Androgens in Health and Disease.pdf - E Library

170 Marcelli et al.
The above data support the possibility that AR can be activated in a nonsteroid hormone-dependent
way and still is able to support (or inhibit) transcription of typical ARdependent
genes.
NONGENOMIC EFFECTS OF AR ACTIVATION
The dogma of the steroid-receptor mechanism of action is that following ligand binding,
the receptor translocates to the nucleus, where it functions as a transcription factor.
However, there is increasing evidence that estrogens and progestins, acting through their
cognate receptor (174,175) activate nongenomic pathways. These pathways are known
to stimulate cellular proliferation and survival. Evidence has now accumulated that the
AR also works at least in part by stimulating alternative pathways leading to activation
of various protein kinases. Using primary cells obtained from genital skin, prostatic
smooth muscle cells, and established prostate cancer cell lines, Peterzile and colleagues
demonstrated that DHT leads to a rapid activation of the extracellular signal-regulated
kinases (ERKs) ERK-1 and ERK-2. These observations were confirmed and expanded
recently (176,177). Migliaccio (174) and collaborators identified activation of a Src/
Raf-1/Erk-2 pathway in prostate cancer LNCaP cells by the androgen agonist R1881.
Stimulation of this pathway was associated with cell proliferation. Kousteni et al. (177)
showed that DHT or estradiol, acting on the AR, estrogen receptor (ER)α or ERβ of
osteoblast, osteocyte, embryonic fibroblasts, and HeLa cells, had the ability to activate
a Src/Shc/ERK pathway and to inhibit apoptosis. This is a novel way to look at apoptosis
that follows hormone withdrawal. It could provide a model for androgen-ablation-induced
apoptosis in prostatic epithelium. Efforts to identify apoptotic genes induced by
androgen ablation in prostatic epithelium have not been successful, so far (see below).
It may be that both nongenomic and genomic mechanisms determine whether a cell
undergoes apoptosis.
BENIGN PROSTATIC HYPERPLASIA
The prostate on average weighs 20 g in normal 21- to 30-yr-old men, and the weight
changes little thereafter unless the man develops BPH (178). However, because of the
prevalence of this disorder, the mean prostate weight at autopsy increases after age 50. The
prevalence of histologically diagnosed prostatic hyperplasia increases from 8% in men
aged 31–40, to 40–50% in men aged 51–60, and to over 80% in men older than age 80.
A major difficulty in comparing the prevalence of clinical BPH among different
populations has been the lack of a common definition. As an example, in a communitybased
group of 502 men aged 55–74 yr without prostate cancer, the prevalence of BPH
was 19% using the criteria of a prostate volume above 30 mL and a high International
Prostate Symptom Score (IPSS) (179). However, the prevalence was only 4% if the
criteria were a prostate volume above 30 mL, a high score, a maximal urinary flow rate
below 10 mL/s, and a postvoid residual urine volume greater than 50 mL. Although
symptoms are a major factor in the diagnosis and treatment of BPH, one must recognize
that aging men and women have similar urinary symptom scores even though they differ
greatly in bladder outlet obstruction (180). For this reason, it is more useful to conduct
population-based studies evaluating BPH that rely more on measurements of prostate
volume than on symptoms.
One study compared prostate volumes in Japanese men with that in American men,
40–79 yr of age (181). Prostate size increased 6ml/decade in American men, as compared