4. www.freelivedoctor.com 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 None Hot flashes, sleep disorders, mood changes, problems with memory? Alzheimer’s disease?? Breast Stimulates 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 Vagina Increased thickening of skin, better blood supply to tissue Vaginal discharge, feelings of pelvic congestion Dryness, vaginal infections, painful sex, incontinence of urine, pelvic weakness
5. Molecular Action of Estrogen www.freelivedoctor.com Adopted from George et al hsp90 – heat shock protein90
6. Molecular Action of Estrogen www.freelivedoctor.com 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
10. Molecular Action of Estrogen www.freelivedoctor.com Different response in different tissues Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly
11. Molecular Action of www.freelivedoctor.com 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.
12. Molecular Action of www.freelivedoctor.com 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.
13. Molecular Action of www.freelivedoctor.com 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.
14. Mechanism of Tissue Response - Summary www.freelivedoctor.com 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
15. Selective Ostrogen Receptor Modulators www.freelivedoctor.com Estrogens Anti Estrogens SERMs SERMs- designed to act in specific ways at each of the oestrogen receptor sites in different tissues ERDR Phytoestrogens
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18. www.freelivedoctor.com 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
19. www.freelivedoctor.com 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
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24. ORMELOXIFENE www.freelivedoctor.com 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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26. ORMELOXIFENE www.freelivedoctor.com 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 No Progestational, Androgenic or Antiandrogenic properties
27. ORMELOXIFENE www.freelivedoctor.com 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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29. ORMELOXIFENE www.freelivedoctor.com 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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32. www.freelivedoctor.com “ 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.
33. www.freelivedoctor.com Women have reason to say SERMs have the potential of providing a new paradigm for maintaining the health of women.
Editor's Notes
Estradiol (E) binds with high affinity to estrogen receptor (ER) and dissociates heat shock protein 90 (HSP90) E-ER complex homodimerizes and localizes preferentially in the cell nucleus E-ER homodimer binds DNA sequence at palindromic estrogen response element (ERE) in the promotor region of estrogen-sensitive genes Activation of transcription by ER involves interaction of the transcription activation functions of ER, AF1 and AF2 with transcriptional coactivators to stimulate the activity of RNA polymerase II (RNA POL II)
Tamoxifen (T) binds to ER with low affinity compared with estradiol (E) and dissociates heat shock protein 90 (HSP90) T-ER complex homodimerizes and translocates to the cell nucleus, and activation function (AF1) (but not AF2) is active T-ER dimer binds DNA to sequence at palindromic ERE in the promotor region of estrogen-sensitive genes Transcription of E-responsive genes(s) is attenuated because AF2 is inactive, and coactivator binding is attenuated by the T-ER complex; partial agonist activity results from AF1, which remains active in the T-ER complex
Estradiol (E) binds with high affinity to estrogen receptor (ER) and dissociates heat shock protein 90 (HSP90) E-ER complex homodimerizes and localizes preferentially in the cell nucleus E-ER homodimer binds DNA sequence at palindromic estrogen response element (ERE) in the promotor region of estrogen-sensitive genes Activation of transcription by ER involves interaction of the transcription activation functions of ER, AF1 and AF2 with transcriptional coactivators to stimulate the activity of RNA polymerase II (RNA POL II)
