Advertisement

Journal of Bone and Mineral Metabolism

, Volume 14, Issue 1, pp 1–9 | Cite as

A pharmacological review of raloxifene

  • Henry U. Bryant
  • Andrew L. Glasebrook
  • Na N. Yang
  • Masahiko Sato
Review Article

Summary

In view of its highly tissue-selective pharmacological properties (i.e., relatively pure antagonist in reproductive tissue with minimal agonist effects to nearly full agonist properties in bone and on cholesterol metabolism), terms used to define compounds with slightly related pharmacology (i.e., antiestrogen, partial estrogen agonist) do not adequately describe raloxifene's activity. Thus, raloxifene is distinct from agents such as tamoxifen (which does stimulate the uterus), or frank estrogen (which do not sufficiently antagonize estrogen's agonistic effects in reproductive tissue). In this regard, raloxifene and its pyrrolidine analogue, LY117018, (81) are the first representatives of a novel class of pharmacological agents, which we have termed “selective estrogen receptor modulator” (SERM). While we now have considerable evidence to distinguish estrogen recepto-mediated effects on bone from those on reproductive tissue, the precise mechanism for this tissue-specific mechanism remains an active area of investigation. Clearly, many important issues remain to be explored.

Key words

estrogen raloxifene bone uterus breast cancer cholesterol 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lindsay R, Aitken JM, Anderson JB (1976) Long-term prevention of post-menopausal osteoporosis by estrogen. Lancet 1:1038–1041PubMedGoogle Scholar
  2. 2.
    Stampfer MJ, Colditz GA, Willet WC, Manson JE, Rosner B, Speizer FE, Hennekens CH (1991) Post-menopausal estrogen therapy, and cardiovascular disease: Ten-year follow-up from the nurses health study. N Engl J Med 325:756–762PubMedGoogle Scholar
  3. 3.
    Wiznitzer I, Benz C (1983) Tamoxifen vs. LY156758 for treatment of human breast and prostate cancer in vitro (abstract). Breast Cancer Res Treat. 3:305Google Scholar
  4. 4.
    Wakeling AE, Valcaccia B, Newboult E, Green LR (1984) Non-steroidal antioestrogens—receptor binding and biological response in rat uterus, rat mammary carcinoma and human breast cancer cells. J Steroid Biochem 20:111–120PubMedGoogle Scholar
  5. 5.
    Sato M, Glasebrook AL, Bryant HU (1995) Raloxifene: A selective estrogen receptor modulator. J Bone Miner Met 12 [Suppl II]:S9-S20Google Scholar
  6. 6.
    Labrie F, Poulin R, Simard J, Zhao HF, Labrie C, Dauvois S, Dumont M, Hatton AC, Poirier D, Merand Y (1990) Interactions between estrogens, androgens, progestins and glucocorticoids in ZR-75-1 human breast cancer cells. Ann NY Acad Sci 595:130–148PubMedGoogle Scholar
  7. 7.
    Labrie F, Veilleux R, Fournier A (1988) Glucocorticoids stimulate the growth of mouse mammary carcinoma Shionogi cells in culture. Molec Cell Endocrinol 58:207–211PubMedGoogle Scholar
  8. 8.
    Thompson EW, Reich R, Shima TB, Albini A, Graf J, Martin GR, Dickson RB, Lippman ME (1988) Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens. Cancer Res 48:6764–6768PubMedGoogle Scholar
  9. 9.
    Clemens JA, Bennett DR, Black LJ, Jones CD (1983) Effects of a new anti-estrogen, keoxifene LY156758, on growth of carcinogen-induced mammary tumors and on LH and prolactin levels. Life Sci 32:2869–2875PubMedGoogle Scholar
  10. 10.
    Wakeling AE, Valcaccia B (1983) Antioestrogenic and antitumor activities of a series of non-steroidal antioestrogens. J Endocr 99:455–464PubMedGoogle Scholar
  11. 11.
    Gottardis MM, Jordan VC (1987) Antitumor actions of keoxifene and tamoxifen in the N-nitrosomethylurea-induced rat mammary carcinoma model. Cancer Res 47:4020–4024PubMedGoogle Scholar
  12. 12.
