Selective estrogen receptor modulators: Tissue selectivity and differential uterine effects

Climacteric

Volumn 2, Issue 4, 1999, Pages 268-283

  Silfen, S L ^a   Ciaccia, A V ^a   Bryant, H U ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

Endometrium; Estrogen; Raloxifene; Selective estrogen receptor Modulator; Serm; Uterus

Indexed keywords

1,1,2 TRIPHENYLETHYLENE DERIVATIVE; 4 [4 METHYL 2 [4 [2 (1 PIPERIDINYL)ETHOXY]PHENYL] 7 PIVALOYLOXY 2H 1 BENZOPYRAN 3 YLPHENYL] PIVALATE; ARZOXIFENE; BENZOPYRAN DERIVATIVE; BENZOTHIOPHENE; CLOMIFENE; CONJUGATED ESTROGEN; DROLOXIFENE; ESTROGEN RECEPTOR; FULVESTRANT; IDOXIFENE; LASOFOXIFENE; NAPHTHALENE DERIVATIVE; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; TAMOXIFEN; TOREMIFENE;

ANIMAL EXPERIMENT; ANIMAL MODEL; BREAST CANCER; CARDIOVASCULAR DISEASE; CONTROLLED STUDY; DRUG EFFECT; DRUG RECEPTOR BINDING; ENDOMETRIUM HYPERPLASIA; ESTROGEN THERAPY; FEMALE; HISTOPATHOLOGY; HORMONAL REGULATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; RAT; REVIEW; RISK ASSESSMENT; RISK FACTOR; UTERUS WEIGHT;

EID: 0033368173     PISSN: 13697137     EISSN: None     Source Type: Journal    
DOI: 10.3109/13697139909038087     Document Type: Review

References (131)

1. 1. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975;293:1167-70
2. 2. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975;293:1164-7
3. 3. Beresford SA, Weiss NS, Voigt LF, McKnight BS. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349:458-61
4. 4. Panay N, Studd J. Progestogen intolerance and compliance with hormone replacement therapy in menopausal women. Hum Reprod Update 1997;3:159-71
5. 5. Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1995;122:9-16
6. 6. Mitlak BH, Cohen FJ. In search of optimal long-term female hormone replacement: the potential of selective estrogen receptor modulators. Horm Res 1997;48:155-63
7. 7. MacGregor JI, Jordan VC. Basic guide to the mechanisms of antiestrogen action. Pharmacol Rev 1998;50:151-96
8. 8. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998;339:1609-18
9. 9. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479-84
10. 10. Grey AB, Stapleton JP, Evans MC, Tatnell MA, Ames RW, Reid IR. The effect of the anti-estrogen tamoxifen on bone mineral density in normal late postmenopausal women. Am J Med 1995;99:636-41
11. 11. Love RR, Newcomb PA, Wiebe DA, et al. Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst 1990; 82:1327-32
12. 12. Barakat RR. Tamoxifen and the endometrium. Cancer Treat Res 1998;94:195-207
13. 13. 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-1 Study. J Natl Cancer Inst 1998;90:1371-88
14. 14. Siris ES, Schussheim DH, Muchmore DB. Selective estrogen receptor modulators. In Rosen CJ, Glowacki J, Bilezikian JP, eds. The Aging Skeleton. San Diego, CA: Academic Press, 1999, Ch 42: 507-20
15. 15. McDonnell DP, Clemm DL, Hermann T, Goldman ME, Pike JW. Analysis of estrogen receptor function in vitro reveals three distinct classes of antiestrogens. Mol Endocrinol 1995; 9:659-69
16. 16. Paige LA, Christensen DJ, Gron H, et al. Estrogen receptor (ER) modulators each induce distinct conformational changes in ERα and ERβ. Proc Natl Acad Sci USA 1999;96: 3999-4004
17. 17. Tora L, White J, Brou C, et al. The human estrogen receptor has two independent nonacidic transcriptional activation functions. Cell 1989; 59:477-87
18. 18. 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;8:21-30
