RU486 (mifepristone): Mechanisms of action and clinical uses

Annual Review of Medicine

Volumn 48, Issue , 1997, Pages 129-156

  Cadepond, F ^a   Ulmann, A ^b   Baulieu, E E ^a  

^a INSERM   (France)

^b SANOFI   (France)

Author keywords

Glucocorticoid receptor; HRE binding; Progesterone receptor; Steroid antagonist; Transcriptional activation

Indexed keywords

ANTIGESTAGEN; GLUCOCORTICOID RECEPTOR; MIFEPRISTONE; PROGESTERONE RECEPTOR; PROSTAGLANDIN;

CONTRACEPTION; DRUG EFFICACY; INDUCED ABORTION; LABOR COMPLICATION; LEIOMYOMA; LIGAND BINDING; PRIORITY JOURNAL; RECEPTOR AFFINITY; REVIEW; SIGNAL TRANSDUCTION; TARGET CELL;

ABORTIFACIENT AGENTS; ABORTION, DRUG INDUCED; ABORTION, INDUCED; BIOLOGY; CONTRACEPTION; CONTRACEPTIVE AGENTS; CONTRACEPTIVE MODE OF ACTION; DEVELOPED COUNTRIES; ENDOCRINE SYSTEM; EUROPE; FAMILY PLANNING; FERTILITY CONTROL, POSTCONCEPTION; FRANCE; HORMONE ANTAGONISTS; HORMONES; LITERATURE REVIEW; MEDITERRANEAN COUNTRIES; PHYSIOLOGY; PROSTAGLANDIN ANTAGONISTS; PROSTAGLANDINS; RU-486--PHARMACODYNAMICS; RU-486--THERAPEUTIC USE; WESTERN EUROPE;

ABORTIFACIENT AGENTS, STEROIDAL; CLINICAL TRIALS; FEMALE; GENITAL NEOPLASMS, FEMALE; HORMONE ANTAGONISTS; HUMANS; INFANT, NEWBORN; MALE; MENSTRUATION-INDUCING AGENTS; MIFEPRISTONE; NEOPLASMS, HORMONE-DEPENDENT; PREGNANCY; RECEPTORS, GLUCOCORTICOID; RECEPTORS, PROGESTERONE;

EID: 0031051692     PISSN: 00664219     EISSN: None     Source Type: Book Series    
DOI: 10.1146/annurev.med.48.1.129     Document Type: Review

References (181)

