THE PROSTATE: DEVELOPMENT AND PHYSIOLOGY

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The principal function of the prostate is to provide the proteins and ions that form the bulk of the seminal fluid. The adult human prostate is a tubuloalveolar gland composed of ducts lined with a pseudostratified columnar epithelium. The cells lining the ducts are tall columnar and secretory with basal nuclei. A nearly continuous layer of basal epithelial cells abut the epithelial basement membrane. The prostatic epithelium is, in turn, surrounded by a dense fibromuscular stroma.

Development of the prostate begins with the growth of prostatic buds from the urogenital sinus at about 10 weeks of fetal development in the human.56, 77 Androgen receptors (AR) in the urogenital sinus mesenchyme (UGM) are stimulated by testicular androgens to induce epithelial budding, proliferation, and differentiation to form ductal structures.23 The epithelium differentiates into luminal and basal subtypes and expresses characteristic secretory markers. Concurrent with epithelial differentiation the UGM proliferates and differentiates into prostatic smooth muscle and interfascicular fibroblasts.39, 40, 41 In the mature prostate androgens are believed to act upon prostatic smooth muscle (which expresses AR) to maintain a fully differentiated growth-quiescent epithelium via paracrine stromal–epithelial interactions.25, 84 The role of the epithelial AR is apparently restricted to regulating secretory functions.29 Growth factors are obvious candidates for the mesenchymally produced paracrine androgen-regulated factors (andromedins) that act on the epithelium.

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DEVELOPMENT AND ADULT FUNCTION OF THE PROSTATE

Prostatic development has been most widely studied in animal models with a limited number of studies of human fetal prostatic development. Androgenic stimulation is absolutely required for prostatic development.93 The development of prostatic tissue is not determined by fetal genetic sex, but rather by exposure to androgens. Urogenital sinuses (UGS) from either male or female fetuses form functional prostatic tissue if stimulated by androgens during the appropriate developmental period.22, 54,

STEROID HORMONES

In the prostate the biologically active androgen is 5α-dihydrotestosterone (DHT), which is produced by the local reduction of testosterone (produced in the testes) by the enzyme Δ4-3-ketosteroid-5α-reductase (5α-reductase). Two forms of 5α-reductase have been described.3, 4 In the genital tract the active form is the type 2 5α-reductase gene product, which is localized to both the epithelial and stromal compartments of developing and adult prostates.69

The links between testicular and prostatic

PROSTATIC FUNCTION

The prostate and seminal vesicles produce most of the ejaculate. Seminal fluid contains a number of secreted proteins. In general, the primary functions of the prostatic secretion relate to semen gelation, coagulation, and liquefaction.7 Prostatic secretory proteins are also involved in the coating and uncoating of spermatozoa and in interactions with cervical mucus.7 The specific components of seminal fluid and their individual biologic roles vary widely between species. For example, in

5α-Reductase Deficiencies

Evidence for the role of DHT in prostatic development is provided by pseudohermaphroditism caused by congenital 5α-reductase deficiency (Fig. 2). This condition is rare in the general population. Affected boys, however, are born with feminization of the external genitalia, including a blind vaginal pouch, and are normally raised as girls. Individuals with congenital 5α-reductase deficiency masculinize at puberty. The phallus enlarges becoming penis-like, and the voice deepens. Beard growth is

TESTICULAR FEMINIZATION

Testicular feminization (Tfm) or androgen insensitivity syndrome has been known for many years. The first comprehensive description of this syndrome in humans dates from 1953 with a review of 82 patients with a female phenotype and bilateral testes.82 Tfm is recognized as being caused by functional mutations in the AR gene.100 The AR gene is carried on the X chromosome, allowing a single mutation to induce a phenotype in an affected individual. Therefore, the AR gene has a long list of

MESENCHYMAL–EPITHELIAL INTERACTIONS

Mesenchymal–epithelial interactions mediate androgenic signaling in the developing and adult prostate. A series of tissue recombination experiments utilizing urogenital mesenchyme and epithelium from wild-type and Tfm mice22 established that mesenchymal AR are required for epithelial budding and ductal branching morphogenesis to occur (Fig. 3). Epithelial AR were not required for these processes. In the absence of epithelial AR, however, prostatic secretory proteins were not expressed.31 These

GROWTH FACTORS AS MEDIATORS OF MESENCHYMAL–EPITHELIAL INTERACTIONS

In the prostate growth factors are implicated in two sets of androgen-regulated paracrine interactions (Fig. 4). The first of these is the proliferative and differentiative response, which results from the action of androgens on UGM or on the stroma of a postcastration regressed prostate. The second response is the androgen-dependent maintenance of a growth-quiescent phenotype in the adult prostate. It is likely that each of these end points is a result of a balance of the effects of various

SUMMARY

The development of the prostate is controlled by steroid hormones that in turn induce and maintain a complex and little understood cross talk between the various cell types making up the gland. The result of this intercellular communication can be either new growth or growth quiescence, depending upon the differentiation state of the cell type being stimulated. Secretory function of the prostate is dependent upon direct stimulation of fully differentiated prostatic epithelial cells by

ACKNOWLEDGMENTS

The authors gratefully acknowledge research support from the National Institutes of Health through Grants DK52721, DK 45861, CA 64872, DK 47517, and CA 59831, and from the California Urology Foundation. We are also indebted to Joel Brody for his expertise in preparing the figures.

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    Address reprint requests to Simon W. Hayward, PhD, Department of Urology, U-575, University of California, San Francisco, San Francisco, CA 94143–0738, e-mail: [email protected]

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