19. 19. Brzozowski AM, Pike ACW, Dauter Z, et al. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature (London) 1997; 389:753-8
20. 20. Green S, Walter P, Kumar V, et al. Human oestrogen receptor cDNA: sequence, expression and homology to v-erb-A. Nature (London) 1986;320:134-9
21. 21. Mosselman S, Polman J, Dijkema R. ERβ: identification and characterization of a novel human estrogen receptor. FEBS Lett 1996;392:49-53
22. 22. Moore JT, McKee DD, Slentz-Kesler K, et al. Cloning and characterization of human estrogen receptor β isoforms. Biochem Biophys Res Commun 1998;247:75-8
23. 23. Cowley SM, Hoare S, Mosselman S, Parker MG. Estrogen receptors α and β form heterodimers on DNA. J Biol Chem 1997;272: 19858-62
24. 24. Shughrue PJ, Lane MV, Scrimo PJ, Merchenthaler I. Comparative distribution of estrogen receptor-α (ERα) and β (ER β) mRNA in the rat pituitary, gonad, and reproductive tract. Steroids 1998;63:498-504
25. 25. Cooke PS, Buchanan DL, Young P, et al. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci USA 1997;94:6535-40
26. 26. Buchanan DL, Setiawan T, Lubahn DB, et al. Tissue compartment-specific estrogen receptor-α participation in the mouse uterine epithelial secretory response. Endocrinology 1999;140: 484-91
27. 27. Klein-Hitpass L, Schorpp M, Wagner U, Ryffel GL. An estrogen-responsive element derived from the 5′ flanking region of the Xenopus vitellogenin A2 gene functions in transfected human cells. Cell 1986;46:1053-61
28. 28. Yang NN, Venugopalan M, Hardikar S, Glasebrook A. Identification of an estrogen response element activated by metabolites of 17 β-estradiol and raloxifene. Science 1996;273: 1222-5
29. 29. Webb P, Lopez GN, Uht RM, Kushner PJ. Tamoxifene 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
30. 30. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science 1997;277:1508-10
31. 31. Elgort MG, Zou A, Marschke KB, Allegretto EA. Estrogen and estrogen receptor antagonists stimulate transcription from the human retinoic acid receptor-a-1 promoter via a novel sequence. Mol Endocrinol 1996;10:477-87
32. 32. Hart JE. Endocrine pathology of estrogens: species differences. Pharmacol Ther 1990;47: 203-18
33. 33. Tang FY, Bonfiglio TA, Tang LK. Effect of estrogen and progesterone on the development of endometrial hyperplasia in the Fischer rat. Biol Reprod 1984;31:399-413
34. 34. Drill VA. Evaluation of the carcinogenic effects of estrogens, progestins and oral contraceptives on cervix, uterus and ovary of animals and man. Arch Toxicol 1979;15(Suppl 2):59-84
35. 35. Wakeling AE, O'Connor KM, Newboult E. Comparison of the biological effects of tamoxifen and a new antioestrogen (LY117018) on the immature rat uterus. J Endocrinol 1983;99: 447-53
36. 36. Wakeling AE, Valcaccia B. Antioestrogenic and antitumour activities of a series of nonsteroidal antioestrogens. J Endocrinol 1983;99: 455-64
37. 37. Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996;10:905-12
38. 38. Black LJ, Goode RL. Uterine bioassay of tamoxifen, trioxifene and a new estrogen antagonist (LY117018) in rats and mice. Life Sci 1980;26:1453-8
39. 39. Luo S, Martel C, Sourla A, et al. Comparative effects of 28-day treatment with the new antiestrogen EM-800 and tamoxifen on estrogen-sensitive parameters in intact mice. Int J Cancer 1997;73:381-91
40. 40. Mantyla E, Karlsson S, Nieminen L. Induction of endometrial cancer by tamoxifen in the rat. Horm Carcinogen 1996;2:442-5
