Abstract
Selective estrogen receptor modulators (SERMs) are structurally diverse compounds that bind to estrogen receptors (ER) and elicit agonist or antagonist responses depending on the target tissue and hormonal milieu. They are being evaluated primarily for conditions associated with aging, including hormone-responsive cancer, osteoporosis and cardiovascular disease. Several SERMs are marketed or are in clinical development, including triphenylethylenes (tamoxifen and its derivatives: toremifene, droloxifene and idoxifene), chromans (levormeloxifene), benzothiophenes (raloxifene, LY353381) and naphthalenes (CP336,156). Tamoxifen and toremifene, both used to treat advanced breast cancer, also have beneficial effects on bone mineral density and serum lipids in postmenopausal women. Tamoxifen was recently shown to decrease the risk of invasive breast cancer in women at high risk. Unfortunately, both drugs also have stimulatory effects on the endometrium. Raloxifene, used for prevention of postmenopausal osteoporosis and fragility fractures, also has favourable effects on bone mineral density, serum lipids and the incidence of invasive breast cancer in postmenopausal women but does not stimulate the endometrium. Like replacement estrogens, SERMs increase the risk of venous thromboembolism. SERMs offer postmenopausal women many of the advantages of estrogen replacement while mitigating some of the disadvantages, particularly the concern over breast cancer. Newer SERMs, exemplified by raloxifene, also eliminate the concerns over endometrial stimulation that were not addressed by first generation SERMs. The clinical success of SERMs has set the stage for a variety of drug therapies based on selective modulation of nuclear receptor activity.
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References
Ray S, Dwivedy I. Development of estrogen antagonists as pharmaceutical agents. Adv Drug Res 1997; 29: 171–270
Stevenson J, Gaspard U, Avouac B, et al. Points to consider for the development of new indications for hormone replacement therapies and estrogen-like molecules. Climacteric 1998; 1: 12–7
Brzozowski AM, Pike ACW, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 1997; 389: 753–8
Grese TA, Sluka JP, Bryant HU, et al. Molecular determinants of tissue selectivity of estrogen receptor modulators. Proc Natl Acad Sci U S A 1997; 94: 14105–10
Katzenellenbogen JA, O’Malley BW, Katzenellenbogen BS. Tripartite steroid hormone receptor pharmacology: interaction with multiple effector sites as a basis for the cell- and promoter-specific action of these hormones. Mol Endocrinol 1996; 10: 119–31
McDonnell DP, Norris JD. Analysis of the molecular pharmacology of estrogen receptor agonists and antagonists provides insights into the mechanism of action of estrogen in bone. Osteoporos Int 1997; 7 (1 Suppl.): 29–34
Jensen EV, Jacobson HI. Basic guides to the mechanism of estrogen action. In: Pincus G, editor. Recent progress in hormone research: The Proceedings of the 1961 Laurentian Hormone Conference. New York: Academic Press, 1962: (18) 387–414
Gorski J, Toft D, Shyamala G, et al. Hormone receptors: studies on the interaction of estrogen with the uterus. In: Astwood EB, editor. Recent progress in hormone research: The Proceedings of the 1961 Laurentian Hormone Conference. New York: Academic Press, 1968: (24) 45–80
Anstead GM, Carlson KE, Katzenellenbogen JA. The estradiol pharmacophore: ligand structure-estrogen receptor binding affinity relationships and a model for the receptor binding site. Steroids 1997; 62: 268–303
Giguere V, Tremblay A, Tremblay GB. Estrogen receptor β: re-evaluation of estrogen and antiestrogen signalling. Steroids 1998; 63: 335–9
Murphy LC, Leygue E, Dotzlaw H, et al. Oestrogen receptor variants and mutations in human breast cancer. Ann Med 1997; 29: 221–34
