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TISSUE SPECIFIC
ESTROGEN
RECEPTOR
MODURATORS
Wanwisa tharnprisarn
Advisor
Assist.Prof.
Nimit Daechkrichana
By
Introduction
 phenanthrene nucleus –
stilbene nucleus
 MER 25
 MRL 41
E-page40
Des ‘’
p.116-7tam+metabolism
Definitions
Selective estrogen receptor
modurator
Estrogen agonism in desired
target tissues and either
antagonism or clinically
insignificant agonism in
reproductive tissues
(AJOG 1999)
• Non-steriod
• ideal SERMs :
- strong estrogen agonist
in bone , cardiovascular,
vulva , vagina and
potentially CNS
- estrogen antagonist in
uterus and breast
Classification

Synthetics
1.triphenylethylene derivatives
: clomiphene citrate
tamoxifen,
idoxifene(4-OH tamoxifen)
droloxifene (3-OH tamoxifen)
toromifene (chloro-tamoxifen)
2. Benzothiophene derivatives
: Raloxifene and derivatives
3. Others
: benzopyrans (centchroman)
• Natural
: Phytoestrogens
Anti-estrogens
 Compounds that block the
actions of estrogen
 Physiologic :
progesterone,testosterone
 Synthetics :
2-major types (Pharmacol Rev1998)
Type 
• Mixed estrogenic/antiestrogenic
: triphenylethylene
: benzothiophene
Type II
• Pure antiestrogenic
Compound breast
Uterus bone CHL.
E2 , EE
+
+
+
+
Tamoxifen
_
+(partial)
+
+
Raloxifene
_
_
+
+
ICI 164384
ICI 182780
_
_
_
_
E-antagonist
Sheet ”fig.1,2b
Mechanism of action
• general overview of ER pathway
• 3-main level of moduration of
estrogen receptor
: type of ligand
: species of ER
: type of effector site
Steroid receptors
A/B
AF-1
C
D
E
F
AF-2
Transactivation
Dimerization
Nuclear localization
Hsp 90 binding
Estrogen receptors
A/B
C
TAF 1
A/B
D
E
F
TAF 2
Estrogen receptor-alpha
C
D
E
TAF 2
Estrogen receptor-beta
F
Zinc fingers
D box : dimerization
P box : specific recognition of the HRE
conformational change
Dimerization
A/B
Hsp90
Lig
LBD
DBD
A/B
Lig
Lig
LBD
LBD
DBD
DBD
HRE
A/B
DNA binding
General TF
Sequencespecific TF
H-R complex
Chromatin factor
Co-activator
Co-repressor
Transcription activity of
SERMs
 two well-recognized pathways
for activation of gene
transcription
: classical ERE-pathway
: AP-1 pathway
coactivator
ER ER
ERE
Transcript.p.
ERregulated
ERE
ER
F
AP-1
J
ERregulated
AP-1 element
Fig.scan H12
Conclusion
SERMs function as
:TAF-2 antagonist
:TAF-1 agonist
Distribution of ER
 ER  : uterus, breast, liver,
kidney
 ER  :bone, brain, vascular,
ovary, testis
 Both : ovary,bone,brain,
breast,cardiovascular
Pharmacokinetics of
SERMs
CC
Ralox. Tamox.
T1/2
5d
28h
5-7d
elimination
fecal
fecal
fecal
Metabolize
Cyto.P450
yes
no
yes
• first pass hepatic effect
• conjugation with
glucuronide
• enterohepatic circulation
• circulated binding protein
:albumin,1 acid glycoprotein
• drug interaction
:tamoxifen-warfarin
Skeletal effects of SERMs
• TGF-3 from osteoclasts
and osteoblast inhibits
osteoclast differentiation
• encourage osteoblast
production
• resulting in reduction of
bone loss
Tamoxifen
Animal model
: reduce number and size
of osteoclasts
: inhibit bone resorption
: less effective than E2
: no effect when endogenous
E2 is normal
(Endocrinology1994)
• human study
: a number of surveys
show a decrease in
biological markers
- bone resorption
- bone formation
: some early reports
found no significant
differences
• Breast cancer prevention
trial (RCT 6,681cases)
tamoxifen 20 mg./d
compared with placebo
: fewer hip, spine ,
Colles’fracture
: bias – indiscriminate
inclusion of
pre-/post menopause
-- no radiograph
Summary
• in short scientific evidence
on bone seems to parallel
animal trials
• benificial effects in
post-menopausal, but not
pre-menopausal
Raloxifene
 animal model
: lower bone remodelling
markers
: increased fracture force
(Endocrinology 1996)
• human study
MOREstudy
randomized7705
placebo2575
Ralox.5129
Follow radiograph 24,36month
BMD
120R
60R
placebo
0
-1
VERTEBRAL
-2
12
24
36
months
BMD
Femoral neck
120R
60R
0
placebo
-1
-2
12
24
36 months
%vertebral fracture
RR0.5
RR0.7
RR0.6
RR0.5
No preexiting Fx.
