Download Ian Gans Bio 421 Estrogen: molecular properties and function

Ian
Gans
Bio
421
Estrogen:
molecular
properties
and
function
Estrogen
is
one
of
the
major
sex
hormones
in
vertebrates,
synthesized
primarily
in
the
gonads
of
both
males
and
females.
Estrogen
is
also
synthesized
by
some
insects‐
illuminating
the
fact
that
its
evolutionary
history
is
an
ancient
one1.
Estrogen
is
the
primary
human
female
sex
hormone,
and
thus
it
is
found
at
its
highest
levels
in
healthy
women
of
reproductive
age,
for
whom
the
hormone
regulates
reproductive
cycles
as
well
as
development
of
secondary
sex
traits
such
as
growth
of
breast
tissue
as
well
as
the
storage
of
fat.
To
a
lesser
degree
estrogen
is
also
involved
in
the
sexual
development
of
men.
Male
sex
drive,
while
primarily
dependent
on
androgens
such
as
testosterone,
requires
the
presence
of
estrogen,
as
does
the
maturation
of
sperm
cells.
Estrogen
is
a
member
of
the
steroid
family
of
molecules,
meaning
it
is
a
lipophilic
molecule
containing
the
steroid
nucleus
of
four
carbon
rings
made
up
of
17
carbon
atoms2.
The
singular
term
“estrogen”
is
actually
a
little
misleading,
as
the
term
estrogen
actually
refers
to
a
family
of
related
molecules
that,
in
humans,
includes
estrone,
estradiol,
and
estriol.
These
molecules
differ
structurally
by
having
either
a
hydroxyl
and
a
ketone
group
or
two
or
three
hydroxyl
groups
added
to
their
common
steroid
nucleus,
and
these
structural
differences
lead
to
varying
chemical
potencies.
Estradiol,
also
known
as
E2,
is
the
most
potent
of
the
three,
and
is
the
most
abundant
estrogen
during
the
reproductive
years
of
a
woman’s
life.
In
most
cases
when
people
refer
to
estrogen
they
are
referring
to
estradiol.
Estriol,
or
E3,
the
weakest
of
the
three,
is
the
most
abundant
estrogen
in
a
woman’s
body
during
pregnancy,
and
estrone,
or
E1,
is
the
most
abundant
during
menopause.
The
synthesis
of
natural
estrogen
steroids
begins
with
cholesterol
and
proceeds
through
a
number
of
catalytic
steps
before
ending
with
the
conversion
of
either
testosterone
or
androstenedione
(both
androgens,
or
masculinizing
hormones)
by
the
enzyme
aromatase
into
estradiol
or
estrone
respectively.
Either
of
these
estrogens
may
then
by
further
modified
into
estriol.
In
addition
to
the
estrogens
normally
produced
by
mammals,
numerous
substances
have
been
found
which
behave
like
estrogen,
although
this
does
not
necessarily
mean
they
have
similar
chemical
structures.
These
substances
are
known
as
xenoestrogens
(xeno­
being
latin
for
foreign).
Some
plants
synthesize
estrogenic
chemicals,
and
these
are
called
phytoestrogens.
When
these
plants
are
commonly
consumed
these
estrogens
may
also
be
referred
to
as
dietary
estrogens.
It
is
theorized
that
some
plants,
such
as
cereal
grains
and
legumes,
evolved
the
synthesis
of
these
estrogenic
compounds
as
a
defense
mechanism
to
control
the
male
fertility
and
thus
the
population
of
herbivores
in
their
ecosystem3.
The
broad
category
of
xenoestrogens
also
includes
synthetic
substances.
Some
of
these
substances
are
pharmaceuticals,
such
as
birth
control
or
the
breast
cancer
drug
tamoxifen.
Others
are
widely
used
industrial
chemicals
like
the
pesticide
DDT
or
the
plastic
additive
BPA
used
in
water
bottles
and
to
line
aluminum
cans,
or
the
plastic
softening
agents
called
phthalates
which
are
found
in
vinyl,
car
seats,
cosmetics
and
more.
Alarming
studies
have
found
that
the
ubiquitous
use
of
such
chemicals
over
the
past
several
decades
has
led
to
hormonal
disruption
of
wildlife
species.
Certain
populations
of
fish,
exposed
to
these
chemicals
via
runoff
from
human
settlement,
seem
to
have
suffered
significant
consequences,
with
the
results
being
fewer
reproductive
cycles
for
females,
and
lowered
sperm
concentration
and
motility
in
males,
and
even
significant
numbers
of
fish
suffering
partial
sex
reversals
or
being
born
intersex.
In
this
negative
context,
xenoestrogens
fall
into
a
larger
category
of
chemicals
known
as
endocrine
disruptors‐
chemicals
that
have
the
ability
to
disrupt
or
affect
the
function
of
the
endocrine
system.
In
humans,
there
is
debate
over
what
effects
these
chemicals,
which
we
encounter
everyday
in
our
environment,
are
having.
Some
say
the
environmental
concentration
is
too
low
to
have
any
effect,
while
others
argue
that
xenoestrogens
can
be
linked
to
breast
cancer,
prostate
cancer,
problems
with
fetal
brain
development,
early
onset
of
puberty
in
girls,
falling
sperm
counts
in
men,
and
more.
Because
estrogens
(and
steroids
in
general)
are
non‐polar
molecules,
they
are
able
to
freely
pass
through
cell
membranes.
Within
cells,
estrogen
is
synthesized
in
the
hydrophobic
environment
of
the
smooth
endoplasmic
reticulum.