Tzukerman M, Esty A, Santiso-Mere D, et al. Human estrogen receptor transactivational capacity is determined by both cellular and promoter context and mediated by two functionally distinct intramolecular regions. Mol Endocrinol 1994; 8(1): 21–30
Danielian PS, White R, Lees JA, et al. Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors [published erratum appears in EMBO J 1992; 11: 2366]. EMBO J 1992; 11: 1025–33
Nrris JD, Fan D, Kerner SA, et al. Identification of a third autonomous activation domain within the human estrogen receptor. Mol Endocrinol 1997; 11: 747–54
Berry M, Metzger D, Chambon P. Role of the two activating domains of the oestrogen receptor in the cell-type and promoter-context dependent agonistic activity of the anti-oestrogen 4-hydroxytamoxifen. EMBO J 1990; 9: 2811–8
McDonnell DP, Clemm DL, Hermann T, et al. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995; 9: 659–69
Feng W, Ribeiro RCJ, Wagner RL, et al. Hormone-dependent coactivator binding to a hydrophobic cleft on nuclear receptors. Science 1998; 280: 1747–9
Levenson AS, Jordan VC. The key to the antiestrogenic mechanism of raloxifene is amino acid 351 (aspartate) in the estrogen receptor. Cancer Res 1998; 58(9): 1872–5
Yang NN, Venugopalan M, Hardikar S, et al. Identification of an estrogen response element activated by metabolites of 17beta-estradiol and raloxifene [published erratum appears in Science 1997; 275: 1249]. Science 1996; 273: 1222–5
Elgort MG, Zou A, Marschke KB, et al. Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-α-1 promoter via a novel sequence. Mol Endocrinol 1996; 10: 477–87
Webb P, Lopez GN, Uht RM, et al. Tamoxifen activation of the estrogen receptor/AP-1 pathway: potential origin for the cell-specific estrogen-like effects of antiestrogens. Mol Endocrinol 1995; 9: 443–56
Paech K, Webb P, Kuiper GGJM, et al. Differential ligand activation of estrogen receptors ER alpha and ER beta at AP1 sites. Science 1997; 277: 1508–10
Enmark E, Pelto-Huikko M, Grandien K, et al. Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab 1997; 82: 4258–68
White R, Parker MG. Molecular mechanisms of steroid hormone action. Endocr Rel Cancer 1998; 5: 1–14
Robyr D, Wolffe AP. Hormone action and chromatin remodelling. Cell Mol Life Sci 1998; 54: 113–24
Bedford GR, Richardson DN. Preparation and identification of cis and trans isomers of a substituted triarylethylene. Nature 1966; 212: 733–4
Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature 1966; 212: 87
Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI 46474. Br J Cancer 1971; 25: 270–5
Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–67
Fisher B, Dignam J, Bryant J, et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 1996; 88: 1529–42
Turken S, Siris E, Seldin D, et al. Effects of tamoxifen on spinal bone density in women with breast cancer. J Natl Cancer Inst 1989; 81: 1086–8
Love RR, Mazess RB, Barden HS, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 1992; 326: 852–6
McDonald CC, Alexander FE, Whyte BW, et al. Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 1995; 311: 977–80
Grey AB, Stapleton JP, Evans MC, et al. The effect of the anti-estrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 1995; 99: 636–41
Powles TJ, Hickish T, Kanis JA, et al. Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996; 14: 78–84
Chang J, Powles TJ, Ashley SE, et al. The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 1996; 7: 671–5
Gotfredsen A, Christiansen C, Palshof T. The effect of tamoxifen on bone mineral content in premenopausal women with breast cancer. Cancer 1984; 53: 853–7
Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-l Study. J Natl Cancer Inst 1998; 90(18): 1371–88
Veronesi U, Maisonneuve P, Costa A, et al. Prevention of breast cancer with tamoxifen: preliminary findings from the Italian randomised trial among hysterectomised women. Italian Tamoxifen Prevention Study. Lancet 1998; 352: 93–7
