic mice models. Another approach is to use transplantation of the prostate tissue, either embryonic or pathologically hyperplasic. Some of the aspects of BPH can be studied in alternative models, for example, in the phenylephrine-induced increase of intraurethral pressure (Akiyama et al., 1999).
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