1. SELECTIVE ESTROGEN
RECEPTOR MODULATORS
Dr. SOHIN THAIM
Date : 11/03/2014
Dept. of Pharmacology
JNMC, Sawangi (W)

2. ESTROGEN
• History :
• Greek word
‘oistros’ meaning ‘gadfly’ or ‘mad impulse’-sexual passion or
desire
‘gens’ meaning ‘producer of’
 1900 – Knauer and Halban established that Ovaries control female
reproductive function
 1923 – Allen and Doisy found that alcoholic extract of Ovaries was
capable of producing Estrus
 1928 - Zondek reported excretion of estrogen in Urine
 1929 – Butendant and Doisy isolated principle Estradiol in pure
form

3. Physiology
• Synthesized from Cholestrol in Graffian follicle, Corpus
Luteum and Placenta
• Natural Estrogens : Estradiol
Estrone
Estriol
• Synthetic Estrogens : Ethinylestradiol, Mestranol, Tibolone
Diethylstilbestrol
• Regulation :
• Estrogen after Ovulation produces negative feedback
inhibition of FSH by direct action on Pituitary

4. • Normally :
Daily secretion-10-100 µg in menstruating women
Depends on the phase of the cycle.
• During pregnancy :
Placenta secrets Estrogen
Peak up to 30mg/day
• Postmenopausal women :
Daily production – 2- 10 µg
From Extra glandular size

5. Chemical Structure
Phenolic A ring – Principal Structure
Hydroxyl Group at Carbon 3
ß – OH or Ketone at Carbon 17

6. Actions of Estrogen
1. Sex Organs :
Pubertal changes in female
Growth of
- Uterus
- Fallopian tubes
- Vagina
• Estrogen augments rhythmic contractions of fallopian tube
and uterus
• Induce watery alkaline secretion from cervix making sperm
penetration favorable

7. 2. Secondary Sex Characters :
- Growth of Breast
Proliferation of ducts and stroma
Accumulation of fat
- Pubic and Axillary Hair
- Feminine Body Contour and behaviour

8. 3. Metabolic Effects :
Bone : maintains bone mass
Inhibits Osteoclast formation
Promotes positive calcium balance
Fluid Balance :
mild salt and water retention
Edema and mild rise in BP after prolonged use
Lipid Profile :
Increase in HDL
Increase in Triglycerides
Decrease in LDL

9. Molecular Action

10. What is SERM ?
• SERM is a group of drugs which are
- Synthetic
- Non Steroidal
- Tissue selective Estrogenic and Anti Estrogenic actions
• So SERM may have one or combination of
- Full agonist such as the natural endogenous estrogen
- Mixed agonist /antagonist such as tamoxifen
- Full antagonist such as Fulvestrant

11. Ideal SERM
• The ideal SERM is one that
- Prevents bone loss
- No risk of uterine or breast cancer
- + ve effect on lipids & cardiovascular system
- Relieves PMS
- Maintains cognitive function of the brain

12. • Examples : Tamoxifen Citrate
Tamoxifen Analogue
Toremifene
Droloxifene
Idoxifene
Raloxifene
Lasofoxifene
Arzoxifene

13. TAMOXIFEN CITRATE
• History :
 The first true SERM
 In use since 1966 for Breast cancer
 Developed as an Oral Contraceptive but was found to induce
ovulation
 Approved for Prophylactic use in Breast cancer since 1997

14. Chemical Structure
l
Trans Clomiphene or
Enclomiphene
Trans conformation –Anti-
estrogenic
Cis conformation-
Estrogenic
Tamoxifen is marketed as
Trans isomer

15. Molecular Action

16. • Potent Estrogen Receptor Antagonist at :
- Breast
- Blood vessels
- Peripheral sites
• Potent Estrogen Receptor Agonist at :
- Uterus
- Bone
- Pituitary
- Liver

17. • Mechanism of Action :
 Competitive inhibitor of estradiol binding to the ER
 Binding of Estradiol and SERM to Estrogen binding sites of ER.
 Initiate a change in conformation of ER
 Dissociation of ER from Heat Shock Protein
 Inhibition of ER Dimiresation

18. • Pharmacological Actions :
• Anti estrogenic effects :
Inhibition human breast cancer cells
Hot flushes
• Estrogenic effects :
Endometrial Proliferation
Improvement in Bone density
Decrease in total and LDL cholesterol
No change in HDL and Triglyceride
Increase in Thromboembolism

19. • Pharmacokinetics :
- effective orally
- biphasic half life – 10hrs and 7days
- major metabolite 4 hydroxytamoxifen
- long duration of action
- excreted in bile and stool
• Side effects :
- Hot flushes
- Vaginal bleeding
- Vaginal discharge
- Menstrual irregularities

20. - Increased risk of thromboembolism
- Dermatitis
- Anorexia
- Depression
- Mild Leucopenia

21. • Therapeutic Uses :
- Pre and Postmenopausal breast cancer
- Primary prophylaxis of Breast cancer in High risk women
- Post menopausal Osteoporosis
- Male infertility – alternative to Clomiphene
• Dose :
- 20mg/day in 1 or 2 doses
- maximum 40mg/day.

