The document discusses selective estrogen receptor modulators (SERMs), which are designed to act in tissue-specific ways at estrogen receptor sites. Ormeloxifene is presented as a potential ideal SERM due to its varied tissue responses. It has antagonistic effects in the uterus and breast but mild estrogenic effects on bone, brain, and lipids. Ormeloxifene is currently approved to treat dysfunctional uterine bleeding and is being evaluated for additional uses like breast cancer prevention and treatment. However, more clinical trials are still needed before it can be introduced internationally.

1. SELECTIVE ESTROGEN RECEPTOR MODULATORS

2. www.freelivedoctor.com Estrogen

3. That Nourishes & Nurtures womanhood www.freelivedoctor.com The Feminine Hormone Estrogen

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

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

8. Estrogen Receptor Distribution  &  - CNS, blood vessels, bone, heart, breast, ovary, uterus, testes, prostate  - Liver  - Lungs, kidney, bladder, intestines www.freelivedoctor.com 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

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

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

16. Designer drugs which exhibit tissue specific desirable Estrogenic & Antiestrogenic actions in different tissues “ Designer Estrogens” “ Fantasy Estrogens” Selective Ostrogen Receptor Modulators www.freelivedoctor.com They have the potential of providing a new paradigm for maintaining the health of women.

17. www.freelivedoctor.com Mer 25 (1958) Clomiphene Tamoxifen Toremifene Droloxifene Iodoxifene Raloxifene Ormeloxifene As of Today Selective Ostrogen Receptor Modulators

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

20. 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 +. www.freelivedoctor.com

21. 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. www.freelivedoctor.com

22. 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. www.freelivedoctor.com

23. 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 www.freelivedoctor.com

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

25. 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 www.freelivedoctor.com The perfect SERM ORMELOXIFENE

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

28. 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 www.freelivedoctor.com The perfect SERM

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

30. ORMELOXIFENE www.freelivedoctor.com 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

31. ORMELOXIFENE www.freelivedoctor.com WARNING: - Indian contribution Not introduced in the international arena Not approved by FDA Not yet fully evaluated - extensive clinical trials needed The perfect SERM

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.