41. 41. Carthew P, Edwards RE, Nolan BM, Martin EA, Smith LL. Tamoxifen associated uterine pathology in rodents: relevance to women. Carcinogenesis 1996;17:1577-82
42. 42. Li D, Dragan Y, Jordan VC, Wang M, Pitot HC. Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus. Cancer Res 1997;57: 1438-41
43. 43. di Salle E, Zaccheo T, Ornati G. Antiestrogenic and antitumor properties of the new triphenylethylene derivative toremifene in the rat. J Steroid Biochem 1990;36:203-6
44. 44. Kallio S, Kangas L, Blanco G, et al. A new triphenylethylene compound, Fc-1157a. I. Hormonal effects. Cancer Chemother Pharmacol 1986;17:103-8
45. 45. Karlsson S, Hirsimaki Y, Mantyla E, et al. A two-year dietary carcinogenicity study of the antiestrogen toremifene in Sprague-Dawley rats. Drug Chem Toxicol 1996;19:245-66
46. 46. Martel C, Labrie C, Belanger A, et al. Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse. Endocrinology 1998;139:2486-92
47. 47. Nuttall ME, Bradbeer JN, Stroup GB, et al. Idoxifene: a novel selective estrogen receptor modulator prevents bone loss and lowers cholesterol levels in ovariectomized rats and decreases uterine weight in intact rats. Endocrinology 1998;139:5224-34
48. 48. Adrian MD, Cole HW, Shetler PK, et al. Comparative pharmacology of a series of selective estrogen receptor modulators. Presented at the 18th Annual Meeting of the Society for Bone and Mineral Research, Seattle, September 1996. J Bone Miner Res 1996;11:S447(abstr T590)
49. 49. Bryant HU, Wilson PK, Adrian MD, et al. Selective estrogen receptor modulators: pharmacological profile in the rat uterus. J Soc Gynecol Invest 1996;3:152A
50. 50. Ke HZ, Chen HK, Simmons HA, et al. Comparative effects of droloxifene, tamoxifen, and estrogen on bone, serum cholesterol, and uterine histology in the ovariectomized rat model. Bone 1997;20:31-9
51. 51. Eppenberger U, Wosikowski K, Kung W. Pharmacologic and biologic properties of droloxifene, a new antiestrogen. Am J Clin Oncol 1991;14:S5-14
52. 52. Chakraborty PK, Brown JL, Ruff CB, Nelson MF, Mitchell AS. Effects of long-term treatment with estradiol or clomiphene citrate on bone maintenance, and pituitary and uterine weights in ovariectomized rats. J Steroid Biochem Mol Biol 1991;40:725-9
53. 53. Jimenez MA, Magee DE, Bryant HU, Turner RT. Clomiphene prevents cancellous bone loss from tibia of ovariectomized rats. Endocrinology 1997;138:1794-800
54. 54. Hosie MJ, Murphy CR. A scanning and light microscope study comparing the effects of clomiphene citrate, estradiol 17β and progesterone on the structure of uterine luminal epithelial cells. Eur J Morphol 1995;33:39-50
55. 55. Mehrotra PK, Srivastava S. Phenotypical response in different cell types of rat uterus to centchroman. A qualitative analysis. Contraception 1998;58:137-45
56. 56. Trivedi RN, Chauhan SC, Dwivedi A, Kamboj VP, Singh MM. Time-related effects of a triphenylethylene antiestrogen on estrogen-induced changes in uterine weight, estrogen receptors, and endometrial sensitivity in rats. Contraception 1995;51:367-79
57. 57. Imam SK, Srivastava K, Dasgupta PR, Kar AB. Effect of 3,4-trans-2,2-dimethyl-3-phenyl-4-P-(β-pyrrolidinoethoxy)phenyl-7-methoxy chroman (centchroman) on the biochemistry of the fallopian tube and uterus of rhesus monkeys (Macaca mulatta). Contraception 1975;11: 309-16
58. 58. Chauhan SC, Singh MM, Maitra SC, Kamboj VP. Inhibition of progesterone-induced development of giant mitochondria in uterine glandular epithelial cells by an antiestrogen in rat. Contraception 1996;54:259-64