Powles T, Eeles R, Ashley S, et al. Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial. Lancet 1998; 352: 98–101
Ray A. Side effects of tamoxifen are distressing and common [letter]. BMJ 1996; 313: 1484
Love RR, Cameron L, Connell BL, et al. Symptoms associated with tamoxifen treatment in postmenopausal women. Arch Intern Med 1991; 151: 1842–7
Gershanovich M, Hayes DF, Ellmen J, et al. High-dose toremifene vs tamoxifen in postmenopausal advanced breast cancer. Oncology 1997; 11: 29–36
Saarto T, Blomqvist C, Ehnholm C, et al. Antiatherogenic effects of adjuvant antiestrogens: a randomized trial comparing the effects of tamoxifen and toremifene on plasma lipid levels in postmenopausal women with node-positive breast cancer. J Clin Oncol 1996; 14: 429–33
Marttunen MB, Hietanen P, Tiitinen A, et al. Comparison of effects of tamoxifen and toremifene on bone biochemistry and bone mineral density in postmenopausal breast cancer patients. J Clin Endocrinol Metab 1998; 83: 1158–62
Rauschning W, Pritchard KI. Droloxifene, a new antiestrogen: its role in metastatic breast cancer. Breast Cancer Res Treat 1994: 31: 83–94
Coombes RC, Haynes BP, Dowsett M, et al. Idoxifene: report of a phase 1 study in patients with metastatic breast cancer. Cancer Res 1995; 55: 1070–4
Weiss S, Mulder H, Chesnut C, et al. Idoxifene reduces bone turnover in osteopenic postmenopausal women [abstract]. 80th Annual Meeting of the Endocrine Society. The Endocrine Society Program & Abstracts: 1998 June 24–27; New Orleans (LA), 403
Bolognese M, Moffett A, Jensen C, et al. Idoxifene is well tolerated in osteopenic postmenopausal women. [abstract no. 98.072]. North American Menopause Society 9th Annual Meeting program: 1998 Sep 16–19; Toronto (ON), 80
SmithKline Beecham. SmithKline Beecham emphasises research and development strengths after failed merger talks [press release]. Scrip 1998 April 22
Kamboj VP, Ray S, Dhawan B. Centcroman. Drugs Today 1992; 28: 227–32
Salman M, Ray S, Anand N, et al. Studies in antifertility agents. Stereoselective binding of d- and 1-centchromans to estrogen receptors and their antifertility activity. J Med Chem 1986; 29: 1801–3
Skrumsager BK, Kiehr B, Bjarnason K. Levormeloxifene: escalating single oral doses in healthy postmenopausal women [abstract]. J Bone Miner Res 1997; 12: S346
Skrumsager BK, Kiehr B, Bjarnason K. Levormeloxifene: safety and pharmacokinetics after multiple dosing of fifty-six postmenopausal women [abstract]. J Bone Miner Res 1997; 12: S346
Bjarnason K, Skrumsager BK, Kiehr B. Levormeloxifene, a new partial estrogen receptor agonist demonstrates anti-resorptive and antiatherogenic properties in postmenopausal women [abstract]. J Bone Miner Res 1997; 12: S346
Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001–9
Kannel WB, Wolf PA, Castelli WP, et al. Fibrinogen and risk of cardiovascular disease: The Framingham Study. JAMA 1987; 258: 1183–6
Novo Nordisk, Bagsvaerd, Denmark. Novo Nordisk levormeloxifene phase 2 clinical trial: Novo Nordisk presents phase 2 data on levormeloxifene to clinical investigators [press release]. PRNewswire 1998 June 19
Glasebrook AL, Phillips DL, Sluka JP. Multiple binding-sites for the antiestrogen raloxifene (LY156758) [abstract no. 607]. J Bone Miner Res 1993; 8: S268
Gize EA, Venugopalan M, Glasebrook AL, et al. Characterization of raloxifene binding and transactivation properties of the estrogen receptor-beta (ER beta) [abstract]. J Bone Miner Res 1997; 12: S460
Heaney RP, Draper MW. Raloxifene mimics estrogen in human bone remodelling kinetics. J Bone Miner Res 1996; 11 (1 Suppl.): S446
Delmas PD, Bjarnason NH, Mitlak BH, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997; 337(23): 1641–7
