SERM & SERD

ESTROGEN – PHYSIOLOGICAL
EFFECTS
On blood:
Decreased antithrombin III
Increased Factor II, VII, IX, X
Thrombolic predisposition
Lipid profile:
Increase in HDL
Decrease in LDL
Increase in triglycerides

Uterine endometrium
Induction of secretory phase
Mammary glands
Development of alveo-lobular
system
Cervix
Viscous, scanty mucus secretion
Bones:
Maintains bone mass
Decrease in bone resorption

FSH / LH secretion
Feedback control
Carbohydrate metabolism
Increases basal insulin levels
Insulin response to glucose
Fat deposition
Increased
Increased appetite

WHAT IS SERM ?
 Selective Estrogen Receptor Modulator
(SERM) are non steroidal synthetic agents
whose agonist or antagonist activities on
estrogen receptor (ER) are tissue selective.

SERM - DRUGS
 Prototype : Tamoxifen
 Tamoxifen analogs :
Toremifine, Droloxifene, Idoxifene
 Fixed ring compounds :
Raloxifene, Lasofoxifene, Arzoxifene,
Miproxifene, Levormeloxifene, EM652

CLOMIPHENE
Orally active SERM
Acts as competitive antagonist of ER in
hypothalamus
Inhibits negative feedback effects on
the release of GnRH
Increases the pulse frequency of GnRH

CLOMIPHENE - USES
 Infertility due to anovulation
 Male infertility due to oligozoospermia
 In vitro fertilization

CLOMIPHENE – ADVERSE
EFFECTS
 Twins / Multiple pregnancy
 Ovarian enlargement
 Polycystic ovaries (can rupture leading to
internal hemorrhage)
 Hot flushes
 Weight gain
 Reversible alopecia
 Vertigo

TAMOXIFEN
 Potent ER antagonist at:
Breast
Blood vessel
Peripheral sites
 ER agonist at:
Uterus
Bone
Liver
Pitutary

TAMOXIFEN - MOA
Competitive inhibitor of estradiol
binding to the ER
Binding of estradiol & SERM to the
estrogen binding sites of the ER’s
initiate a change in conformation of the
ER, dissociates the ER form heat-shock
proteins and inhibition of ER
dimerisation

TAMOXIFEN - MOA
Up regulates Transforming Growth
Factor β (TGF- β)
Decreases total serum cholesterol
Decreases LDL cholesterol
Increases apolipoprotein A1

TAMOXIFEN -
PHARMACOKINETICS
Readily absorbed on oral
administration
Peak concentration – 3-7 hours
Steady state – 4-6 weeks
Oral dose 20mg/day
At high doses 200mg/day can cause
retinal degeneration

TAMOXIFEN -
PHARMACOKINETICS
Metabolites
CYP3A4/5  N desmethyl tamoxifen
CYP2D6  4 hydroxytamoxifen
4 hydroxy N desmethyltamoxifen
(Retains affinity)
T ½ Parent drug – 7days
Metabolites – 14 days
Enterohepatic circulation
Excreted in stool

TAMOXIFEN – USES
Breast Carcinoma – Pre &
Postmenopausal
Prevents post-menopausal osteoporosis
Improves bone density
Decreases incidences of Coronary
Artery Disease (CAD)
Improves lipid profile

TAMOXIFEN – ADVERSE
EFFECTS
Hot flushes
Menstrual irregularities
Nausea
Vomiting
Anorexia
Hair loss
Vaginal bleeding and discharge
Pruritis vulvae and dermatitis
Atrophy of lining of vagina

TAMOXIFEN RESISTANCE
Polymorphism of CYP2D6
Cross talk between ER & HER2/neu
pathway
Interaction between PAX2 and the ER
coactivator AIB-1 / SRC-3 determine
tamoxifen response in breast cancer
cells

TOREMFINE
Triphenylethylene derivative of
Tamoxifen
Similar pharmacological profile
Used to treat Brest cancer with ER+ or
unknown receptor states
Not hepatocarcinogenic in
experimental animals

