ABSTRACT
The prostate develops and grows under the controlling influence of the hypothalamopituitary axis (Figure 9). The hypothalamus normally secretes the decapeptide luteinizing hormone releasing hormone (LHRH) in a pulsatile fashion, which then passes down the pituitary stalk to the pituitary gland to provoke the release of luteinizing hormone (LH). LH enters the circulation and acts on the Leydig cells of the testes, thereby stimulating testosterone formation and release. Testosterone in the circulation is mainly bound to sex hormone binding globulin (SHBG); only the unbound portion is available, to enter the cytoplasm and nucleus of prostatic cells by a process of simple diffusion. In addition to testicular testosterone, a further 5% or so of circulating androgens is derived from the adrenal glands under the stimulatory influence of adrenocorticotrophic hormone (ACTH). In health, the effects of these adrenal androgens, mainly in the form of androstenedione and androstenediol, are relatively insignificant. However, these adrenal androgens assume some importance after chemical or surgical castration because they remain in the circulation and may, after conversion to DHT within the prostate, stimulate continuing growth and division of prostate cancer cells. Once inside a prostate cell, testosterone is rapidly metabolized by the enzyme 5αreductase, located on the nuclear membrane, to DHT10,11. It is this 5α-reduced form of testosterone that binds with the androgen receptor. The process of DHT binding involves the release of so called heat-shock protein (hsp 90) and the dimerization, together with conformational change, of paired androgen receptor structures. Thus, a segment of DNA within the genome of the prostate cell initiates DNA transcription, producing mRNA, which encodes, among other cytokine molecules, epidermal growth factor (EGF) and platelet-derived growth factor (PdGF). These growth factors, in turn, stimulate prostate cell growth by specifically activating growth factor receptors located on the cell membrane of epithelial and stromal cells12 (Figure 10). In the normal prostate, growth homeostasis is achieved by a balance between release of growth stimulating factors, such as EGF and PdGF, and growth inhibitors, such as transforming growth factor-β (TGF-β). TGF-β not only inhibits cell division, but is also involved in inducing programmed cell death by apoptosis (Figure 11).