    Buzdar AU, Marcus C. Holmes F, Hug V, Hortobagyi G (1988) Phase II evaluation of LY156758 in metastatic breast cancer. Oncology 45:344–345PubMedGoogle Scholar
  13. 13.
    Nicholson RI, Gotting KE, Gee J, Walker KJ (1988) Actions of oestrogens and antioestrogens on rat mammary gland development: Relevance to breast cancer prevention. J Steroid Biochem 30:95–103PubMedGoogle Scholar
  14. 14.
    Kleinberg DI, Todd J, Babitsky G (1983) Inhibition by estradiol of the lactogenic effect of prolactin in primate mammary tissue: Reversal by antiestrogens LY156758 and tamoxifen. Proc Natl Acad Sci USA 80:4144–4148PubMedGoogle Scholar
  15. 15.
    Daniel CW, Silberstein G, Strickland P (1987) Direct action of 17β-estradiol on mouse mammary ducts analyzed by sustained release implants and steroid autoradiograhy. Cancer Res 47:6052–6057PubMedGoogle Scholar
  16. 16.
    Launoit Y, Veilleux R, Dufour M, Simard J, Labrie F (1991) Characteristics of the biphasic action of androgens and of the potent anti-proliferative effects of the new pure antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells. Cancer Res 51:5165–5170PubMedGoogle Scholar
  17. 17.
    Mariotti A, Durham J, Frederickson R (1987) Actions and interactions of estradiol and retinoic acid in mouse anterior prostate gland. Biol Reprod 37:1023–1035PubMedGoogle Scholar
  18. 18.
    Liehr JG, Sirbasku DA, Jurka E (1988) Inhibition of estrogen-induced renal carcinogenesis in male Syrian hamsters by tamoxifen without decreases in DNA adduct levels. Cancer Res 48:779–783PubMedGoogle Scholar
  19. 19.
    Liehr JG, Folse DS, Roy D (1987) Lack of effectiveness of antiestrogens RU39,411 or keoxifene in the prevention of estrogen-induced tumors in Syrian hamsters. Cancer Lett 64:23–29Google Scholar
  20. 20.
    Jordan VC, Murphy CS (1990) Endocrine pharmacology of antiestrogens as antitumor agents. Endocrine Rev 11:578–610Google Scholar
  21. 21.
    White INH, De Matteis R, Davies A. Smith LL, Crofton-Sleigh C, Venitt S, Hewer A, Phillips DH (1992) Genotoxic potential of tamoxifen and analogs in female Fisher F344/N rats, DBA/2 and C57BL/6 mice and in huma MCL/5 cells. Carcinogenesis 13:2197–2203PubMedGoogle Scholar
  22. 22.
    Fisher B, Constantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst 86:527–537PubMedGoogle Scholar
  23. 23.
    Gottardis MM, Ricchio ME, Satyaswaroop PG (1990) Effect of steroidal and non-steroidal antiestrogens on the growth of a tamoxifen-stimulated human endometrial carcinoma (EnCa101) in athymic mice. Cancer Res 50:3189–3192PubMedGoogle Scholar
  24. 24.
    Jordan VC, Gottardis MM, Satyaswaroop PG (1991) Tamoxifen-stimulated growth of human endometrial carcinoma. Ann NY Acad Sci 622:439–446PubMedGoogle Scholar
  25. 25.
    Feldmann S, Minne HW, Parvizi S, Pfeifer M, Lempert UG, Bauss, F Ziegler R (1989) Antiestrogen and antiandrogen administration reduce bone mass in the rat. Bone Miner 7:245–254PubMedGoogle Scholar
  26. 26.
    Jordan VC, Phelps E, Lindgren JU (1987) Effects of anti-estrogens on bone in castrated and intact female rats. Breast Cancer Res Treat 10:31–35PubMedGoogle Scholar
  27. 27.
    Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, Cullinan GJ, Bendele R, Kauffman RF, Bensch WR, Frolik CA, Termine JD, Bryant, HU (1994) Raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hyertrophy in ovariectomized rats. J Clin Invest 93:63–39PubMedGoogle Scholar
  28. 28.
    Sato M, McClintock C, Kim J, Turner C, Bryant HU, Magee DE, Slemenda CW (1994) Dual-energy X-ray absorptiometry of raloxifene effects on the lumbar vertebrae and femora of ovariectomized rats. J Bone Miner Res 9:715–724PubMedGoogle Scholar
  29. 29.