1. Wahli W, Martinez E. 1991. Superfamily of steroid nuclear receptors: positive and negative regulators of gene expression. FASEB J. 5:2243-49
2. Tsai MJ, O'Malley BW. 1994. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu. Rev. Biochem. 63:451-86
3. Baulieu E-E. 1993. RU486 - A decade on, today and tomorrow. In Clinical Applications of Mifepristone RU 486 and Other Antiprogestins, ed. MS Donalson, D Dorflinger, SS Brown, LZ Benet, pp. 71-119. Washington: Natl. Acad. Inst. Med.
4. Teutsch G, Bélanger A. 1979. Regio and stereospecific synthesis for 11b-substituted 19-norsteroids. Tetrahedron Lett. 22: 2051-54
5. Herrmann WL, Wyss R, Riondel A, et al. 1982. Effets d'un stéroïde anti progestérone chez la femme: interruption du cycle menstruel et de la grossesse au début. C. R. Acad. Sci. Paris 294:933-38
6. Baulieu EE, Segal SJ, eds. 1985. The Antiprogestin Steroid RU486 and Human Fertility Control, pp. 1-347. New York: Plenum
7. Jung-Testas I, Baulieu EE. 1983. Inhibition of glucocorticosteroid action in cultured L-929 mouse fibroblasts by RU486, a new anti-glucocorticosteroid of high affinity for the glucocorticosteroid receptor. Exp. Cell Res. 147:177-82
8. Gaillard RC, Riondel A, Muller MF, et al. 1984. RU486: a steroid with antiglucocorticosteroid activity that only disinhibits the human pituitary-adrenal system at a specific time of day. Proc. Natl. Acad. Sci. USA 81:3879-82
9. Bertagna X, Bertagna C, Luton JP, et al. 1984. The new steroid analog RU486 inhibits glucocorticoid action in man. J. Clin. Endocrinol. Metab. 59:25-38
10. Baulieu EE. 1985. RU486: an antiprogestin steroid with contragestive activity in women. In The Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ Segal, pp. 1-25. New York: Plenum
11. Philibert D, Costerousse G, Gaillard-Moguilewsky M, et al. 1991. From RU38486 towards dissociated antiglucocorticoid and antiprogesterone. In Antihormones in Health and Disease, ed. MK Agarwal, 19:1-17. Basel: Karger
12. Teutsch G, Ojasoo T, Raynaud JP. 1988. 11b-Substituted steroids, an original pathway to antihormones. J. Steroid Biochem. 31:549-65
13. Spitz IM, Bardin CW. 1993. Clinical applications of the antiprogestin RU486. Endocrinologist 3:58-66
14. Chrousos GP, Lane L, Nieman LK, et al. 1989. Clinical applications of RU 486, a prototype glucocorticoid and progestin antagonist. In Adrenal and Hypertension: From Cloning to Clinic, ed. F Mantero, BA Scoggins, R Takeda, et al, pp. 273-84. New York: Raven
15. Baulieu EE. 1989. Contragestion and other clinical applications of RU486, an antiprogesterone at the receptor. Science 245: 1351-57
16. Bertagna X, Escourolle H, Pinquier JL, et al. 1994. Administration of RU486 for 8 days in normal volunteers: antiglucocorticoid effect with no evidence of peripheral cortisol deprivation. J. Clin. Endocrinol. Metab. 78:375-80
17. Kloosterboer HJ, Deckers GH, de Gooyer ME, et al. 1995. Pharmacological properties of a new selective antiprogestagen. Ann. NY Acad. Sci. 761:192-201
18. Hamann LG, Farmer LJ, Johnson MG, et al. 1995. Synthesis and biological activity of novel nonsteroidal progesterone receptor antagonists. Ann. NY Acad. Sci. 761: 383-87
19. Mizutani T, Bhakta A, Kloosterboer HJ, et al. 1992. Novel antiprogestins ORG31806 and 31710: interaction with mammalian progesterone receptor and DNA binding of antisteroid receptor complexes. J. Steroid Biochem. Mol Biol. 42:695-704
20. Wehle H, Moll J. Cato ACB. 1995. Molecular identification of steroid analogs with dissociated antiprogestin activities. Steroids 60:368-74
21. Nath R, Bhakta A, Moudgil VK. 1991. ZK98299 - a new antiprogesterone: biochemical characterization of steroid binding parameters in the calf uterine cytosol. Arch. Biochem. Biophys. 292:303-10
22. Evans RM. 1988. The steroid and thyroid hormone receptor superfamily. Science 240:889-95
23. Gronemeyer H. 1992. Control of transcription activation by steroid hormone receptors. FASEB J. 6:2524-29
