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The role of Eralpha and ERbeta in the prostate: insights from genetic models and isoform-selective ligands.
[aromatase deficiency]
Androgens
are
known
regulators
of
the
growth
and
differentiation
of
the
prostate
gland
and
are
effective
during
development
and
maturity
as
well
as
in
disease
.
The
role
of
estrogens
is
less
well
characterized
,
but
dual
direct
and
indirect
actions
on
prostate
growth
and
differentiation
have
been
demonstrated
,
facilitated
via
both
ERalpha
,
and
ERbeta
.
Previous
studies
using
animal
models
to
determine
the
role
of
ERbeta
in
the
prostate
have
been
problematic
due
to
the
centrally
mediated
responses
to
estrogen
administration
via
ERalpha
that
can
lower
androgen
levels
and
lead
to
epithelial
regression
,
thereby
masking
any
direct
effects
on
the
prostate
mediated
by
ERbeta
.
Our
alternate
approach
was
to
use
the
estrogen-
deficient
aromatase
knockout
(
ArKO
)
mouse
and
the
method
of
tissue
recombination
to
provide
new
insight
into
estrogen
action
on
prostate
growth
and
pathology
.
Firstly
,
utilizing
homo-
and
heterotypic
tissue
recombinants
,
we
demonstrate
that
stromal
aromatase
deficiency
results
in
the
induction
of
hyperplasia
in
previously
normal
prostatic
epithelium
and
that
this
response
is
the
result
of
local
changes
to
the
paracrine
interaction
between
stroma
and
epithelium
.
Secondly
,
using
tissue
recombination
and
an
ERbeta-
specific
agonist
,
we
demonstrate
that
the
activation
of
ERbeta
results
in
an
anti-proliferative
response
that
is
not
influenced
by
alterations
to
systemic
androgen
levels
or
activation
of
ERalpha
.
Finally
,
using
intact
ArKO
mice
this
study
demonstrates
that
the
administration
of
an
ERbeta-
specific
agonist
abrogates
existing
hyperplastic
epithelial
pathology
specifically
in
the
prostate
but
an
ERbeta-
specific
agonist
does
not
.
Therefore
,
in
the
absence
of
stromal
aromatase
gene
expression
,
epithelial
proliferation
,
leading
to
prostatic
hypertrophy
and
hyperplasia
,
may
result
from
a
combination
of
androgenic
stimulation
of
proliferation
and
failed
activation
of
ERbeta
by
locally
synthesized
estrogens
.
These
data
demonstrate
essential
and
beneficial
effects
of
estrogens
that
are
necessary
for
normal
growth
of
the
prostate
and
distinguish
them
from
those
that
adversely
alter
prostate
growth
and
differentiation
.
This
indicates
the
potential
of
antiandrogens
and
SERMS
,
as
opposed
to
aromatase
inhibitors
,
for
the
management
of
prostate
hyperplasia
and
hypertrophy
.
Diseases
Validation
Diseases presenting
"specific agonist abrogates"
symptom
aromatase deficiency
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