Androgens in Health and Disease.pdf - E Library

172 Marcelli et al.
up to 9 yr later (187). The age-related increase in the serum estrogen/androgen ratio is
associated with an increase in the estrogen/androgen ratio in prostatic tissue, especially
in the stroma (194). Prostatic stromal cells contain estrogen receptors, but the concentrations
are lower in hyperplastic than in normal prostatic tissue (195). The concentrations
of progesterone receptors in the two types of tissue are similar. Treatment of men
with BPH with atamestane, an aromatase inhibitor, reduced serum estrogen concentrations
but did not relieve symptoms, increase the urine flow rate, or reduce prostatic size
(196). However, another aromatase inhibitor, mepartricin, has been reported to reduce symptoms
and increase peak flow rates without changing prostate volume or PSA levels (196). In
summary, there is only suggestive evidence that estrogen may contribute to human BPH.
Growth Factors and BPH
Because BPH is primarily a disease of the stroma, the stroma could have intrinsic
properties that would enable it to proliferate and also to induce hyperplasia of the epithelium.
In the presence of androgen, mesenchymal tissue derived from the urogenital
sinus can induce differentiation of epithelium (197). In contrast, stroma lacking functional
ARs cannot induce differentiation of normal epithelium. These observations
emphasize the importance of the stroma in prostate development. It has been suggested
that BPH occurs because prostatic tissue reverts to an embryonic-like state in which it
is unusually sensitive to various growth factors. Tissue concentrations of several growth
factors are increased in hyperplastic prostatic tissue as compared with normal prostatic
tissue. The most consistent increases are in fibroblast growth factors (FGF) 2, 7, 8, or 9,
and IGF-II and transforming growth factor-β (TGF-β) and the mRNAs for these substances
(198–203). In vitro, epidermal growth factor (EGF), TGF-α, basic FGFs 2–10,
IGF-I, and IGF-II stimulate and TGF-β inhibits prostatic epithelial cell growth. Most of
these factors stimulate stromal cell growth.
In summary, there is considerable evidence that the androgen signaling pathway
contributes to the development of BPH. Differences in androgen signaling and estrogen
signaling during normal prostate development may be important. Androgen appears to
be required for pathological prostate enlargement, and many of its effects are mediated
by growth factors. The growth factors act by both autocrine and paracrine mechanisms
to enhance cell proliferation and reduce apoptosis. Estrogen may contribute to this
process. Although both epithelial and stromal cells are increased in BPH, the increase
in stromal cells dominates in most glands with macronodular BPH.
TREATMENT BASED ON HORMONAL MANIPULATION
Androgen-Ablation-Induced Apoptosis
The precise mechanisms causing apoptosis of prostatic epithelium following castration
are not clear. However, a significant amount of information has been generated
during the last few years, and many of the intracellular events associated with induction
of apoptosis have been clarified. Two major apoptotic pathways originating from two
separate subcellular compartments have been identified (204) (see Fig. 2). The receptormediated
(or extrinsic) pathway originates at the level of the plasma membrane (205),
following interaction of death receptors with their ligands. The mitochondrial (or intrinsic)
pathway originates from the mitochondria following activation by proapoptotic
Bcl-2 family members (206). Although each pathway is initially centered around unique