24. Carson-Jurica MA, Schrader WT, O'Malley BW. 1990. Steroid receptor family: structure and functions. Endocrine Rev. 11: 201-20
25. Vegeto E, Allan GF, Schrader WT, et al. 1992. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell 69:703-13
26. Lanz RB, Rusconi S. 1994. A conserved carboxy-terminal subdomain is important for ligand interpretation and transactivation by nuclear receptors. Endocrinology 135: 2183-95
27. Groyer A, Le Bouc Y, Joab I, et al. 1985. Chick oviduct glucocorticosteroid receptor. Specific binding of RU486 and immunological studies with antibodies to chick oviduct progesterone receptor. Eur. J. Biochem. 149:445-51
28. Benhamou B, Garcia T, Lerouge T, et al. 1992. A single amino acid that determines the sensitivity of progesterone receptors to RU486. Science 255:206-9
29. Garcia T, Benhamou B. Gofflo D, et al. 1992. Switching agonistic, antagonistic, and mixed transcriptional responses to 11b-substituted progestins by mutation of the progesterone receptor. Mol. Endocrinol. 6: 2071-78
30. DeMarzo AM, Oñate SA, Nordeen SK, et al. 1992. Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor. Biochemistry 31: 10491-501
31. Allan GF, Leng X, Tsai SY, et al. 1992. Hormone and antihormone induce distinct conformational changes which are central to steroid receptor activation. J. Biol. Chem. 267:19513-20
32. Weigel NL, Beck CA, Estes PA, et al. 1992. Ligands induce conformational changes in the carboxyl-terminus of progesterone receptors which are detected by a site-directed antipeptide monoclonal antibody. Mol Endocrinol 6:1585-97
33. Baulieu EE, Catelli MG. 1989. Steroid hormone receptors and heat shock protein Mr 90,000 (hsp90): a functional interaction? In Stress-Induced Proteins, ed. ML Pardue, JR Feramisco, S Lindquist, pp. 203-19. New York: Liss
34. Baulieu EE, Binart N, Cadepond F, et al. 1989. Do receptor-associated nuclear proteins explain earliest steps of steroid hormone function? In The Steroid/Thyroid Hormone Receptor Family and Gene Regulation, ed. J Carlstedt-Duke, H Eriksson, JA Gustafsson, pp. 301-18. Basel: Birhäuser Verlag
35. Lebeau MC, Binart N, Cadepond F, et al. 1993. Steroid receptor associated proteins: heat shock protein 90 and p59 immunophilin. In Steroid Hormone Receptors: Basic and Clinical Aspects, ed. VK Moudgil, pp. 261-80. Boston: Birkhäuser
36. Groyer A, Schweizer-Groyer G, Cadepond F, et al. 1987. Antiglucocorticosteroid effects suggest why steroid hormone is required for receptors to bind DNA in vivo but not in vitro. Nature 328:624-26
37. Rajpert EJ, Lemaigre FP, Eliard PH, et al. 1987. Glucocorticoid receptors bound to the antagonist RU486 are not down-regulated despite their capacity to interact in vitro with defined gene regions. J. Steroid Biochem. 26:513-20
38. Lefebvre P, Danze PM, Sablonnière B, et al. 1988. Association of the glucocorticoid receptor binding subunit with the 90K non-steroid-binding component is stabilized by both steroidal and nonsteroidal antiglucocorticoids in intact cells. Biochemistry 27: 9186-94
39. Segnitz B, Gehring U. 1990. Mechanism of action of a steroidal antiglucocorticoid in lymphoid cells. J. Biol. Chem. 265: 2789-96
40. Renoir JM, Radanyi C, Baulieu EE. 1989. The antiprogesterone RU486 stabilizes the heterooligomeric, non DNA-binding, 8S-form of the rabbit uterus cytosol progesterone receptor. Steroids 53:1-20
41. Beck CA, Estes PA, Bona BJ, et al. 1993. The steroid antagonist RU486 exerts different effects on the glucocorticoid and progesterone receptors. Endocrinology 133: 728-40
42. Edwards DP, Altmann M, DeMarzo A, et al. 1995. Progesterone receptor and the mechanism of action of progesterone antagonists. J. Steroid Biochem. Mol. Biol. 53:449-58
43. Skafar DF. 1991. Differences in the binding mechanism of RU486 and progesterone to the progesterone receptor. Biochemistry 30:10829-32
