2. 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
3. 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
5. 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.
7. 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
8. CLOMIPHENE - USES
Infertility due to anovulation
Male infertility due to oligozoospermia
In vitro fertilization
9. CLOMIPHENE – ADVERSE
EFFECTS
Twins / Multiple pregnancy
Ovarian enlargement
Polycystic ovaries (can rupture leading to
internal hemorrhage)
Hot flushes
Weight gain
Reversible alopecia
Vertigo
10. TAMOXIFEN
Potent ER antagonist at:
Breast
Blood vessel
Peripheral sites
ER agonist at:
Uterus
Bone
Liver
Pitutary
11. 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
13. 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
14. 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
15. TAMOXIFEN – USES
Breast Carcinoma – Pre &
Postmenopausal
Prevents post-menopausal osteoporosis
Improves bone density
Decreases incidences of Coronary
Artery Disease (CAD)
Improves lipid profile
16. 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
17. 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
19. 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
22. 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
23. 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
28. 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
30. 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
36. 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.
37. 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
38. 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
39. BAZEDOXIFENE
Prevention and treatment of
postmenopausal osteoporosis
Favorable effects on lipid parameters
total cholesterol
low-density lipoprotein cholesterol
high-density lipoprotein cholesterol