59. 59. Nowak J, Hornby SB, Andersen A, Sjögren T, Festersen U, Christensen ND. Effect of 12 months treatment with levormeloxifene on bone, serum cholesterol, osteocalcin, and uterus in the ovariectomized rat. Presented at Second Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society, San Francisco, December 1998. Bone 1999;23:6(abstr F612)
60. 60. Holm P, Shalmi M, Korsgaard N, Guldhammer B, Skouby SO, Stender S. A partial estrogen receptor agonist with strong antiatherogenic properties without noticeable effect on reproductive tissue in cholesterol-fed female and male rabbits. Arterioscler Thromb Vasc Biol 1997; 17:2264-72
61. 61. Nowak J, Sjögren I, Festersen U, Christensen ND. Effect of levormeloxifene, a partial estrogen receptor agonist, on body weight, food conversion efficacy, and uterus in the ovariectomized rat. Presented at the 19th Annual Meeting of the American Society for Bone and Mineral Research, Cincinnati, September, 1997. J Bone Miner Res 1997;12:S346(abstr F482)
62. 62. Salman M, Ray S, Anand N, et al. Studies in antifertility agents. 50. Stereoselective binding of d-and 1-centchromans to estrogen receptors and their antifertility activity. J Med Chem 1986;29:1801-3
63. 63. Wassermann K, Vinterby A, Hoiberg SD, Damgaard J, Fetterlein BW, Fledelius C. Levormeloxifene and NNC 45-0781 retain agonism in the skeleton while exhibiting antagonism in uterine tissue in the estrogen proficient rat. Presented at Second Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society, San Francisco, December 1998. Bone 1998;23: S368(abstr W274)
64. 64. Fledelius C, Hoiberg SD, Vinterby J, Damgaard J, Fetterlein BW, Wassermann K. Levormeloxifene, NNC 45-0320, and NNC 45-0781 prevent bone loss in the ovariectomized rat: a comparitive study of peripheral quantitative computed tomography (pQCT), ash BMD, and histomorphometry. Presented at Second Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society, San Francisco, December 1998. Bone 1998;23:S369(abstr W280)
65. 65. Sourla A, Luo S, Labrie C, Belanger A, Labrie F. Morphological changes induced by 6-month treatment of intact and ovariectomized mice with tamoxifen and the pure antiestrogen EM-800. Endocrinology 1997;138:5605-17
66. 66. Luo S, Sourla A, Labrie C, Belanger A, Labrie F. Combined effects of dehydroepiandrosterone and EM-800 on bone mass, serum lipids, and the development of dimethylbenz(A) anthracene-induced mammary carcinoma in the rat. Endocrinology 1997;138:4435-44
67. 67. Ke HZ, Paralkar VM, Grasser WA, et al. Effects of CP-336,156, a new, nonsteroidal estrogen agonist/antagonist, on bone, serum cholesterol, uterus and body composition in rat models. Endocrinology 1998;139:2068-76
68. 68. Cole HW, Adrian MD, Shetler PK, et al. Comparative pharmacology of high potency selective estrogen receptor modulators (SERMs): LY353381·HCl and CP336,156. Presented at the 19th Annual Meeting of the American Society for Bone and Mineral Research, Cincinnati, September, 1997. J Bone Miner Res 1997;12:S349(abstr F491)
69. 69. Black LJ, Sato M, Rowley ER, et al. Raloxifene (LY139481 HCl) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 1994;93:63-9
70. 70. Bjarnason NH, Haarbo J, Byrjalsen I, Kauffman RF, Christiansen C. Raloxifene inhibits aortic accumulation of cholesterol in ovariectomized, cholesterol-fed rabbits. Circulation 1997;96: 1964-9
