SELECTIVE ESTROGEN RECEPTOR MODULATORS

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SELECTIVE ESTROGEN RECEPTOR MODULATORS
Dr. ROHIT JAIN M.D. (Obstetrics
Gynaecology)

• SCL Hospital, Saraspur, Ahemadabad

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Estrogen
What is behind these beautiful women?
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Estrogen
The Feminine Hormone

• That Nourishes Nurtures womanhood

But Estrogen is an ambivalent steroid hormone,
erratic, inconsistent mercurial in behavior.
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Effects of Estrogen at Various Sites in the Body
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Molecular Action of Estrogen
hsp90 heat shock protein90
Adopted from George et al
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Molecular Action of Estrogen
AP I activator protein CRP co regulator
protein ER estrogen receptor ERE estrogen
response element Poly II polymerase II TATA-
adenine-thymine-rich sequence important for gene
transcription
Adopted from Stanley J Birge et al
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Estrogen Receptor
Molecular Action of Estrogen
Illustration by Anne Erickson
Two types have been so far identified - ? and ?
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Estrogen Receptor Distribution
Molecular Action of Estrogen

• ? ? -CNS, blood vessels, bone, heart, breast,
  ovary, uterus, testes, prostate
• ? - Liver
• ? - Lungs, kidney, bladder, intestines

• Based on the level of ER mRNA levels
• Awaits confirmation till subtype specific
  monoclonal antibodies are available

Adopted from George GJM Kuiper et al
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Molecular Action of Estrogen
Alternating estrogen signaling pathways

• ? homodimer
• ? homodimer
• ? ? heterodimer
• Non-genomic effects

Adopted from George GJM Kuiper et al
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Molecular Action of Estrogen
Different response in different tissues
Adopted from Lewis J. Kleinsmith Ph.D, Donna
Kerrigan M.S., Jeanne Kelly
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Molecular Action of
Estradiol
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Molecular Action of
SERM(Tamoxifen)
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Molecular Action of
Estrogen Receptor Down regulator A Promising
Area of Research
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Mechanism of Tissue Response - Summary
Oestrogen Receptor
Ligand E / SERM / PE/ERD
? / ?
AF 1 2
Coregulatory Proteins
Oestrogen Receptor Ligand Complex
Gene Transcription
DNA Oestrogen Response element
Tissue Response
Agonistic or Antagonistic
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Selective Ostrogen Receptor Modulators
SERMs
Estrogens
SERMs- designed to act in specific ways at each
of the oestrogen receptor sites in different
tissues
Phytoestrogens
ERDR
Anti Estrogens
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Selective Ostrogen Receptor Modulators

• Designer Estrogens
• Fantasy Estrogens

• Designer drugs which exhibit tissue specific
  desirable Estrogenic Antiestrogenic actions in
  different tissues

They have the potential of providing a new
paradigm for maintaining the health of women.
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Selective Ostrogen Receptor Modulators
As of Today

• Mer 25 (1958)
• Clomiphene
• Tamoxifen
• Toremifene
• Droloxifene
• Iodoxifene
• Raloxifene
• Ormeloxifene

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The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
The Search goes on
The ideal SERM is one that prevents bone loss,
has no risk of uterine or breast cancer, a ve
effect on lipids cardiovascular system,
relieves PMS and maintains cognitive function of
the brain
Adopted from Rita de Cassia M Dardes V Craig
Jordan
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The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
The Search goes on
TISSUE Endometrium Breast Vagina Bone Liver/CVS CN
S
Perfect AE AE E E E E
Tamo E AE AE E E AE
Ralo AE AE AE E E E?
Ormelo AE ? AE ? E ? E ? E ? E ?
E-Estrogenic, AE-Anti Estrogenic
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Tamoxifen

• The first true SERM.
• In use for breast cancer treatment since 1968,
  10m patient use years.
• Approved for prophylactic use in1997.
• Beneficial effect on osteoporosis.
• Effect on CVS ?
• Lipid profile .