44. Guiochon-Mantel A, Loosfelt H, Ragot T, et al. 1988. Receptors bound to antiprogestin form abortive complexes with hormone responsive elements. Nature 336: 695-98
45. Delabre K, Guiochon-Mantel A, Milgrom E. 1993. In vivo evidence against the existence of antiprogestins disrupting receptor binding to DNA. Proc. Natl. Acad. Sci. USA 90:4421-25
46. Bocquel MT, Ji J, Ylikomi T, et al. 1993. Type II antagonists impair the DNA binding of steroid hormone receptors without affecting dimerization. J. Steroid Biochem. Mol. Biol. 45:205-15
47. Beck CA, Zhang Y, Weigel NL, et al. 1996. Two types of anti-progestins have distinct effects on site-specific phosphorylation of human progesterone receptor. Science 271: 1209-17
48. Klein-Hitpass L, Cato ACB, Henderson D, et al. 1991. Two types of antiprogestins identified by their differential action in transcriptionally active extracts from T47D cells. Nucl. Acids Res. 19:1227-34
49. Becker PB, Gloss B, Schmid W, et al. 1986. In vivo protein-DNA interactions in a glucocorticoid response element require the presence of the hormone. Nature 324: 686-88
50. Truss M, Bartsch J, Beato M. 1994. Antiprogestins prevent progesterone receptor binding to hormone responsive elements in vivo. Proc. Natl. Acad. Sci. USA 91: 11333-37
51. Archer TK, Lee HL, Cordingley MG, et al. 1994. Differential steroid hormone induction of transcription from the mouse mammary tumor virus promoter. Mol. Endocrinol. 8:568-76
52. Mymryk JS, Archer TK. 1995. Dissection of progesterone receptor-mediated chromatin remodeling and transcriptional activation in vivo. Genes Dev. 9:1366-76
53. Archer TK, Zaniewski E, Moyer ML, et al. 1994. The differential capacity of glucocorticoids and progestins to alter chromatin structure and induce gene expression in human breast cancer cells. Mol. Endocrinol. 9:1154-62
54. Gronemeyer H. 1991. Transcription activation by estrogen and progesterone receptors. Annu. Rev. Genet. 25:89-123
55. Meyer MC, Pornon A, Ji J, et al. 1990. Agonistic and antagonistic activities of RU486 on the functions of the human progesterone receptor. EMBO J. 9:3923-32
56. Vegeto E, Shahbaz MM, Wen DX, et al. 1993. Human progesterone receptor A form is a cell- and promoter-specific repressor of human progesterone receptor B function. Mol. Endocrinol. 7:1244-55
57. Schweizer-Groyer G, Cadepond F, Groyer A, et al. 1988. Stimulation of specific transcription and DNA binding studies suggest that in vitro transformed RU486-glucocorticosteroid receptor complexes display agonist activity. J. Steroid Biochem. 30: 291-94
58. Bourguet W, Ruff M, Chambon P, et al. 1995. Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-α. Nature 375:377-82
59. Clemm DL, Macy BL, Santiso-Mere D, et al. 1995. Definition of the critical cellular components which distinguish between hormone and antihormone activated progesterone receptor. J. Steroid Biochem. Mol. Biol. 53:487-95
60. Saatcioglu F, Claret K, Karin M. 1994. Negative transcriptional regulation by nuclear receptors. Cancer Biol. 5:347-59
61. Cairns C, Cairns W, Okret S. 1993. Inhibition of gene expression by steroid hormone receptors via a negative glucocorticoid response element: evidence for the involvement of DNA-binding and agonist effects of the antiglucocorticoid/antiprogestin RU486. DNA Cell Biol. 12:695-702
62. Liu W, Hillmann AG, Harmon JM. 1995. Hormone-independent repression of AP-1 inducible collagenase promoter activity by glucocorticoid receptors. Mol. Cell. Biol. 15:1005-13
63. McDonnell DP, Shahbaz MM, Vegeto E, et al. 1994. The human progesterone receptor A-form functions as a transcriptional modulator of mineralocorticoid receptor transcriptional activity. J. Steroid Biochem. Mol. Biol. 48:425-32
64. McDonnell DP, Goldman ME. 1994. RU486 exerts antiestrogenic activities through a novel progesterone receptor A form-mediated mechanism. J. Biol Chem. 269:11945-49