71. 71. Ashby J, Odum J, Foster JR. Activity of raloxifene in immature and ovariectomized rat uterotrophic assays. Regul Toxicol Pharmacol 1997; 25:226-31
72. 72. Evans GL, Bryant HU, Magee DE, Turner RT. Raloxifene inhibits bone turnover and prevents further cancellous bone loss in adult ovariectomized rats with established osteopenia. Endocrinology. 1996;137:4139-44
73. 73. Frolik CA, Bryant HU, Black EC, Magee DE, Chandrasekhar S. Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: effects of raloxifene HCl, tamoxifen, estrogen, and alendronate. Bone 1996;18:621-7
74. 74. Bryant HU, Turner CH, Frolik CA, et al. Long-term effects of raloxifene on bone, cholesterol and uterus in ovariectomized rats. Presented at The XII International Conference on Calcium Regulating Hormones, Melbourne, February, 1995. Bone 1995;16:116S(abstr 125)
75. 75. Fanning PM, Kuehl TJ, Lee R, et al. Video mapping to assess efficacy of an antiestrogen (raloxifene) on spontaneous endometriosis in the rhesus monkey. Fertil Steril 1997;67:S38
76. 76. Swisher DK, Tague RM, Seyler DE. Effect of the selective estrogen receptor modulator raloxifene on explanted uterine growth in rats. Drug Dev Res 1995;36:43-5
77. 77. Porter KB, Tsibris JCM, Porter GW, et al. Effects of raloxifene in a guinea pig model for leiomyomas. Am J Obstet Gynecol 1998;179: 1283-7
78. 78. Sato M, Zeng GQ, Rowley E, Turner CH. LY353381·HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34). Endocrinology 1998;139:4642-51
79. 79. Sato M, Turner CH, Wang T, Adrian MD, Rowley E, Bryant HU. LY353381·HCl: a novel raloxifene analog with improved SERM potency and efficacy in vivo. J Pharmacol Exp Ther 1998;287:1-7
80. 80. Bryant HU, Glasebrook A, Knadler MP, et al. LY353381: a highly potent, orally active selective estrogen receptor modulator. In The Endocrine Society 79th Annual Meeting Program; 11-14 June 1997; Minneapolis, MN. Bethesda, MD: The Endocrine Society Press, 1997:548
81. 81. Sibonga JD, Dobnig H, Harden RM, Turner RT. Effect of the high-affinity estrogen receptor ligand ICI 182,780 on the rat tibia. Endocrinology 1998;139:3736-42
82. 82. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867-73
83. 83. Dukes M, Miller D, Wakeling AE, Waterton JC. Antiuterotrophic effects of a pure antioestrogen, ICI 182,780: magnetic resonance imaging of the uterus in ovariectomized monkeys. J Endocrinol 1992;135:239-47
84. 84. Center for Drug Evaluation and Research. Memorandum: Approvability of a synthetic generic version of Premarin. http://www.fda. gov/cder/news/celetterjw.htm. Food and Drug Administration, 1999
85. 85. Ferenczy A. Anatomy and histology of the uterine corpus. In Kurman RJ, ed. Blaustein's Pathology of the Female Genital Tract, 4th edn. New York: Springer-Verlag, 1994, Ch 9: 327-66
86. 86. Kaku T, Tsukamoto N, Hachisuga T, et al. Endometrial carcinoma associated with hyperplasia. Gynecol Oncol 1996;60:22-5
87. 87. Azziz R. Adenomyosis: current perspectives. Obstet Gynecol Clin North Am 1989;16: 221-35
88. 88. Wyeth-Ayerst Laboratories. Premarin (conjugated estrogens). In Physician's Desk Reference Montvale, NJ: Medical Economics Company, 1998:3111-13
89. 89. Langer RD, Pierce JJ, O'Hanlan KA, et al. Transvaginal ultrasonography compared with endometrial biopsy for the detection of endometrial disease. Postmenopausal Estrogen/ Progestin Interventions Trial. N Engl J Med 1997;337:1792-8