Ettinger B, Black D, Cummings S, MORE Study Group et al. Raloxifene reduces the risk of incident vertebral fractures: 24-month interim analyses [abstract no. OR23]. Osteoporos Int 1998; 8 (3 Suppl.): 11
Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgically menopausal women. Psychoneuroendocrinology 1992; 17(5): 485–95
Polo-Kantola P, Portin R, Polo O, et al. The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women. Obstet Gynecol 1998; 91(3): 459–66
Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women. JAMA 1998; 279: 688–95
Bryant HU, Bales KR, Paul SM, et al. Estrogen agonist effects of selective estrogen receptor modulators in ovariectomized rat brain [abstract]. Soc Neurosci Abstr 1997; 23: 2377
Wu X, Glinn M, Su Y, et al. Raloxifene increases hippocampal choline acetyltransferase activity in ovariectomized rats [abstract]. Soc Neurosci Abstr 1998; 24(1): 732
Nilsen J, Mor G, Naftolin F. Raloxifene induces neurite outgrowth in estrogen receptor positive PC12 cells. Menopause 1998; 5(4): 211–6
Nickelsen T, Lufkin EG, Riggs BL, et al. Raloxifene hydrochloride, a selective estrogen receptor modulator: safety assessment of effects on cognitive function and mood in postmenopausal women. Psychoneuroendocrinology 1999; 24: 115–28
Walsh BW, Kuller LH, Wild RA, et al. Effects of raloxifene on serum lipids and coagulation factors in healthy postmenopausal women. JAMA 1998; 279: 1445–51
Hulley S, Grady D, Bush T, Heart and Estrogen/progestin Replacement Study (HERS) Research Group, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998; 280: 605–13
Bjarnason NH, Haarbo J, Byrjalsen I, et al. Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 1997; 96(6): 1964–9
Kauffman RF, Bean JS, Bensch WR. Effects of estrogen and raloxifene, a selective estrogen receptor modulator, in animal models of vascular injury. In: Rubanyi GM, Kauffman R, editors. Estrogen and the vessel wall. Amsterdam: Harwood Academic Publishers, 1998
Clarkson TB, Anthony MS, Jerome CP. Lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys. J Clin Endocrinol Metab 1998; 83: 721–6
Bryant HU, Kauffman RF, Iversen P, et al. Comment on lack of effect of raloxifene on coronary artery atherosclerosis of postmenopausal monkeys [letter]. J Clin Endocrinol Metab 1998; 83(8): 3001–2
Clarkson TB, Anthony MS. Lack of effect of raloxifene on coronary atherosclerosis of postmenopausal monkeys: authors’ response [letter]. J Clin Endocrinol Metab 1998; 83(8): 3002–4
Jordan VC, Glusman J, Eckert S, et al. Incident primary breast cancers are reduced by raloxifene: integrated data from multicenter, double-blind, randomized trials in ≈12,000 postmenopausal women [abstract]. Program/Proceedings of the American Society of Clinical Oncology, 34th Annual Meeting 1998; Los Angeles (CA), 466
Castellsague J, Perez-Gutthann S, Garcia Rodriguez LA. Recent epidemiological studies of the association between hormone replacement therapy and venous thromboembolism: a review. Drug Saf 1998; 18: 117–23
Bryant HU, Glasebrook AL, Knadler MP, et al. A highly potent orally active selective estrogen receptor modulator [abstract]. 79th Annual Meeting of the Endocrine Society. The Endocrine Society Program & Abstracts: 1997 June 11–14; Minneapolis (MN), 548
Sato M, Turner CH, Wang T, et al. LY353381.HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J Pharmacol Exp Ther 1998; 287: 1–7
Cole HW, Adrian MD, Shetler PK, et al. Comparative pharmacology of high potency selective estrogen receptor modulators (SERMs) [abstract]. J Bone Miner Res 1997; 12: S349
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Mitlak, B.H., Cohen, F.J. Selective Estrogen Receptor Modulators. Drugs 57, 653–663 (1999). https://doi.org/10.2165/00003495-199957050-00001
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DOI: https://doi.org/10.2165/00003495-199957050-00001