This document discusses selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs), which are drugs that act as agonists or antagonists of estrogen receptors in a tissue-selective manner. It provides details on commonly used SERMs like tamoxifen, clomiphene, raloxifene, and newer drugs. It also discusses the prototype SERD fulvestrant and its mechanism of downregulating estrogen receptors. The document summarizes the pharmacological properties, mechanisms of action, uses and side effects of these estrogen-modulating drugs.

1. SERM & SERD
Tulasi Raman P

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

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

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.

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

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

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

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

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

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

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

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

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

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

25. FULVESTRANT - USES
Tamoxifen resistant Breast Cancer

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

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

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

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

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

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

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

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

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

35. RECENT ADVANCES

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

40. THANK YOU !