90. 90. Ettinger B, Bainton L, Upmalis DH, Citron JT, VanGessel A. Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women. Am J Obstet Gynecol 1997;176:112-17
91. 91. Warren MP, Biller BMK, Shangold MM. A new clinical option for hormone replacement therapy in women with secondary amenorrhea: effects of cyclic administration of progesterone from the sustained-release vaginal gel Crinone (4% and 8%) on endometrial morphologic features and withdrawal bleeding. Am J Obstet Gynecol 1999;180:42-8
92. 92. PEPI Trial Writing Group. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. J Am Med Assoc. 1996;275:370-5
93. 93. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In Kurman RJ, ed. Blaustein's Pathology of the Female Genital Tract. New York: Springer-Verlag, 1994, Ch 11: 411-27
94. 94. Notelovitz M, Varner RE, Rebar RW, et al. Minimal endometrial proliferation over a two-year period in postmenopausal women taking 0.3 mg of unopposed esterified estrogens. Menopause 1997;4:80-8
95. 95. van den Ouweland FA, Lim PC, Shangold G. Efficacy and safety of oral 17β-estradiol for the treatment of vasomotor symptoms in postmenopausal women. Obstet Gynecol 1999;93: 38S-9S
96. 96. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304-13
97. 97. Cushing KL, Weiss NS, Voigt LF, McKnight B, Beresford SA. Risk of endometrial cancer in relation to use of low-dose, unopposed estrogens. Obstet Gynecol 1998;91:35-9
98. 98. Ismail SM. Pathology of endometrium treated with tamoxifen. J Clin Pathol 1994;47: 827-33
99. 99. Kennedy MM, Baigrie CF, Manek S. Tamoxifen and the endometrium: review of 102 cases and comparison with HRT-related and non-HRT-related endometrial pathology. Int J Gynecol Pathol 1999;18:130-7
100. 100. Dal Cin P, Timmerman D, Van den Berghe I, et al. Genomic changes in endometrial polyps associated with tamoxifen show no evidence for its action as an external carcinogen. Cancer Res 1998;58:2278-81
101. 101. Goldstein SR. Unusual ultrasonographic appearance of the uterus in patients receiving tamoxifen. Am J Obstet Gynecol 1994;170: 447-51
102. 102. McGonigle KF, Shaw SL, Vasilev SA, Odom-Maryon T, Roy S, Simpson JF. Abnormalities detected on transvaginal ultrasonography in tamoxifen-treated postmenopausal breast cancer patients may represent endometrial cystic atrophy. Am J Obstet Gynecol 1998;178: 1145-50
103. 103. Tomas E, Kauppila A, Blanco G, Apaja-Sarkkinen M, Laatikainen T. Comparison between the effects of tamoxifen and toremifene on the uterus in postmenopausal breast cancer patients. Gynecol Oncol 1995;59:261-6
104. 104. Gull B, Karlsson B, Wikland M, Milsom I, Granberg S. Factors influencing the presence of uterine cavity fluid in a random sample of asymptomatic postmenopausal women. Acta Obstet Gynecol Scand 1998;77:751-7
105. 105. Zeneca Pharmaceuticals. Nolvadex (tamoxifen citrate). In Physician's Desk Reference. Montvale, NJ: Medical Economics Company, 1998:3175-7
106. 106. Cohen CJ. Tamoxifen and endometrial cancer: tamoxifen effects on the human female genital tract. Semin Oncol 1997;24:S1-64
107. 107. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351:1451-67
108. 108. Fornander T, Rutqvist LE, Cedermark B, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989;1:117-20
109. 109. Carmichael P, Ugwumadu A, Neven P, Hewer A, Poon G, Phillips D. Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res 1996;56:1475-9
110. 110. Hemminki K, Rajaniemi H, Lindahl B, Moberger B. Tamoxifen-induced DNA adducts in endometrial samples from breast cancer patients. Cancer Res 1996;56:4374-7
