This document provides information about selective estrogen receptor modulators (SERMs). It discusses the history and physiology of estrogen, then describes various SERMs including tamoxifen, toremifene, raloxifene, ormeloxifene, clomiphene, and fulvestrant. Each SERM is discussed in terms of its chemical structure, molecular action, pharmacological effects, pharmacokinetics, therapeutic uses and side effects. SERMs demonstrate tissue-selective estrogenic or anti-estrogenic actions depending on the receptor binding site. The ideal SERM prevents bone loss without increasing cancer or cardiovascular risks.

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….