Role of testosterone in the development and maintenance of the prostate

The urogenital sinus is the embryonic anlagen from which the prostate develops in utero. For the prostate to develop normally, a critical level of androgenic stimulation is required at specific times during its development in utero (Wilson 1984). In the developing male, the fetal testis secretes testosterone into the fetal circulation at sufficient levels to stimulate the differentiation and growth of a portion of the urogenital sinus tissue, producing the definitive prostate gland. This usually begins during the first three months of fetal growth. If sufficient serum testosterone is not present at this critical state of intrauterine development, the prostate does not develop (Wilson 1984).

After birth, serum testosterone levels decrease to a low baseline value until puberty, when they rise to the adult range (Frasier et al. 1969) (Fig. 12.2). Until puberty, the prostate remains small (approximately 1-2 g) (Isaacs 1984a). During puberty, the prostate grows to its adult size of approximately 20 g (Isaacs 1984a). Between the age of 10 and 20 years, the rate of prostatic growth is exponential with a prostatic weight-doubling time of 2.78 years (Isaacs 1984a) (Fig. 12.3). This period of exponential growth corresponds to the time period when the serum testosterone levels are rising from initially low levels seen before the age of 10 to the high levels seen in an adult male (Frasier etal. 1969) (Fig.12.2). If a boy is castrated

30.0

20.0

AGE (years)

Fig. 12.3 Growth of the normal human prostate from birth to adulthood (Data from Boyd 1962).

20.0

AGE (years)

Fig. 12.3 Growth of the normal human prostate from birth to adulthood (Data from Boyd 1962).

before the age of ten, the serum testosterone levels do not rise to their normal adult level and the proliferative growth of the human prostate between 10 and 20 years of life is completely blocked (Moore 1944; Huggins and Johnson 1947). These results demonstrate that a physiological level of testosterone is chronically required for the normal growth of the human prostate. This chronic requirement for testosterone derives from the necessity for androgens to regulate the total prostatic cell number by affecting both the rate of cell proliferation and cell death. Androgen does this by stimulating the rate of cell proliferation (i.e., agonistic ability of androgen) while simultaneously inhibiting the rate of cell death (antagonistic ability of androgen) (Isaacs 1984b). Because of this dual agonist/antagonist effect of androgen on the prostate, the rate of cell proliferation is greater than the rate of cell death during the normal prostatic growth period occurring between 10 and 20 years of age. Having reached its maximum adult size by 20 years of age, the prostate normally ceases its continuous net growth (Isaacs 1984a). This does not mean, however, that the cells of the adult prostate in men over 20 years of age do not continuously turn over with time, but that the rate of prostatic cell proliferation is balanced by an equal rate of prostatic cell death, such that neither involution nor overgrowth of the gland normally occurs with time. Thus the adult prostate in men over 20 is an example of a steady-state self-renewing tissue. If an adult male whose prostate is in this steady-state maintenance condition is castrated, serum testosterone levels rapidly decrease to low values comparable to those seen in males younger than 10 years of age. As a result, the prostate rapidly involutes. Such involution demonstrates that a physiological level of testosterone is chronically required, not only for initial development, but also for maintenance of the normal prostate. In order to define the molecular mechanism[s] responsible for how testosterone maintains

Peripheal ;

Central ;

Peripheal ;

Central ;

Fig. 12.4 Anatomy of the prostate, B1, bladder; Sv, seminal vesicle; Vd, vas deferens; Uth, urethra.

- Ejaculatory duct

- Transition zone

Fig. 12.4 Anatomy of the prostate, B1, bladder; Sv, seminal vesicle; Vd, vas deferens; Uth, urethra.

the normal prostate, an understanding of the cellular organization of the gland is required.

The normal human prostate is not composed of anatomically separate lobes as in many animals, but is insteaddivided into four zones (Fig. 12.4). The peripheral zone comprises 70 to 75% of the gland, the central zone 20 to 25%, and the transitional zone 5%, while the anterior surface consists of the fibromuscular stroma (McNeal et al. 1988). Most cancers develop in the peripheral zone. Benign prostatic hyperplasia (BPH) develops in the transition zone as a part of the aging process. Although hyperplastic changes develop, the mass of the peripheral zone remains constant at 20 to 25 g (McNeal etal. 1988). Within the peripheral, central, and transition zones, the tissue is organized as tubular-alveolar glands composed of a well-developed stromal compartment containing nerves, fibroblasts, infiltrating lymphocytes and macrophages, endothelial cell capillaries, and smooth muscle cells surrounding glandular acini composed ofatwo-layered (i.e., basal and secretory luminal) epithelium (Fig. 12.5). Scattered throughout this epithelial compartment are occasional neuroendocrine (NE) cells which are characterized by expression of chromogranin A, serotonin, and neuron-specific enolase, but not the androgen receptor (Bonkhoff 1998). Functionally, the epithelium is composed of multiple stem cell units supported by paracrine interaction from the stromal compartment (Bonkhoff and Remberger 1996; Bonkhoff et al. 1994; Hudson et al. 2000; Isaacs 1987; Isaacs and Coffey 1989; Robinson et al. 1998; Van Leenders et al. 2000) (Fig. 12.5). In an individual stem cell unit, the stem cell which has the capacity for unlimited self-renewal characteristically expresses a2p1-integrins (Collins et al. 2001), but only rarely proliferates to provide progeny which differentiate to become either transit amplifying or NE cells (Bonkhoff et al. 1994). The stem and the majority

Pregnancy And Childbirth

Pregnancy And Childbirth

If Pregnancy Is Something That Frightens You, It's Time To Convert Your Fear Into Joy. Ready To Give Birth To A Child? Is The New Status Hitting Your State Of Mind? Are You Still Scared To Undergo All The Pain That Your Best Friend Underwent Just A Few Days Back? Not Convinced With The Answers Given By The Experts?

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