111. 111. Carmichael PL, Sardar S, Crooks N, et al. Lack of evidence from HPLC 32P-post-labelling for tamoxifen-DNA adducts in the human endometrium. Carcinogenesis 1999;20:339-42
112. 112. Hard GC, Iatropoulos MJ, Jordan K, et al. Major difference in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Crl:CD(BR)rats. Cancer Res 1993;53:4534-41
113. 113. Gams R. Phase III trials of toremifene vs tamoxifen. Oncology 1997;11:23-8
114. 114. Boss SM, Huster WJ, Neild JA, Glant MD, Eisenhut CC, Draper MW. Effects of raloxifene hydrochloride on the endometrium of postmenopausal women. Am J Obstet Gynecol 1997;177:1458-64
115. 115. 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;337:1641-7
116. 116. Goldstein SR, Srikanth R, Parsons AK, et al. Effects of raloxifene on the endometrium in healthy postmenopausal women. Menopause 1998;5:277
117. 117. Cummings S, Eckert S, Krueger K, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women. J Am Med Assoc 1999;281:2189-97
118. 118. Davies GC, Huster WJ, Lu Y, Plouffe L, Lakshmanan M. Adverse events reported by postmenopausal women in controlled trials with raloxifene. Obstet Gynecol 1999;93: 558-65
119. 119. Goldstein SR, Scheele WH, Rajagopalan SK, Wilkie JL, Walsh BW, Parson AK. A 12-month comparative study of raloxifene, estrogen and placebo on the postmenopausal endometrium. Obstet Gynecol 1999;in press
120. 120. Bjarnason NH, Delmas PD, Mitlak BH, et al. Raloxifene maintains favourable effects on bone mineral density, bone turnover and serum lipids without endometrial stimulation in postmenopausal women. 3-year study results. Presented at European Congress on Osteoporosis, Berlin, September 1998. Osteoporos Int 1998; 8:11(abstr OR22)
121. 121. Kistner RW, Lewis JL, Steiner GJ. Effects of clomiphene citrate on endometrial hyperplasia in the premenopausal female. Cancer 1966;19: 115-26
122. 122. Bellmunt J, Sole L. European early phase II dose-finding study of droloxifene in advanced breast cancer. Am J Clin Oncol 1991;14(Suppl 2):S36-9
123. 123. Bolognese M, Moffett A, Jensen C, MacDonald B. Idoxifene is well tolerated in osteopenic postmenopausal women. Menopause 1998;5:271-2
124. 124. Bruning PF. Droloxifene, a new anti-oestrogen in postmenopausal advanced breast cancer: preliminary results of a double-blind dose-finding phase II trial. Eur J Cancer 1992;28A: 1404-7
125. 125. Skrumsager B, Kiehr B, Bjarnason K. Levormeloxifene: safety and pharmacokinetics after multiple dosing of fifty-six postmenopausal women. Presented at the 19th Annual Meeting of the American Society for Bone and Mineral Research, Cincinnati, September 1997. J Bone Miner Res 1997;12:S346(abstr F481)
126. 126. Novo Nordisk drops levormeloxifene. Scrip 1998;23:18
127. 127. SmithKline Beecham drops idoxifene for osteoporosis. Scrip 1999;2431:21
128. 128. Fleischer A, Wheeler J, Kravitz B, MacDonald B. Endometrial assessment in osteopenic postmenopausal women treated with idoxifene. Menopause 1998;5:272
129. 129. SmithKline Beecham emphasizes research and development strengths after failed merger talks. Scrip 1999;2328:11
130. 130. Howell A, DeFriend DJ, Robertson JF, et al. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer. Br J Cancer 1996;74:300-8
131. 131. Smith-Bindman R, Kerlikowske K, Feldstein VA, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. J Am Med Assoc 1998;280: 1510-17