    Sato M, Kim J, Short LL, Slemenda CW, Bryant HU (1995) Longitudinal and cross-sectional analysis of raloxifene effects on tibiae from ovariectomized aged rats. J Pharmacol Exp Ther 272:1252–1259PubMedGoogle Scholar
  30. 30.
    Bryant HU, Turner CH, Frolik CA, Magee DE, Cole HW, Brown CE, Rippy MK, Sato M (1995) Long term effects of raloxifene (LY139478 HCl) on bone, cholesterol and uterus in ovariectomized rats (abstract). Bone 16 [Suppl]:116SGoogle Scholar
  31. 31.
    Evans G, Bryant HU, Magee D, Sato M, Turner RT (1994) The effects of raloxifene on tibia histomorphometry in ovariectomized rats. Endocrinology 134:2283–2288PubMedGoogle Scholar
  32. 32.
    Evans G, Magee D, Bryant HU, Turner RT (1994) Raloxifene is as effective as estrogen in preventing further bone loss in mature rats with established bone loss (abstract). J. Bone Mineral Res 9 [Suppl I]:S198Google Scholar
  33. 33.
    Turner CH, Sato M, Bryant HU (1994) Raloxifene preserves bone strength and bone mass in ovariectomzed rats. Endocrinology 135:2001–2005PubMedGoogle Scholar
  34. 34.
    Frolik CA, Bryant HU. Black EC, Magee DE, Chandrasekhar S (1994) Time-dependent changes in serum cholesterol and osteo-calcin, and in urinary pyridinium crosslinks in ovariectomized rats: Reversal by raloxifene or ethynyl estradiol (abstract). J Bone Miner Res 9 [Suppl I]:S328Google Scholar
  35. 35.
    Cummings SR (1991) Evaluating the benefits and risks of post-menopausal hormone therapy. Am J Med 91 [Suppl 5B]:14S-18SGoogle Scholar
  36. 36.
    Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR (1989) Menopause and risk factors for coronary heart disease. N Engl J Med 321:641–646PubMedGoogle Scholar
  37. 37.
    Brown MS, Goldstein JL (1980) The estradiol-stimulated lipoprotein receptor of rat liver. J Biol Chem. 255:10464–10471PubMedGoogle Scholar
  38. 38.
    Black LJ, Jones CD, Falcone JF (1983) Antagonism of estrogen action with a new benzothiophene derived anti-estrogen. Life Sci 32:1031–1036PubMedGoogle Scholar
  39. 39.
    Jordan VC, Allen KE, Dix CJ (1980) Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep 64:745–759PubMedGoogle Scholar
  40. 40.
    Fuchs-Young R, Magee DE, Cole HW, Short L, Glasebrook AL, Rippy MK, Termine JD, Bryant HU. Raloxifene is a tissue-specific anti-estrogen that blocks tamoxifen or estrogen-stimulated uterotrophic effects (abstract). Endocrinology (in press)Google Scholar
  41. 41.
    Pellerin I, Vuillermoz C, Jouvenot M, Royez M, Ordener C, Marechal G, Adessi G (1992) Superinduction of c-Fos gene expression by estrogen in cultured guinea pig endometrial cells requires priming by a cycloheximide-dependent mechanism. Endocrinology 131:1094–1100PubMedGoogle Scholar
  42. 42.
    Ishihara S, Taketani Y, Mizuno M (1988) Inhibitory effects of estradiol on glycogen synthesis in primary cell cultures of human endometrium. Endocrinol Jpn 35:691–696PubMedGoogle Scholar
  43. 43.
    Palsey JN (1992) Effects of antiestrogen treatment on estradiol-enhanced chlamydial genital infection in female guinea pigs (abstract). Proc Soc Exp Biol Med 200:140Google Scholar
  44. 44.
    Szego C, Roberts S (1953) Steroid action and interactions in uterine metabolism. Recent Prog Horm Res 8:419–468Google Scholar
  45. 45.
    Black LJ, Jones CD, Clark JH (1982) LY156758: A unique antiestrogen displaying high affinity for estrogen receptors, negligible estrogenic activity and near-total estrogen antagonism in vivo (abstract). Breast Cancer Res Treat 2:279Google Scholar
  46. 46.
    Sundstrom S, Komm BS, Xu Q, Boundy V, Lyttle CR (1990) The stimulation of uterine complement C3 gene expression by antiestrogens. Endocrinol 126:1449–1456Google Scholar
  47. 47.
    Knecht M, Brodie AMH, Catt KJ (1985) Aromatase inhibitors prevent granulosa cell differentiation: An obligatory role for estrogens in luteinization hormone receptor expression. Endocrinology 117:1560–1161Google Scholar
