Selective Estrogen Receptor Modulators

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SELECTIVE ESTROGEN RECEPTOR MODULATORS : 

SELECTIVE ESTROGEN RECEPTOR MODULATORS M.K.C.G.MEDICAL COLLEGE, BERHAMPUR DR.SURENDERA NATH PANDA Professor of Obstetrics & Gynaecology This guest lecture was delivered on 9th. January, 2002, at the 45th All India Congress of Obstetrics and Gynaecology, held at Bhubaneswar

Slide 2: 

SERMs - Prof.S.N.Panda - 45th. AICOG 2 Namaskar Welcome M.K.C.G.MEDICAL COLLEGE BERHAMPUR

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SERMs - Prof.S.N.Panda - 45th. AICOG 3 What is behind these beautiful women? Estrogen

Slide 4: 

SERMs - Prof.S.N.Panda - 45th. AICOG 4 That Nourishes & Nurtures womanhood The Feminine Hormone Estrogen But Estrogen is an ambivalent steroid hormone, erratic, inconsistent & mercurial in behavior.

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SERMs - Prof.S.N.Panda - 45th. AICOG 5 Effects of Estrogen at Various Sites in the Body

Molecular Action of Estrogen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 6 Molecular Action of Estrogen Adopted from George et al hsp90 – heat shock protein90

Molecular Action of Estrogen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 7 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

Estrogen Receptor : 

SERMs - Prof.S.N.Panda - 45th. AICOG 8 Estrogen Receptor Two types have been so far identified : -  and  Molecular Action of Estrogen Illustration by Anne Erickson

Estrogen Receptor Distribution : 

SERMs - Prof.S.N.Panda - 45th. AICOG 9 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

Molecular Action of Estrogen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 10 Molecular Action of Estrogen  homodimer  homodimer  &  heterodimer Non-genomic effects Adopted from George GJM Kuiper et al Alternating estrogen signaling pathways

Molecular Action of Estrogen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 11 Molecular Action of Estrogen Different response in different tissues Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly

Molecular Action of : 

SERMs - Prof.S.N.Panda - 45th. AICOG 12 Estradiol Molecular Action of

Molecular Action of : 

SERMs - Prof.S.N.Panda - 45th. AICOG 13 SERM(Tamoxifen) Molecular Action of

Molecular Action of : 

SERMs - Prof.S.N.Panda - 45th. AICOG 14 Estrogen Receptor Down regulator A Promising Area of Research Molecular Action of

Mechanism of Tissue Response - Summary : 

SERMs - Prof.S.N.Panda - 45th. AICOG 15 Mechanism of Tissue Response - Summary Oestrogen Receptor Ligand Complex Oestrogen Receptor Ligand E / SERM / PE/ERD DNA Oestrogen Response element Gene Transcription Tissue Response Coregulatory Proteins  /  Agonistic & or Antagonistic AF 1 & 2

Selective Ostrogen Receptor Modulators : 

SERMs - Prof.S.N.Panda - 45th. AICOG 16 Selective Ostrogen Receptor Modulators Estrogens Anti Estrogens SERMs SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissues ERDR Phytoestrogens

Selective Ostrogen Receptor Modulators : 

SERMs - Prof.S.N.Panda - 45th. AICOG 17 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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SERMs - Prof.S.N.Panda - 45th. AICOG 18 Mer 25 (1958) Clomiphene Tamoxifen Toremifene Droloxifene Iodoxifene Raloxifene Ormeloxifene As of Today Selective Ostrogen Receptor Modulators

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SERMs - Prof.S.N.Panda - 45th. AICOG 19 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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SERMs - Prof.S.N.Panda - 45th. AICOG 20 The Ideal Selective Ostrogen Receptor Modulator The perfect SERM TISSUE Endometrium Breast Vagina Bone Liver/CVS CNS Perfect AE AE E E E E E-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

Tamoxifen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 21 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 +.

Tamoxifen : 

SERMs - Prof.S.N.Panda - 45th. AICOG 22 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.

Raloxifene : 

SERMs - Prof.S.N.Panda - 45th. AICOG 23 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.

Raloxifene : 

SERMs - Prof.S.N.Panda - 45th. AICOG 24 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 25 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

Slide 26: 

SERMs - Prof.S.N.Panda - 45th. AICOG 26 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 27 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. The perfect SERM ORMELOXIFENE No Progestational, Androgenic or Antiandrogenic properties

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 28 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 29 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 30 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 31 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

ORMELOXIFENE : 

SERMs - Prof.S.N.Panda - 45th. AICOG 32 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

Slide 33: 

SERMs - Prof.S.N.Panda - 45th. AICOG 33 “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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SERMs - Prof.S.N.Panda - 45th. AICOG 34 THANK YOU SERMs Women have reason to say SERMs have the potential of providing a new paradigm for maintaining the health of women.

Slide 35: 

SERMs - Prof.S.N.Panda - 45th. AICOG 35 Thank you

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