65. Nordeen SK, Bona BJ, Beck CA, et al. 1995. The two faces of a steroid antagonist: when an antagonist isn't. Steroids 60: 97-104
66. Hoeck W, Rusconi S, Groner B. 1989. Down-regulation and phosphorylation of glucocorticoid receptor in cultured cells. J. Biol. Chem. 264:14396-402
67. Burnstein KL, Jewell CM, Cidlowski JA. 1990. Human glucocorticoid receptor contains sequences sufficient for down-regulation. J. Biol. Chem. 265:7284-91
68. Wolf JP, Hsiu JG, Anderson TL, et al. 1989. Noncompetitive antiestrogenic effect of RU486 in blocking the estrogen-stimulated luteinizing hormone surge and the proliferative action of estradiol on endometrium in castrate monkeys. Fertil. Steril. 52: 1055-60
69. Bigerson L, Odlind V. 1987. Early pregnancy termination with antiprogestins. A comparative clinical study of RU486 given in two dose regimens and Epostane. Fertil. Steril. 48:565-70
70. Couzinet B, LeStrat N, Ulmann A, et al. 1986. Termination of early pregnancy by the progesterone antagonist RU486 (mifepristone). N. Engl. J. Med. 315:1565-70
71. Grimes DA, Mishell DR, David HP. 1992. A randomized clinical trial of mifepristone (RU486) for induction of delayed menses: efficacy and acceptability. Contraception 46:1-10
72. Bygdeman M, Swahn ML. 1985. Progesterone receptor blockage. Effect on uterine contractility and early pregnancy. Contraception 32:45-51
73. Brooks J, Holland P, Kelly R. 1990. Comparison of antiprogestin stimulation of uterine prostaglandin synthesis in vitro. Prostaglandins Leukot. Essent. Fatty Acids 40: 191-97
74. Ulmann A, Silvestre L, Chemama L, et al. 1992. Medical termination of early pregnancy with mifepristone (RU486) followed by a prostaglandin analogue. Study in 16,369 women. Acta Obstet. Gynecol. Scand. 71:278-83
75. Aubény E, Baulieu EE. 1991. Activité contragestive de l'association au RU486 d'une prostaglandine active par voie orale. C. R. Acad. Sci. Paris 312:539-45
76. Schoenhoefer PS. 1991. Brazil: Misuse of misoprostol as an anbortifacient may induce malformations. Lancet 337:1534-35
77. Henrion R. 1989. RU486 abortions. Nature 338:110
78. Heard M, Guillebeau J. 1992. Medical abortion. Lancet 304:914
79. Jost A. 1986. Nouvelles données sur le besoin hormonal de la lapine gestante: grossesses partielles et anomalies foetales après un antagoniste hormonal à dose subabortive. C. R. Acad. Sci. Paris 303:281-84
80. Lim BH, Lees DAR, Bjornsonn S, et al. 1990. Normal development after exposure to mifepristone in early pregnancy. Lancet 2:257-58
81. Wolf JP, Chilik CF, Dubois C, et al. 1990. Tolerance of perinidatory primate embryos to RU486 exposure in vitro and in vivo. Contraception 41:85-92
82. Konigsberg D, Porte J, Hull J, et al. 1987. Medical treatment of residual ectopic pregnancy: RU486 and methotrexate. Fertil. Steril. 47:702-3
83. Cabrol D, Bouvier d'Yvoire M, Mermet E, et al. 1985. Induction of labour with mifepristone after intrauterine fetal death. Lancet 8462:1019
84. Cabrol D, Dubois C, Cronje H, et al. 1990. Induction of labor with mifepristone (RU486) in intra-uterine fetal death. Am. J. Obstet. Gynecol. 162:540-42
85. Henshaw RC, Templeton AA. 1991. Preoperative cervical preparation before first trimester vacuum aspiration: a randomized controlled comparison between gemeprost and mifepristone (RU486). Br. J. Obstet. Gynaecol. 98:1025-30
86. Carbonne B, Brennand JE, Maria B, et al. 1995. Effects of gemeprost and mifepristone on the mechanical properties of the cervix prior to first trimester termination of pregnancy. Br. J. Obstet. Gynecol. 102: 553-58
87. Lefebvre Y, Proulx L, Elie R, et al. 1990. The effects of RU38486 on cervical ripening. Am. J. Obstet. Gynaecol. 162:61-65
88. Radestad A, Bygdeman M, Green K. 1990. Induced cervical ripening with mifepristone (RU486) and bioconversion of arachidonic acid in human pregnant uterine cervix in the first trimester. Contraception 41: 283-82