  48. 48.
    Veldhuis JD, Azimi P, Juchter D, Germey J (1986) Mechanisms subserving the bipotential actions of estrogen on ovarian cells: Studies with a selective anti-estrogen, LY156758, and the sparingly metabolizable estrogen agonist, moxestrol. J Steroid Biochem 5:977–982Google Scholar
  49. 49.
    Iyo M (1991) The effect of FSH, diethylstilbesterol and 2-hydroxyestradiol on steroidogenesis in cultured rat granulosa cells. Jpn J Fertil Steril 36:513–519Google Scholar
  50. 50.
    Kessel B, Hsueh AJW (1987) Keoxifene (LY156758) inhibits follicle-stimulating hormone-induced differentiation of cultured rat granulosa cells. Life Sci 40:1089–1097PubMedGoogle Scholar
  51. 51.
    Banks PK, Meyer K, Brodie AMH (1991) Regulation of ovarian steroid biosynthesis by estrogen during proestrus in the rat. Endocrinology 129:1295–1304PubMedGoogle Scholar
  52. 52.
    Neubauer BL, Biser P, Jones CD, Mariotti A, Hoover DM, Thornton T, Thornton MO, Goode R (1989) Antagonism of androgen and estrogen effects in guinea pig seminal vessicle epithelium and fibromuscular stroma by keoxifene (LY156758). Prostate 15:273–286PubMedGoogle Scholar
  53. 53.
    Chou YC, Iguchi I, Bern HA (1992) Effects of antiestrogens on adult and neonatal mouse reproductive organs. Reprod Toxicol 6:439–446PubMedGoogle Scholar
  54. 54.
    Ortmann O, Emons G, Knuppen R, Catt KJ (1988) Inhibitory actions of keoxifene on luteinizing hormone secretion in pituitary gonadotrophs. Endocrinology 123:962–968PubMedGoogle Scholar
  55. 55.
    Ortmann O, Sturm R, Knuppen R, Emons G (1990) Weak estrogenic activity of phenol red in the pituitary gonadotroph: Reevaluation of estrogen and antiestrogen effects. J Steroid Biochem 35:17–22PubMedGoogle Scholar
  56. 56.
    Awata S (1992) Effects of RU486 and keoxifene on the dispersed pituitary cells of pregnant rats. Jpn J Fertil Steril 37:22–28Google Scholar
  57. 57.
    Simard J, Labrie F (1985) Keoxifene shows pure antiestrogen activity in pituitary gonadotrophs. Mol Cell Endocrinol 34:141–144Google Scholar
  58. 58.
    Petersen SL, Cheuk C, Hartman RD, Barraclough CA (1989) Medial preoptic microimplants of the antiestrogen, keoxifene, affect luteinizing hormone-releasing hormone mRNA levels, median eminence luteininzing hormone concentrations and luteinizing release in ovariectomized estrogen-treated rats. J Neuroendocrinol 1:279–283Google Scholar
  59. 59.
    Petersen SL, Barraclough CA (1989) Suppression of spontaneous LH surges in estrogen-treated ovariectomized rats by microimplants of antiestrogens into the pre-optic brain. Brain Res 484: 279–289PubMedGoogle Scholar
  60. 60.
    Snyder BW, Beecham GD, Winneker RC (1990) Danazol suppression of luteinizing hormone in the rat: Evidence for mediation by both androgen and estrogen receptors. Proc Soc Exp Biol Med 194:54–57PubMedGoogle Scholar
  61. 61.
    Simard J, Labrie C, Merand, Dufour JM, Levesque C, Labrie F (1990) Pure antagonistic effect of a new steroidal antiestrogen in rat anterior pituitary cells in culture and in mouse uterus. Ann NY Acad Sci 595:25–427Google Scholar
  62. 62.
    Simard J, Hubert JF, Hosseinzadeh T (1986) Stimulation of growth hormone release and synthesis by estrogens in rat anterior pituitary cells in culture. Endocrinology 119:2004–2011PubMedGoogle Scholar
  63. 63.
    Martinoli MG, Veilleux R, Pelletier G (1991) Effects of triiodot-hyronine, dexamethasone and estradiol-17β on GH mRNA in rat pituitary cells in culture as revealed by in situ hybridization. Acta Endocrinologica 124:83–90PubMedGoogle Scholar
  64. 64.
    Meisl RL, Dohanich GP, McEwen BS, Pfaff DW (1987) Antagonism of sexual behvior in female rats by ventromedial hypothalamic implants of antiestrogen. Neuroendocrinology 45:201–207PubMedGoogle Scholar