WHAT IS SERD ?
Selective Estrogen Receptor Down
regulator (SERD) are pure anti-
estrogens.
Paradoxically SERM down-regulates
ER’s and also promotes degradation of
ER’s by proteosomal enzymes

SERD - DRUGS
Fulvestrant – Prototype
SR16234
ZK191703
RU58668
ZK191703

FULVESTRANT
Steroidal anti-estrogen that binds to
the ER with an affinity >100 times that
of tamoxifen
Pure anti-estrogen

FULVESTRANT - MOA
 Inhibits binding of estrogen
 Alters the receptor structure such that the
receptor is targeted for proteosomal
degradation
 Inhibits receptor dimerisation
 Decreases number of ER molecules in cells
 ER downregulation  abolishes ER
mediated transcription of estrogen
dependant genes

FULVESTRANT -
PHARMACOKINETICS
Given i.m.
Max plasma concentration: 7 days
t ½: 40 days
Steady state 3-6 months
Dosing
Loading dose 500mg on day 0
250 mg on 14th
& 28th
day
250 mg every month

FULVESTRANT -
PHARMACOKINETICS
Extensive, rapid distribution &
extensive protein binding
CYP3A4  metabolites
<1% of drug is excreted intact in urine

FULVESTRANT - USES
Tamoxifen resistant Breast Cancer

FULVESTRANT – ADVERSE
EFFECTS
Nausea
Asthma
Pain
Vasodilation
Headache

RALOXIFENE
Antiestrogen effect at:
Breast
Endometrial tissue
Estrogenic effect at:
Bone
Lipid metabolism
Blood coagulation

RALOXIFENE
Dose dependant increase in
osteoblast activity and decreased
osteoclast action
Increases Bone density
Maintains favorable lipid profile
Does not stimulate endometrial
carcinoma
No risk of endometrial cancer

RALOXIFENE -
PHARMACOKINETICS
Orally absorbed
Poor bioavailability
Extensive first pass metabolism
in liver
Large aVd & longer t ½
Hence once a day administration
60mg/day

RALOXIFENE - USES
Prevention of osteoporosis in post-
menopausal women
Decrease risk of Breast cancer (ER
positive)
Decreases risk of vertebral compression
fracture
Alternative for Hormone Replacement
Therapy

RALOXIFENE – ADVERSE
EFFECTS
Hot flushes
Leg cramps
Increased risk of
Deep Vein Thrombosis
Pulmonary embolism
Estrogenic effect on blood
coagulation

ORMELOXIFENE
Estrogen antagonist at breast and
uterus
Has anti-estrogen activity as well as
anti-progestogenic action

ORMELOXIFENE - USES
Dysfunctional Uterine Bleeding (DUB)
Non-hormonal oral contraceptive
Investigated for
Osteoporosis
Breast cancer
Endometrial cancer

ORMELOXIFENE - USES
Nausea
Headache
Fluid retention
Weight gain

LASOFOXIFENE
Investigated for the prevention and
treatment of osteoporosis and for the
treatment of vaginal atrophy in
postmenopausal women.
Increased endometrial thickness.
Lasofoxifene was not approved by the
US FDA for the treatment of vaginal
atrophy.

OSPEMIFENE
Similar effect on most markers of bone
resorption and bone formation
compared with raloxifene
Does not induce vasomotor symptoms
in postmenopausal women
Increased endometrial thickness and
uterine volume

ARZOXIFENE
 Treatment and prevention of breast cancer
 Reduction in vertebral fractures and breast
cancer in postmenopausal women
 Failed to meet secondary endpoints of reduction
in non-vertebral fractures and cardiovascular
events and improvements in cognitive function
 The drug company announced they are
discontinuing further development of the drug
and would not seek regulatory approval

BAZEDOXIFENE
Prevention and treatment of
postmenopausal osteoporosis
Favorable effects on lipid parameters
total cholesterol
low-density lipoprotein cholesterol
high-density lipoprotein cholesterol

SERM & SERD

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SERM & SERD