That Nourishes & Nurtures womanhood

1. Estrogen The Feminine Hormone That Nourishes & Nurtures womanhood But Estrogen is an ambivalent steroid hormone, erratic, inconsistent & mercurial in behavior.

2. 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 Effects of Estrogen at Various Sites in the Body

3. Molecular Action of Estrogen hsp90 – heat shock protein90 Adopted from George et al

4. 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

5. Estrogen Receptor Molecular Action of Estrogen Illustration by Anne Erickson Two types have been so far identified : -  and

6. 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

7. Molecular Action of Estrogen •  homodimer •  homodimer •  &  heterodimer • Non-genomic effects Alternating estrogen signaling pathways Adopted from George GJM Kuiper et al

8. Molecular Action of Estrogen Different response in different tissues Adopted from Lewis J. Kleinsmith Ph.D, Donna Kerrigan M.S., Jeanne Kelly

9. 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 Estradiol

10. 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 SERM(Tamoxifen)

11. 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 Estrogen Receptor Down regulator A Promising Area of Research

12. 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

13. Estrogen Signaling in Breast Cancer Tabular Format Interactive Pathway In Progress

14. 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

15. Designer drugs which exhibit tissue specific desirable Estrogenic& Antiestrogenic actions in different tissues “Designer Estrogens” “Fantasy Estrogens” Selective Ostrogen Receptor Modulators They have thepotential of providing a new paradigm for maintaining the healthof women.

16. Selective Ostrogen Receptor Modulators As of Today • Mer 25 (1958) • Clomiphene • Tamoxifen • Toremifene • Droloxifene • Iodoxifene • Raloxifene • Ormeloxifene

17. 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

18. The Ideal Selective Ostrogen Receptor Modulator The perfect SERM The Search goes on TISSUE Endometrium Breast Vagina Bone Liver/CVS CNS Perfect AE AE E E E E Ormelo AE  AE  E  E  E  E  Ralo AE AE AE E E+ E? Tamo E AE AE E E AE E-Estrogenic, AE-Anti Estrogenic

19. 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 +.

20. 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.

21. 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.

22. 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

23. ORMELOXIFENE The perfect SERM Chemical Name- Trans -7-methyl-2-2-dimethyl-3-phenyl-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

24. ORMELOXIFENE The perfect SERM • 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

25. 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

26. 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.

27. 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

28. 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

29. 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

30. 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

31. THANK YOUSERMs Women have reason to say SERMs have the potential of providing a new paradigm for maintaining the health of women.

32. Chemopreventive Phytochemicals

34. ER in cell cycle progression Myc ER Cdc25A CyclinD1 Cdk4 CyclinE Cdk2 E2F Rb DNA pol a Cyclins E,A B-Myb G1 S

35. Estrogen Receptor

36. Estrogen Receptors http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime

37. Estrogen Receptors • ER-a • Uterus, testis, pituitary, ovary, epididymis, and adrenal gland. • ER-b(Kuiper et al. 1996) • brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis. • 88% identity with rat ER-b; 47% identity with human ER-a • Membrane localized ER (Pietras and Szego, 1997) • ERa and b differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.

38. Estradiol Growth factors MAPK P P P P P DBD AF-1 AF-2 AH

39. Regulation of ER activity by coactivators and corepressors

41. Estrogen Signaling Hall et al. 2001. J. Biol. Chem., 276: 36869-36872

42. ER effects on different cell types

43. Estrogens can activate growth factor receptor signaling Levin ER. Mol.Endocrinol. 2003;17:309-17

44. Non-Genomic Effects of Estradiol Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414.

45. Estrogen has multiple effects

46. Antiestrogens can stop harmful effects of estrogen

47. SERMs (Selective Estrogen Receptor Modulators)

48. Phytoestrogens Aherne and O’Brien, 2002. Nutrition 18:75-81.

49. Phytoestrogens Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

50. Comparison of binding affinities and transactivation of estrogen and phytoestrogens Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414