  65. 65.
    Gomez F, King G, McDermott P, Schreiber AD (1988) Effect of steroid analogues on the clearance of IgG-sensitized cells (abstract). Clin Res 36:565AGoogle Scholar
  66. 66.
    Sanders M, Levinson AI, King M, Schreiber AD (1987) Hormonal modulation of macrophage clearance of IgG-sensitized cells (abstract). Clin Res 35:652AGoogle Scholar
  67. 67.
    Draper MW, Flowers DE, Huster WJ, Nield JA (1993) Effects of raloxifene (LY139481) on biochemical markers of bone and lipid metabolism in healthy postmenopausal women. In: Christiansen C, Riis B (eds) Proceedings of the fourth international symposium on osteoporosis and consensus development conference. Handelstrykkeriet Aalborg Aps, Aalborg, Denmark, pp 119–121Google Scholar
  68. 68.
    Glasebrook AL, Phillips DL, Sluka JP (1993) Multiple binding sites for the anti-estrogen raloxifene (abstract). J Bone Miner Res 8 [Suppl I]:S268Google Scholar
  69. 69.
    Yang NN, Hardikar S, Kim J, Sato M (1993) Raloxifene, an antiestrogen, simulates the effects of estrogen on inhibiting bone resorption through regulating TGFβ-3 expression in bone (abstract). J Bone Miner Res 8 [Suppl I]:S118Google Scholar
  70. 70.
    Centrella M, Horowitz MC, Wozney JM (1993) Transforming growth factorβ-gene family members and bone. Endocrine Rev. 15:27–59Google Scholar
  71. 71.
    Yang NN, Hardikar S (1994) Estrogen receptor: Two ligands, two transcription pathways (abstract). J Bone Miner Res 9 [Suppl I]: S144Google Scholar
  72. 72.
    Jilka RL, Hangoi G, Girasole G, Passeri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992) Increased osteoclast development after estrogen loss: Mediation by interleukin-6. Science 257:88–91PubMedGoogle Scholar
  73. 73.
    Manalagos SC (1995) Role of cytokines in bone resorption (abstract). Bone 16 [Suppl I]:91SGoogle Scholar
  74. 74.
    Sato M, Kim J, Bryant HU (1994) Estrogen, tamoxifen, raloxifene and nafoxidine have different effects on ovariectomized rats and on rat osteoclasts (abstract). J Bone Miner Res 9 [Suppl I]:S197Google Scholar
  75. 75.
    Glasebrook AL, Short LL, Cole HW, Magee DE, Bryant HU (1995) Regulation of serum IL-6 by raloxifene in an ovariectomized rat model (abstract). Bone 16 [Suppl I]:99SGoogle Scholar
  76. 76.
    Arjmandi BH, Salih MA, Hollis BW, Kalu DN (1993) In vivo effect of 17β-estradiol on intestinal calcium absorption (abstract). J Bone Miner Res 8 [Suppl I]:S271Google Scholar
  77. 77.
    Magee DE, Cole HW, Brown CE, Bryant HU (1994) Raloxifene and estrogen retain anti-osteopenic activity in ovariectomized rats fed a low calcium diet (abstract). J Bone Miner Res 9 [Suppl I]: S198Google Scholar
  78. 78.
    Bryant HU, Magee DE, Cole HW, Chandrasekhar S, Hsuing HM, Heiman ML, Sato M (1994) Beneficial effects of ethynyl estradiol and raloxifene in the ovariectomized rat are dependent on an intact pituitary (abstract). J Bone Miner Res 9 [Suppl I]:S135Google Scholar
  79. 79.
    Rudling M, Norstedt G, Olivecrona H, Reihner H, Gustafsson JA, Angelin B (1992) Importance of growth hormone for the induction of hepatic low-density lipoprotein receptors. Proc Natl Acad Sci USA 89:6983–6987PubMedGoogle Scholar
  80. 80.
    Bryant HU, Magee DE, Cole HW, Rowley ER, Wilson P, Adrian MD, Cullinan GJ, Yang NN, Glasebrook AL, Sato M. LY117018, a selective estrogen receptor modulator in the ovariectomized rat (abstract). J Bone Miner Res (in press)Google Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Henry U. Bryant
    • 1
  • Andrew L. Glasebrook
    • 1
  • Na N. Yang
    • 1
  • Masahiko Sato
    • 1
  1. 1.Endocrine Research DivisionLilly Corporate Center, Eli Lilly and Co.IndianapolisUSA

Personalised recommendations