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Tamoxifen

• Has many undesirable E / AE actions.
• E in uterus risk of End. Cancer.
• Alleged as a carcinogen.
• AE in vagina, CNS?
• Unsatisfactory safety/toxicity profile.
• Gave boost to the continued research for SERMs.
• Under evaluation-star trial-6/99, 22000 women for
  5-10 yrs.

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Raloxifene

• Originally approved (1998) for use for treatment
  and prevention of osteoporosis.
• Subsequently (1999) approved for breast cancer
  prevention after MORE study
• Improved safety profile than Tamoxifen
• Cardiovascular effects are unequivocal under
  evaluation.

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Raloxifene

• ? Risk of venous thromboembolism
• No effect on endometrium. AE on vagina
• Effect on CNS?. No improvement in cognitive
  function
• Does not relieve PM hot flashes
• Possible future use as HRT??
• Is on evaluation- STAR trial

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ORMELOXIFENE
The perfect SERM
Chemical Name- Trans -7-methyl-2-2-dimethyl-3-phen
yl-4(4-(2-pyroldinoethoxy)phenyl(-chroman
hydrochloride), related to centchroman
The individual elements of the molecular
structure give a tissue selectivity- different
DNA transcriptions in different tissues
Estrogen agonist
Estrogen antagonist
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The perfect SERM
ORMELOXIFENE

• Enhanced tissue selectivity
• Basic amine side chain uterine AE action
• Pyrolidine base highest degree of antagonistic
  action
• Benzopyran group agonistic action binding
  affinity
• Very strong binding affinity to ER
• Quick potent action
• Slow nuclear build up prolonged retention of ER
• Long half life prolonged action

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ORMELOXIFENE
The perfect SERM
An optimally designed potent SERM with Varied
Tissue Response
Oestrogen Antagonist in UTERUS BREAST
Mild Oestrogenic action on Vagina, Bone mineral
density, CNS and Serum Lipids
No action on Hypothalamic Pituitary Ovarian
function, Thyroid, Adrenal.
No Progestational, Androgenic or Antiandrogenic
properties
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ORMELOXIFENE
The perfect SERM
Currently indicated for the treatment of
Dysfunctional Uterine Bleeding at ANY AGE.
Not suitable for women desiring pregnancy
Special benefit in perimenopausal women Relief
of PMS
Approved for inclusion in National Family Welfare
Program, for social marketing.
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ORMELOXIFENE
The perfect SERM

• Contraindicated in
• H/O recent liver dysfunction or clinical jaundice
• PCOD
• Cervical Dysplasia Chronic Cervicitis
• Hypersensitivity to the drug
• Allergic conditions
• Nursing mothers
• Chronic illness

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ORMELOXIFENE
The perfect SERM
Has an excellent safety profile,very well
tolerated practically without any undesirable
side effects
Easy to administer - 60mg tablet twice a week (
Sunday Wednesday) for 12 weeks followed by one
tablet of 60mg once weekly
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ORMELOXIFENE
The perfect SERM

• Currently being evaluated for use in the
  treatment and prevention of -
• Breast Cancer
• Osteoporosis

• Possible future use -
• Menopause management
• Fibromyoma
• Endometriosis and Adenomyosis
• Contraceptive

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ORMELOXIFENE
The perfect SERM
WARNING -

• Indian contribution
• Not introduced in the international arena
• Not approved by FDA
• Not yet fully evaluated - extensive clinical
  trials needed

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There is no cure for birth and death save to
enjoy the interval --Santayana
Selective Estrogen Receptor Modulators promise to
make the interval really enjoyable for women,
though the final words on Mode Of Action of
Estrogen, Estrogen Receptors and SERMs are yet to
be said.
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THANK YOU SERMs
Women have reason to say
SERMs have the potential of providing a new
paradigm for maintaining the health of women.
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Thank you