Preexiting Fx.
(JAMA1999)
Median percentage changes
in BMD after 24mo.
of raloxifene prevention of
Post-menopausal osteoporosis
n.
European 601
spine Fem. Troch.
2.4
neck
2.5
2.7
US
544
2.0
2.1
2.2
Inter.
619
1.8
1.6
1.3
Breast effects
 interfere development
of initial tumor
• suppress occult tumor
•tamoxifen
 Early Breast Cancer
Trialists’Collaborative
Group : most recent
meta-analysis ;
10-yr survival- node pos.
tam.
= 61%
no tam.
= 50%
• node negative
tam.
= 79 %
no tam. = 73 %
• > 5 yr. controversy
• Ductal carcinoma in situ
after lumpectomy and
radiation :
5-yr.risk of cancer
tam. = 8.2
no tam.= 13.4
• reduced risk of
contralateral second
primary cancer
• U.S.Breast Cancer
Prevention Trial study
high risk 13,388 women
: reduced invasive cancer
risk 49%
: no redution in mortality
due to breast cancer
• tamoxifen reduced risk of
ER-pos. tumors = 69%
but no effect to ER-neg.
• abnormal breast biopsy
LCIS 56% reduction in
invasive cancer
• contrast results from
Italy and British
: small sample size
: included only familial
history of breast cancer
• accurate assessment of
risk and benefit
Raloxifene
•Animal model
: inhibit tumor growth and
MCF –7 breast cancer
cell line in vitro
MORE study :
Breast cancer
RR = 0.24 in raloxifene
compared with placebo
• reduced only ER-pos.
tumor, not ER-neg.
• longer effects and accurate
trial in CORE, STAR 1999
Endometrial effects
Tamoxifen
• increased uterine weight
• double expression of IGF-1
• up-regulate expression of
Ki 67, a marker of
proliferation
•suppress IGFBP-3 and 1
• dysregulation of TGF-
resulting in refractory to
inhibitory signal
• DNA aduct by tamoxifen
(controversy)
(Obstet Gynecol1998)
Tamoxifen
 Early Breast Cancer
Trialists’ Collaborative Group
-endometrial cancer with
tamoxifen
: RR= 2.2 relative to placebo
 incomplete or inconclusive
evidence
Raloxifene
• lack endometrial activity
• block stimulating effects of
E2 and tamoxifen
• no vaginal bleeding
• co-activators
• conformational change
different from tamoxifen –
induced
• MORE study and European
study show no differences
in endometrial thickness
and cancer
(RR = 0.8 , 95% CI =0.2-2.7)
Cardiovascular effects
 decreased circulating LDL
10-12% , total cholesterol 6%
Increased HDL2 15%
total HDL – no change
• increase triglyceride-T
• no effect on triglyceride-R
 lower fibrinogen 10%
and antithrombin III
 not decrease PAI-1
 decrease CRP 5% and
homocystein 6-8 %
• although there are favorable
effects of clotting, raloxifene
increases risk of
thromboembolism
(RR = 3.1, 95%CI=1.5-6.2)
(JAMA 1999)
• Raloxifene Use for The Heart
(RUTH)study results by 2005
Menopausal symptoms
 not improved vasomotor
symptoms
 leg cramps increased
 cognitive function :
inconclusive
Side effects
 hot flush
 atrophic vaginitis
 retinopthy,posterior
subcapsular opacitym
 thromboembolism
Other SERMs
 Droloxifene
: metastatic breast cancer
no endometrial stimulation
 LY353381
: more potent,more sustained
blood level
 Lasofoxifene , Idoxifene,…
Phyto-estrogen
 differential binding to
ER /
 different tissue distribution
of ER
Classification of phyto-estrogen
 isoflavones: genistein,
daidzein (soy)
 lignin
: enterodiol,
enterolactone(flaxseed)
 coumestans:coumestrol(red clover)
potential health benefits of soy
benefit
Hot flashes
Vagina atrophy
Cancer prevent.
Lipid improved
CVS
osteoporosis
Alzheimer’s
++
+/++
++
?+?
+/?
Strength of
data
RCT
RCT
Epidemiologic
”
”
Little data
No data
Tibolone
 3-major metabolites which
bind to a greater or lesser
extent to steroid receptors