Introduction

Despite major progress in the biological sciences during the last 50 years, it is rather remarkable that we have entered the twenty-first century and still the specific function of the prostate gland remains unknown. Indeed, the prostate is the largest organ of unknown specific function in the human body. Although it is believed that the prostate is important in protecting the lower urinary tract from infection and for fertility, it is frequently the site of infection and inflammation, and sperm harvested from the epididymis without exposure to seminal or prostatic fluid can produce fertilization and successful birth (Silver etal. 1988). The fact that the specific in vivo function of prostate is not fully understood might not be so problematic if it were not the case that the prostate is the most common site of neoplastic transformation in men, with approximately one in six men in western industrialized nations eventually developing clinically detected prostatic cancer during their lifetime (Jamal et al. 2003). Furthermore, the prostate is the most common site of benign neoplastic disease in males (Berry et al. 1984). More than 50% of all men above the age of 50 have benign prostatic hyperplasia (BPH) with ^25% of men eventually requiring treatment for this condition (Berry et al. 1984). Thus, it is remarkable that despite the high prevalence of prostatic diseases, the etiologies of neither prostatic cancer nor BPH are known.

A major reason why both the specific function of the prostate and etiology of the prostatic neoplasms have been difficult to elucidate is that the gross structure and histological appearance of this gland vary widely in the animal kingdom and thus comparative animal studies have been problematic. All placental (i.e., euthe-rial) mammals have male sex accessory tissues that minimally include the prostate gland (Price and Williams-Ashman 1961). The term prostate is derived from the Latin word "to stand before." Thus, the gland that in males of placental mammals "stands before" the base of the bladder and produces and releases secretion into the male ejaculate is defined as the prostate. In males of most placental mammals, there are additional glands that likewise release excretion into the ejaculate and these glands are given a variety of names depending on the species (e.g., seminal vesicles, bulbourethral glands, periurethral glands, preputial glands, etc.). Along with the prostate these glands are called male accessory sex tissues. No organ system varies so widely among the animal species as the male sex accessory tissues (Price and Williams-Ashman 1961). In humans, these include the prostate, seminal vesicles, bulbourethral gland, Cowper's glands, and glands of Littre. The dog is the only species other than man which spontaneously develops both BPH and prostatic cancer with aging (Isaacs 1984a). The dog has a well-developed prostate but completely lacks seminal vesicles. In contrast, the rat has a prostate that is composed of four anatomically and biochemically distinct prostatic lobes (i.e., the ventral, dorsal, lateral, and anterior lobes, the latter lobe also called the coagulating gland). In addition, the rat has seminal vesicles and preputial glands. Besides this anatomical variation, there is a large variation among the different species in the secretory products produced and released by the prostate into the ejaculate (Mann and Mann 1981).

For example, the human prostatic epithelial cells synthesize and secrete a series of unique proteins into the ejaculate (Coffey 1992). These include serine protease, prostate-specific antigen (PSA), human glandular kallikrein-2 (hK-2) and prostatic-specific acid phosphatase (PAP). The essentially exclusive production of these proteins by normal and malignant prostatic cells has allowed the abnormal detection of these proteins in the serum of men to be useful as a means of (1) initially detecting prostatic cancer in asymptomatic men, 2) monitoring residual presence of systemic micrometastatic disease in men who have undergone radical

A4-5a-REDUCTASE

NADPh

NADP

TESTOSTERONE T

DIHYDROTESTOSTERONE DHT

Fig. 12.1 Irreversible conversion of testosterone to DHT catalyzed by the NADPH-dependent type I or type II 5a-reductase enzyme.

prostatectomy for presumed localized disease, and 3) monitoring the response of clinical detected metastatic disease to systemic therapy. Although other animal species secrete prostate-specific proteins (e.g., prostatein secreted by rat ventral prostate and the arginines esterase secret by the dog prostate), there are no genes directly homologous to PSA or hK-2, based on DNA sequence, in the dog or rat genome. These is a homologous PAP gene in the rat, however, the level of expression is nearly 1000-fold lower in rat versus human prostate epithelial cells (Coffey 1992).

The human prostate is also unique in that it synthesizes and secretes large amounts of citrate (Coffey 1992). Indeed the concentration of citrate in prostatic secretory fluid (i.e., 75 mM) is 615 times higher than that ofblood serum. Likewise the human prostatic epithelial cells concentrate Zn2+ from the blood and transport it into the prostate secretion. As a result of this activity, the prostate has one of the highest tissue concentrations of zinc in the human body. It is believed that the role of such a high Zn2+ concentration in the prostate and its secretion is to function as a natural bactericidal compound (Coffey 1992). Similarly the prostate is one of the richest sources of the highly charged, basic aliphatic polyamines (e.g., spermine). The biological role of polyamines has not been fully resolved although it is definitively known that polyamine metabolism is correlated with growth and that polyamines bind tightly to DNA and effect its confirmation and template ability for DNA replication and transcription.

Based on such varied anatomy and biochemistry, it has been difficult to define the etiology of either BPH or prostatic cancer. It is known, however, that testosterone and particularly its 5a-reductase metabolite, 5a-dihydrotestosterone (DHT), has at least a permissive role, if not an inductive one, in both of these prostatic neoplasms (Fig. 12.1). To appreciate the role of testosterone and DHT in these neoplastic diseases, an understanding of how testosterone functions in the normal development and physiology of the prostate is required.

AGE (years)

Fig. 12.2 Serum testosterone levels during aging in men (Data from Frasier etal. 1969).

AGE (years)

Fig. 12.2 Serum testosterone levels during aging in men (Data from Frasier etal. 1969).

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