SELECTIVE ESTROGEN RECEPTOR MODULATORS
May 31, 2015
SELECTIVE ESTROGEN RECEPTOR MODULATORS
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Estrogen
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That Nourishes & Nurtures
womanhood
The Feminine Hormone
Estrogen
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Effects of Estrogen at Various Sites in the Body
Tissue Effect of Estrogen Stimulation
Clinical Effect of Stimulation
Clinical Effect of Absence of Stimulation
Bone Increased deposits of calcium into bone
Increased bone density Osteoporosis
Brain Blocks the release of ovarian estrogen
NoneHot flashes, sleep disorders, mood changes, problems with memory? Alzheimer’s disease??
BreastStimulates growth of breast tissue
Bigger breasts,? Increased risk of breast cancer, increased sensitivity of the breast,
Smaller breasts
Blood Clotting
Increased risk of blood clots No change in clotting
Blood Fats Increased HDL, decreased LDL, decreased Cholesterol,
Decreased HDL, increased LDL, increased Cholesterol
Skin Increased fat deposits in skin Softer skin Thinner skin, liver spots, dry skin
Uterus Increased stimulation of uterine lining and muscle
Heavier cycles, increased risk of uterine cancer
No periods
VaginaIncreased thickening of skin, better blood supply to tissue
Vaginal discharge, feelings of pelvic congestion
Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness
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Molecular Action of Estrogen
Adopted from George et al
hsp90 – heat shock protein90
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Molecular Action of Estrogen
Adopted from Stanley J Birge et al
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
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Estrogen Receptor
Two types have been so far identified : -
and
Molecular Action of Estrogen
Illustration by Anne Erickson
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Estrogen Receptor Distribution
& -CNS, blood vessels, bone, heart, breast, ovary, uterus, testes, prostate
- Liver - Lungs, kidney, bladder,
intestines
Adopted from George GJM Kuiper et al
* Based on the level of ER mRNA levels
* Awaits confirmation till subtype specific monoclonal antibodies are available
Molecular Action of Estrogen
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Molecular Action of Estrogen
homodimer homodimer & heterodimer
•Non-genomic effects
Adopted from George GJM Kuiper et al
Alternating estrogen signaling pathways
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Molecular Action of EstrogenDifferent response in different
tissues
Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly
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Estradiol
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
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SERM(Tamoxifen)
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
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Estrogen Receptor Down regulator A Promising Area of Research
Adapted from Howell A, Osborne CK, Morris C, Wakeling AE. ICI 182, 780 (Faslodex®), development of a novel, "pure" antiestrogen. Cancer 2000; 89: 819.
Molecular Action of
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Mechanism of Tissue Response - Summary
Oestrogen Receptor Ligand Complex
Oestrogen Receptor
Ligand
E / SERM / PE/ERD
DNA Oestrogen Response element
Gene Transcriptio
n
Tissue Response
Coregulatory Proteins /
Agonistic & or
Antagonistic
AF 1 & 2
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Selective Ostrogen Receptor Modulators
Estrogens
Anti Estrogens
SERMs
SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissuesERDR
Phytoestrogens
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Designer drugs which exhibit tissue specific desirable Estrogenic &
Antiestrogenic actions in different tissues
“Designer Estrogens”“Fantasy Estrogens”
They have the potential of providing a new paradigm for maintaining the
health of women.
Selective Ostrogen Receptor Modulators
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• Mer 25 (1958)
• Clomiphene
1. Tamoxifen• Toremifene• Droloxifene• Iodoxifene
2. Raloxifene
3.Ormeloxifene
As of Today
Selective Ostrogen Receptor Modulators
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The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
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
The Search goes on
Adopted from – Rita de Cassia M Dardes & V Craig Jordan
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The Ideal Selective Ostrogen Receptor Modulator
The perfect SERM
TISSUE
Endometrium
Breast
Vagina
Bone
Liver/CVS
CNS
Perfect
AE
AE
E
E
E
EE-Estrogenic, AE-Anti Estrogenic
Tamo
E
AE
AE
E
E
AE
Ralo
AE
AE
AE
E
E+
E?
Ormelo
AE
AE
E
E
E
E
The Search goes on
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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 individual elements of the molecular structure give a tissue selectivity- different
DNA transcriptions in different tissues
Estrogen agonist
Estrogen antagonist
Chemical Name- Trans -7-methyl-2-2-dimethyl-3-
phenyl-4(4-(2-pyroldinoethoxy)phenyl(-chroman hydrochloride), related to centchroman
The perfect SERM
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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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An optimally designed potent SERM with Varied Tissue ResponseOestrogen Antagonist in UTERUS &
BREASTMild Oestrogenic action on Vagina, Bone mineral density, CNS and Serum LipidsNo action on Hypothalamic Pituitary Ovarian function, Thyroid, Adrenal.
The perfect SERM
ORMELOXIFENE
No Progestational, Androgenic or Antiandrogenic properties
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ORMELOXIFENE
Special benefit in perimenopausal women – Relief of PMS
Currently indicated for the treatment of Dysfunctional Uterine Bleeding at ANY AGE.Not suitable for women desiring pregnancy
Approved for inclusion in National Family Welfare Program, for social marketing.
The perfect SERM
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ORMELOXIFENE
•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
The perfect SERM
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ORMELOXIFENE
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
The perfect SERM
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ORMELOXIFENE
Currently being evaluated for use in the treatment and prevention of: -•Breast Cancer•Osteoporosis Possible future use: -•Menopause management•Fibromyoma•Endometriosis and Adenomyosis•Contraceptive
The perfect SERM
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ORMELOXIFENE
WARNING: -
Indian contribution
Not introduced in the international arena
Not approved by FDA
Not yet fully evaluated - extensive clinical trials needed
The perfect SERM
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““There is no cure for birth and There is no cure for birth and death save to enjoy the death save to enjoy the
interval”interval”--Santayana--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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Women have reason to say
SERMs have the potential of providing a new paradigm for
maintaining the health of women.