Novel Compounds Acting Through Receptors and Enzyme Mediators

  • Trevor M. Penning
Part of the Medical Science Symposia Series book series (MSSS, volume 17)

Abstract

This article will introduce novel steroids that have an optimal profile for the prevention of postmenopausal osteoporosis. These agents have a duality of function: they can activate the estrogen receptor (ER) but they also regulate the amount of ligand available for the ER via enzyme inhibition in a tissue-specific manner. These agents have the same clinical profile as selective estrogen receptor modulators (SERMS) but a different mode of action. This article will develop these mechanistic concepts.

Keywords

Estrogen Osteoporosis Testosterone Tamoxifen Progesterone 

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References

  1. 1.
    Carcon-Jurica MA, Schrader WT, O’Malley BW. Steroid receptor family: structure and functions. Endocrine Rev 1990; 11:201–20.CrossRefGoogle Scholar
  2. 2.
    Kuiper GGJM, Nilson S, Gustaffsson J-A. Characteristics and function of the novel estrogen receptor β. In: O’Malley BW, editor. Hormones and signaling. New York: Academic Press, 1998: 90–112.Google Scholar
  3. 3.
    Truss M, Beato, M. Steroid hormone receptors: interaction with deoxyribonucleic acid and transcription factors. Endocrine Rev 1993; 14:459–79.Google Scholar
  4. 4.
    Wijayartane AL, Nagel SC, Paige LA, et al. Comparative analysis of mechanistic differences among antiestrogens. Endocrinology 1990; 140:5828–40.CrossRefGoogle Scholar
  5. 5.
    Klinge C. Estrogen receptor interaction with co-activators and co-repressors. Steroids 2000; 65:227–51.PubMedCrossRefGoogle Scholar
  6. 6.
    Brzozwoski AM, Pike AC, Dauter Z, et al. Molecular basis of agonism and antagonism in the estrogen receptor. Nature 1997; 389:753–58.CrossRefGoogle Scholar
  7. 7.
    O’Regan RM, Jordan VC. Tamoxifen to raloxifene and beyond. Semin Oncol 2001; 28:260–73.PubMedCrossRefGoogle Scholar
  8. 8.
    Jordan VC, Morrow M. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocrine Rev 1999; 20:253–78.CrossRefGoogle Scholar
  9. 9.
    Nicholson RI, Francis AB, McClelland RA, Manning DL, Gee JMW. Pure anti-oestrogens (ICI 164,384 and ICI 182,780) and breast cancer: is the attainment of complete oestrogen withdrawal worthwhile? Endocrine Related Cancer 1994; 4:5–19.CrossRefGoogle Scholar
  10. 10.
    Labrie F, Luu-The V, Lin S-X, et al. Intracrinology: Role of the family of 17β-hydroxysteroid dehydrogenases in human pathology and disease. J Mol Endocrinol 2000; 25:1–16.PubMedCrossRefGoogle Scholar
  11. 11.
    Jin Y, Penning, TM. Steroid 5α-reductases and 3a-hydroxysteroid dehydrogenases: Keyenzymes in androgen metabolism. In: Seckl, JR, Walker, BR editors. Disorders of steroid metabolism. Holly, JMP, series editor. Best Practice & Research: Clinical Endocrinology and Metabolism. London: Bailliare Tindall 2000; 15:79–94.Google Scholar
  12. 12.
    Miller WR Aromatase inhibitors. Endocrine Related Cancer 1996; 3:65–79.CrossRefGoogle Scholar
  13. 13.
    Crooji MJ, de Nooyer CC, Rao BR, Berends GT, Gooren LJ, Janssens, J. Termination of early pregnancy by the 3β-hydroxy steroid dehydrogenase inhibitor epostane. N Engl J Med 1988; 319:813–17.CrossRefGoogle Scholar
  14. 14.
    Penning TM. Molecular endocrinology of hydroxysteroid dehydrogenases. Endocrine Rev 1997; 18:281–305.CrossRefGoogle Scholar
  15. 15.
    Peltoketo H, Luu-The V, Simard J, Adamski J. 17ß-hydroxysteroid dehydrogenase (HSD) 17-ketosteroid (KSR) family; nomenclature and main characteristics of the 17-HSD/KSR enzymes. J Mol Endocrinol 1999; 23:1–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Penning TM, Burczynski ME, Jez JM, et al. Human 3a-hydroxysteroid dehydrogenase isoforms (AKR1C1-AK1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J 2000; 351:67–77.PubMedCrossRefGoogle Scholar
  17. 17.
    Miettinen MM, Mustonen MV, Poutanen MH, Isomaa VV, Vihko, RK. Human 17β-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes have opposite activities in cultured cells and characteristic celland tissue-specific expression. Biochem J 1966; 314:839–45.Google Scholar
  18. 18.
    Jarvinen TAH, Pelto-Huikko M, Holli K, Isola J. Estrogen receptor β is co-expressed with ERα and PR and associated with nodal stats, grade and proliferation rate in breast cancer. Amer J Pathol 2000; 156:29–35.CrossRefGoogle Scholar
  19. 19.
    Spiers V, Green, AR, Atkin, SL. Activity and gene expression of 17β-hydroxysteroid dehydrogenase type 1 in primary cultures of epithelial and stromal cells derived from normal and tumorous human breast tissue: The role of IL-8. J Steroid Biochem & Mol Biol 1998; 67:267–74.CrossRefGoogle Scholar
  20. 20.
    Sasano H, Frost AR, Saitoh R, et al. Aromatase and 17β-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endcorinol 1996; 81:4042–46.CrossRefGoogle Scholar
  21. 21.
    Chetrite G, Kloosterboer HJ, Pasqualini JR. Effect of tibolone (Org OD14) and its metabolites on estrone sulphatase activity in MCF-7 and T-47D mammary cancer cells. Anti-cancer Res 1997; 17:135–40.Google Scholar
  22. 22.
    Chetrite G, Kloosterboer HJ, Phillipe J-C, Pasqualini, JR. Effects of Org OD14 (Livial) and its metabolites on 17β-hydroxysteroid dehydrogenase activity in hormone-dependent MCF-7 and T-47D breast cancer cells. Anti-cancer Res 1999; 19:261–68.Google Scholar
  23. 23.
    Kloosterboer HJ, de Gooyer ME. Tibolone inhibits sulfatase activity in breast but not in the bone. Proceedings 9th International Menopause Symposium 1999 Oct 17–21; Yokohama, Japan P349.Google Scholar
  24. 24.
    Kloosterboer HJ. Tibolone a steroid with a tissue-specific mode of action. J Steroid Biochem & Mol Biol 2001; 76:231–38.CrossRefGoogle Scholar
  25. 25.
    Tang B, Markiewicz L, Kloosterboer HJ, Gurpride E. Human endometrial 3β-hydroxysteroid dehydrogenase/isomerase can locally reduce intrinsic estrogenic/progestagenic activity ratios of a steroidal drug (Org OD14). J Steroid Biochem & Mol Biol 1993; 45:345–51.CrossRefGoogle Scholar
  26. 26.
    Al-azzawi F, Wahab M, Habiba M, Akkad A, Mason T. Continuous combined hormone replacement therapy compared with tibolone. Obstet Gynecol 1999; 93:258–64.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Trevor M. Penning

There are no affiliations available

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