22. TOREMIFENE
• Triphenylethylene derivative of Tamoxifen
• Chemical structure same as Tamoxifen with Chlorine
substitution as R2 position
• Similar pharmacological profile
• Used to treat ER positive breast cancer

23. RALOXIFENE
• Developed in 1998 for treatment and prevention of
Postmenopausal Osteoporosis.
• 1999 approved for prophylaxis of breast cancer
• Partial Estrogenic effects : Bone
CVS
• Antiestrogenic Effects : Breast
Endometrium
• Has distinct DNA target ‘raloxifene response element’

24. Chemical Structure
Polyhydroxylated
nonsteroidal compound

25. • Pharmacological Actions :
- Improves Bone Mineral Density, prevents bone loss
- Reduces incidence of Compression vertebral fractures
- Decreases LDL, No increase in HDL and Triglycerides
- Does not stimulate Endometrial Proliferation
• Pharmacokinetics :
- Absorbed orally
- Has low oral bioavailability – only 2%
- Half life 28 hrs
- Excreted in faeces

26. • Side effects :
- Hot flushes
- Leg cramps
- Deep vein thrombosis
- Pulmonary embolism
• Uses :
- Second line drug for Osteoporosis
- Secondary prevention and treatment of vertebral fractures
- Prevention of Breast cancer
- alternative to Hormone replacement therapy

27. ORMELOXIFENE
• Estrogen antagonist at breast and uterus
• Has anti estrogenic as well as anti progestogenic action.
• Uses :
 Dysfunctional Uterine Bleeding
 Non Hormonal Oral Contraceptive
Under Investigation for USE in :
 Osteoporosis
 Breast cancer
 Endometrial Cancer

28. • Adverse Effects :
 Nausea
 Headache
 Weight gain
 Fluid retention

29. CLOMIPHENE CITRATE
• Competitive antagonist of ER at Hypothalamus
• Inhibits negative feedback effects on the release of GnRH
• Release of FSH/LH at each secretory pulse is enhanced
 Pharmacokinetics :
• Well absorbed orally
• Long plasma half life - 5 to 7 days
• Highly plasma protein binding, undergoes enterohepatic
circulation
• Excreted in Urine and Faeces

30.  Adverse Effects :
• Polycystic Ovarian Disease
• Multiple Pregnancy
• Risk of Ovarian Cancer
• Hot flushes
 Uses :
• Infertility due to anovulation
• Male infertility due to Oligozoospermia
• In vitro fertilization

31. FULVESTRANT
7 α Alkylamide
derivative of Estradiol

32. Molecular Action

33. • First member of – SERD
‘ Selective Estrogen Receptor Down-regulators’
• Pure estrogen antagonist
• Introduced for treatment of metastatic ER positive breast
cancer in postmenopausal women
• Inhibits ER Dimerisation-ER interaction with DNA is prevented
• Receptor degradation is enhanced

34. • More complete suppression of ER responsive gene function
• Slowly eliminated, half life more than a month
• Elimination in faeces
 Adverse Effects :
• Nausea, Headache, Asthma, Vasodilatation
 Dose : 250mg monthly i.m. injections in buttocks
 Use : Tamoxifen Resistant Breast Cancer

35. Recent Advances
Lasofoxifene :
 Investigated for the treatment of Post menopausal
Osteoporosis and Vaginal Atrophy
 Not approved by FDA for the treatment of vaginal atrophy
Osmepifene :
 Similar effects on bone as like Raloxifene- Increase BMD
 Does not induce vasomotor symptoms in Post
menopausal women
 Increases endometrial thickness

36.  Arzoxifene :
• Prevention and treatment of Breast cancer
• Reduction in Vertebral Fractures
• Failed to meet secondary endpoints of reduction in non
vertebral fractures and cardiovascular events and cognitive
function
 Bazedoxifene :
• Prevention and treatment of Post menopausal Osteoporosis
• Favorable effects on Lipid profile

37. THANK YOU….