89. World Health Organization. 1990. The use of mifepristone (RU486) for cervical dilatation, labor induction, and delivery in monkeys: effectiveness in combination with oxytocin. Am. J. Obstet. Gynecol. 160: 45-47
90. Frydman R, Taylor S, Ulmann A. 1985. Transplacental passage of mifepristone. Lancet 2:1252
91. Wolf JP, Chilik CF, Itskovitz J, et al. 1988. Transplacental passage of a progesterone antagonist in monkeys. Am. J. Obstet. Gynecol. 159:238-42
92. Frydman R, Lelaidier C, Baton-Saint-Mleux C, et al. 1992. Labor induction in women at term with mifepristone (RU486): a double-blind, randomized, placebo-controlled study. Obst. Gynecol. 80:972-75
93. Baulieu EE. 1991. In The Abortion Pill, pp. 11-216. New York: Simon & Schuster
94. Glasier AK, Thong J, Dewar M, et al. 1992. Mifepristone (RU486) compared with high-dose estrogen and progestogen for emergency postcoital contraception. N. Engl. J. Med. 327:1041-44
95. Webb AMC, Russel J, Elstein M. 1992. Comparison of Yuzpe regimen, danazol, and mifepristone (RU486) in oral postcoital contraception. Br. Med. J. 305:927-31
96. Dubois C, Ulmann A, Baulieu EE. 1988. Contragestion with late luteal administration of RU486 (mifepristone). Fertil. Steril. 50:593-96
97. Bosc MJ, Germain G, Nicolle A, et al. 1985. The use of antiprogesterone compound RU486 to control timing of parturition in rats. In The Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ. Segal, pp. 69-70. New York: Plenum
98. Van Santen MR, Haspels AA. 1987. Failure of mifepristone (RU486) as a monthly contragestive, "lunarette". Contraception 35: 433-38
99. Batista MC, Bristow TL, Mathews J, et al. 1991. Daily administration of the progesterone antagonist RU486 prevents implantation in the cycling guinea pig. Am. J. Obstet. Gynecol. 165:82-86
100. Gravanis A, Zorn JR, Tanguy G, et al. 1984. The "disharmonic luteal phase" syndrome: endometrial progesterone receptor and estradiol dehydrogenase. Fertil. Steril. 42: 730-36
101. Herrmann WL, Schindler AM, Wyss R. 1985. Effects of the antiprogesterone RU486 in early pregnancy and during the menstrual cycle. In The Antiprogestin Steroid RU486 and Human Fertility Control, ed. EE Baulieu, SJ Segal, pp. 179-98. New York: Plenum
102. Schaison G, George M, LeStrat N, et al. 1985. Effects of an antiprogesterone steroid RU486 during midluteal phase in normal women. J. Clin. Endocrinol Metab. 61: 484-89
103. Swahn ML, Johannisson E, Daniore V, et al. 1988. The effect of RU486 administered during the proliferative and secretory phase of the cycle on the bleeding pattern, hormonal parameters and the endometrium. Hum. Reprod. 3:915-21
104. Gemzell-Danielsson K, Svalander P, Swahn ML, et al. 1994. Effects of a single post-ovulatory dose of RU486 on endometrial maturation in the implantation phase. Hum. Reprod. 9:2398-404
105. Batista MC, Cartledgde TP, Zellmer AW, et al. 1992. Evidence for a critical role of progesterone in the regulation of the midcycle gonadotropin surge and ovulation. J. Clin. Endocrinol. Metab. 74:565-70
106. Baulieu EE. 1975. Antiprogesterone effect and midcycle (periovulatory) contraception. Eur. J. Obstet. Gynecol. Reprod. Biol. 4:161-66
107. Cohn M, Stewart P. 1991. Pretreatment of the primigravid uterine cervix with mifepristone 30 h prior to termination of pregnancy: a double blind study. Br. J. Obstet. Gynaecol. 98:778-82
108. Collins RL, Hodgen GD. 1986. Blockade of the spontaneous midcycle gonadotropin surge in monkeys by RU486. A progesterone antagonist? J. Clin. Endocrinol. Metab. 63:1270-76
109. Garzo VG, Liu J, Ulmann A, et al. 1988. Effects of an antiprogesterone (RU486) on the hypothalamic-hypophyseal-ovarian-endometrial axis during the luteal phase of the menstrual cycle. J. Clin. Endocrinol. Metab. 66:508-17
110. Ledger WL, Sweeting VM, Hillier H, et al. 1992. Inhibition of ovulation by low-dose mifepristone (RU486). Hum. Reprod. 7: 945-50
