Introduction to the Prostate

The prostate is a fibromuscular glandular organ involved in the male reproductive system. It is located between the bladder and pelvic floor, and surrounds the prostatic urethra. It is comprised of a large, nonglandular region and a smaller, glandular region that consists of epithelium and stroma, and can be further subdivided into three main zones: the peripheral zone, which constitutes about 70% of the gland; the central zone, comprising 25% of the gland; and the transitional zone, which represents about 5-10% of the gland (see Figure 1). These zones have histological differences, mainly relating to secretory cell structure and the ratio of epithelium-to-stroma, which indicates that they have different functions.1

Transitional zone

Fibromuscular stroma

Preprostatic sphincter

Detrusor

Urethral lume

Central zone

Figure 1 A sagittal section of the prostate, which shows anatomic subdivisions. (Reproduced with kind permission from Dixon, J. S.; Gosling, J. A. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 3-10 © Taylor & Francis.)

External sphincter

Central zone

Detrusor

Figure 1 A sagittal section of the prostate, which shows anatomic subdivisions. (Reproduced with kind permission from Dixon, J. S.; Gosling, J. A. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 3-10 © Taylor & Francis.)

The prostate is androgen dependent, and relies primarily on the androgen testosterone produced by the Leydig cells in the testes and adrenal glands for normal functioning. In the context of benign prostatic hyperplasia (BPH), testosterone is converted to its potent active metabolite dihydrotestosterone (DHT) by 5a-reductase isoenzymes, largely situated on the prostate cell membrane. Once formed, DHT binds to androgen receptors (adrenoceptors), forming a DHT-androgen receptor complex inside the prostate cell, where it produces a number of regulatory effects relating to prostate growth, gene activity, and initiation of other hormone response elements, including estrogen effects.2

A number of other mediators also play an important role in the maintenance of normal prostate functioning, including the 'balancing act' between cell proliferation and apoptosis (programmed cell death). Under the influence of DHT, a key growth factor known as fibroblast growth factor-2 (FGF-2), which is produced by stromal and epithelial cells, promotes stromal fibroblast growth. Fibroblasts produce keratinocyte growth factor (KGF), an important growth-promoting factor that exerts its effects in epithelial cells. In contrast, transforming growth factor beta (TGFb), produced via stromal muscle cells, is a growth inhibitory factor that inhibits the epithelial actions of KGF. The predominant function exerted by FGF-2, KGF, and TGFb varies according to their location in the stroma and/or epithelium: those located in the distal region are largely involved in proliferation, those in the intermediate region are involved in cell differentiation, and those in the proximal region handle apoptosis (see Figure 2). Maintaining a normal balance between these key mediators is essential for regulating prostate cell growth, cell functioning, and death.2

Additional regulatory factors, which are mainly secreted by neuroendocrine cells in the epithelium, also affect prostate function, growth and development, and neuroendocrine, endocrine, and exocrine secretion. These factors include vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGFa), serotonin (5HT), bombesin (a gastrin-releasing peptide), the chromogranin family of polypeptides, the calcitonin family of peptides, somotostatin, parathyroid hormone-releasing protein (PTHrP), thyroid-stimulating hormone-like peptide, and the human chorionic gonadotropin-like peptide. In addition, insulin-like growth factors (IGFs) and interleukins (ILs) are key cell survival factors and Bcl-2 (a 26-kDa protein) and nitric oxide (NO)-synthase influence apoptosis.

It can be seen therefore that the prostate is under the influence of a complex set of pathways and mediators present in both the stroma and epithelium. This process is summarized in Figure 3, which represents a cross-section of a 'typical' working prostate cell.

6.24.1.1 The Aging Prostate

It is well established that testosterone production declines as the human male ages; longitudinal studies have shown that total testosterone falls by approximately 1% per year after the age of 50 years,3 and unbound (free and bioavailable) testosterone falls more steeply, which may be due to an age-related increase in the testosterone binding protein known as sex hormone-binding globulin (SHBG). Epidemiology studies from the USA estimate that 30% of men aged 60-70 years, 70% of men aged 70-80 years, and 80% of men aged over 80 years have low unbound testosterone.4 This age-related decline in testosterone is illustrated in Figure 4.

Multiple etiologies have been reported to play a role in the age-related decrease in testosterone; however, it appears that the Leydig cell, which is responsible for 90-95% of testosterone production, also ages, resulting in lower

Figure 2 The process of prostate cell proliferation and apoptosis DHT, dihydrotestosterone; FGF-2, fibroblast growth factor-2; KGF, keratinocyte growth factor; TGFb, transforming growth factor beta. (Reproduced with kind permission from Turkes, A.; Griffiths, K. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 27-68 © Taylor & Francis.)

Figure 2 The process of prostate cell proliferation and apoptosis DHT, dihydrotestosterone; FGF-2, fibroblast growth factor-2; KGF, keratinocyte growth factor; TGFb, transforming growth factor beta. (Reproduced with kind permission from Turkes, A.; Griffiths, K. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 27-68 © Taylor & Francis.)

Figure 3 The morphology of prostate epithelium and stroma compartments. DHT, dihydrotestosterone; E2, estradiol; FGF-7, fibroblast growth factor-7; IGF, insulin-like growth factor; IGF-BP, insulin-like growth factor-binding protein; KGF, keratinocyte growth factor; PSA, prostate-specific antigen; T, testosterone; TGFb transforming growth factor beta; TSH, thyroid-stimulating hormone. (Reproduced with kind permission from Turkes, A.; Griffiths, K. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 27-68 © Taylor & Francis.)

Figure 3 The morphology of prostate epithelium and stroma compartments. DHT, dihydrotestosterone; E2, estradiol; FGF-7, fibroblast growth factor-7; IGF, insulin-like growth factor; IGF-BP, insulin-like growth factor-binding protein; KGF, keratinocyte growth factor; PSA, prostate-specific antigen; T, testosterone; TGFb transforming growth factor beta; TSH, thyroid-stimulating hormone. (Reproduced with kind permission from Turkes, A.; Griffiths, K. Textbook of Benign Prostatic Hyperplasia, 2nd ed.; Taylor & Francis: London, 2005, pp 27-68 © Taylor & Francis.)

testosterone production. More specifically, steroidogenic (i.e., testosterone) biosynthesis, which is initiated when the substrate cholesterol is transferred to the mitochondrial inner membrane, becomes 'rate-limited' as the steroidogenic acute regulatory (StAR) protein, which facilitates this initiation process, also declines. At the same time, cyclooxygenase-2 (COX-2) expression is upregulated, and this COX isoform may inhibit StAR gene expression and steroidogenesis in Leydig cells.5

In a recent animal (rodent) model study,6 total testosterone decreased from 41% to 33% as the animal aged from 3 to 30 months, respectively. This decrease was accompanied by a 346% increase in COX-2 in Leydig cells and a 33% decrease in StAR protein expression (over that of young cells). When the COX-2 inhibitor

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