Cholesterol
endosomes
fuse
with
the
ER,
and
the
cholesterol
is
then
converted
by
a
series
of
enzymes
into
estrogen,
which
is
released
with
no
storage
occurring
in
the
cell.
As
it
is
a
lipoid
molecule,
there
is
no
gene
that
codes
for
estrogen.
The
genes
necessary
for
estrogen
production
are
those
that
code
for
the
oxidases
involved
in
its
synthesis.
Also
because
of
its
lipid
nature,
when
estrogen
is
transported
in
the
blood,
it
is
bound
to
a
sex
hormone
binding
globulin
(SHBG)
in
order
to
prevent
its
removal
from
circulation
by
the
liver
and
kidneys.
Estrogen
is
produced
primarily
in
the
gonads.
However,
liver,
breast,
adrenal
and
fat
cells
also
contribute
to
estrogen
production
and
these
contributions
become
more
important
in
women
after
menopause.
The
production
of
estrogens
is
regulated
by
circulating
gonadotrophins
(GTH),
which
are
in
turn
controlled
by
the
HPG
axis
(Hypothalamus‐Pituitary‐Gonads)4.
Estrogen’s
main
receptor
is
found
in
the
nucleus
of
target
cells.
It
is
a
member
of
the
nuclear
family
of
receptors,
and
causes
genomic
actions
within
the
target
cell.5
Due
to
it’s
steroidal
nature,
estrogen
molecules
can
freely
diffuse
into
the
nucleus,
where
they
bind
to
these
receptors.
Chaperone
proteins
(also
referred
to
as
heat‐shock
proteins),
help
to
maintain
the
unoccupied
receptor’s
shape.
These
chaperone
proteins
dissociate
from
receptor
molecules
once
they
are
occupied
by
estrogen.
The
structure
of
each
estrogen
receptor
includes
an
80
amino
acid
sequence
comprising
two
peptide
loops
called
zinc
fingers.
The
dissociation
of
the
chaperone
proteins
exposes
these
zinc
fingers.
An
occupied
estrogen
receptor
will
phosphorylate
and
form
a
homodimer
with
another
occupied
receptor
molecule,
becoming
a
ligand‐activated
transcription
factor.
The
combined
four
zinc
fingers
of
this
transcription
factor
can
then
bind
to
a
promoter
region
of
DNA
known
as
a
Hormone
Response
Element
(HRE).
More
specifically
in
estrogen’s
case
this
promoter
region
is
called
an
Estrogen
Response
Element
(ERE).
Additional
nuclear
adaptor
proteins
are
then
recruited
to
the
promoter
site,
causing
interaction
with
RNA
polymerase
and
resulting
in
RNA
transcription
(and
thus
gene
expression).
The
estrogen
receptor
(ER)
molecule
is
thought
to
have
evolved
from
an
ancestral
Estrogen‐Related
Receptor
(ERR),
which
can
still
be
found
in
some
more
primitive
vertebrates6.
A
gene
duplication
event
then
allowed
the
estrogen
receptor
to
evolve.
A
second
gene
duplication
event
allowed
the
ER
to
diverge
further
into
ER
alpha
and
beta
receptors,
which
have
differing
affinities
for
different
estrogens,
as
well
as
different
tissue
distributions,
with
beta
receptors
not
being
present
in
the
liver
and
the
alpha
receptor
not
being
present
in
the
gastrointestinal
tract.
Because
the
alpha
receptor
is
less
selective
in
what
it
will
bind
with,
it
is
this
receptor
which
most
xenoestrogens
bind
with,
as
well
as
many
drugs
such
as
the
birth
control
drug
ethinyl
estradiol
(EE2)
and
the
breast
cancer
drug
Tamoxifen.
Estrogenic
pharmaceuticals
(and
xenoestrogens
in
general)
can
have
either
agonistic
or
antagonistic
effects.
In
the
case
of
the
birth
control
drug
EE2,
the
drug
binds
to
the
receptor
and
mimics
natural
estrogen,
manipulating
its
level
and
that
of
interrelated
hormones
in
order
to
prevent
ovulation.
Tamoxifen,
on
the
other
hand,
has
antagonistic
behavior
in
breast
tissue,
where
it
blocks
estrogen
receptors
without
activating
them7.
Preventing
the
receptors
from
binding
with
estrogen
in
turn
inhibits
the
growth
of
some
types
of
breast
cancer
cells
which
require
estrogen
to
grow.
In
addition
to
its
nuclear
receptor,
estrogen
also
has
been
found
to
have
membrane
bound
receptors
in
some
cells.
In
one
such
case,
estradiol
binds
to
a
G
Protein
Coupled
Receptor
(GPCR)
in
the
membrane,
which
in
turn
activates
a
cascade
of
other
proteins
within
the
cell,
culminating
in
the
release
of
intracellular
Ca++
ions,
inducing
exocytosis
by
the
cell
of
other
hormones
or
secretory
proteins.
This
method
of
hormonal
action
is
called
the
second
messenger
system
(extracellular
estrogen
being
the
first
messenger,
and
internal
cellular
proteins
being
the
second).
The
results
of
this
pathway
differ
from
those
of
the
standard
genomic
pathway,
but
may
occur
more
rapidly
than
the
genomic
pathway
which
typically
requires
hours.
1. http://en.wikipedia.org/wiki/Estrogen
2. textbook,
page
65
3. http://en.wikipedia.org/wiki/Xenoestrogen
4. textbook,
page
318
5. text,
page
74
6. text,
page
77
7. http://en.wikipedia.org/wiki/Tamoxifen