111. Liu JH, Garzo G, Morris S. et al. 1987. Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486. J. Clin. Endocrinol Me tab. 65:1135-40
112. Luukkainen T. Heikinheimo O, Haukkamaa M, et al. 1988. Inhibition of folliculogenesis and ovulation by the antiprogesterone RU486. Fertil. Steril. 49: 961-63
113. Shoupe D, Mishell DR, Page MA. et al. 1987. Effects of an antiprogesterone RU486 in normal women. II. Administration in the late follicular phase. Am. J. Obstet. Gynecol 157: 1421-26
114. Croxatto HB, Salvatierra AM, Croxatto HD, et al. 1993. Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle. Hum. Reprod. 8: 201-10
115. Permezel JM, Lenton EA, Roberts I, et al. 1989. Acute effects of progesterone and the antiprogestin RU486 on gonadotropin secretion of the follicular phase of the menstrual cycle. J. Clin. Endocrinol. Metab. 68:960-65
116. Gravanis A, Schaison G, George M, et al. 1985. Endometrial and pituitary responses to the steroidal antiprogestin RU486 in postmenopausal women. J. Clin. Endocrinol. Metab. 60:156-63
117. Croxatto HB, Salvatierra AM, Fuentealba B, et al. 1995. Follicle stimulating hormone-granulosa cell axis involvement in the antifolliculotrophic effect of low dose mifepristone (RU486). Hum. Reprod. 10: 1987-91
118. Murphy AA, Kettel LM, Morales AJ, et al. 1995. Endometrial effects of long-term, low-dose administration of RU486. Fertil. Steril. 63:761-66
119. Croxatto HB, Salvatierra AM, Fuentealba B, et al. 1994. Effect of the antiprogestin onapristone on follicular growth in women. Hum. Reprod. 9:1442-47
120. Greene KE, Kettel LM, Yen SSC. 1992. Interruption of endometrial maturation without hormonal changes by an antiprogesterone during the first half of luteal phase of the menstrual cycle: a contraceptive potential. Fertil. Steril. 58:338-43
121. Gemzell-Danielsson K, Westlund P, Johannisson E, et al. 1996. Effect of low weekly doses of mifepristone on ovarian function and endometrial development. Hum. Reprod 11:256-64
122. Baldi E, Casano R, Falsetti C, et al. 1994. Intracellular calcium accumulation and responsiveness to progesterone in capacitating human spermatozoa. J. Androl. 12: 323-30
123. Yang J, Serres C, Philibert D, et al. 1994. Progesterone and RU486: opposing effects on human sperm. Proc. Natl. Acad. Sci. USA 91:529-33
124. Blackmore PF, Neulen J, Lattanzio F, et al. 1991. Cell surface-binding sites for progesterone mediate calcium uptake in human sperm. J. Biol. Chem. 266:18655-59
125. Baulieu E-E, Schorderet-Slatkine S, Le Goasgogne C, et al. 1985. A membrane receptor mechanism for steroid hormones reinitiating meiosis in Xenopus laevis oocytes. Develop. Growth Differ. 27:223-31
126. Kettel LM, Murphy AA, Morales AJ, et al. 1995. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil. Steril. 63:761-66
127. Murphy AA, Kettel LM, Morales AJ, et al. 1993. Regression of uterine leiomyomata in response to the antiprogesterone RU486. J. Clin. Endocrinol. Metab. 76:513-17
128. Murphy AA, Morales AJ, Kettel LM, et al. 1995. Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect. Fertil. Steril. 64:187-90
129. Bardon S, Vignon F, Chalbos D, et al. 1985. RU486, a progestin and glucocorticoid antagonist inhibits the growth of breast cancer cells via the progesterone receptor. J. Clin. Endocrinol. Metab. 50:692-97
130. Horwitz KB. 1992. The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer ? Endocr. Rev. 13:146-63
131. Michna H, Nishino Y, Neef G, et al. 1992. Progesterone antagonists: tumor-inhibiting potential and mechanism of action. J. Steroid Biochem. Mol. Biol. 41:339-48
132. Thomas M, Monet JD. 1992. Combined effects of RU486 and tamoxifen on the growth and cell cycle phases of the MCF-7 cell line. J. Clin. Endocrinol. Metab. 75: 865-70
133. Klijn JAGM, de Jong FH, Bakker GH, et al. 1989. Antiprogestins, a new form of endocrine therapy for human breast cancer. Cancer Res. 49:2851-56
134. Romieu G, Maudelonde T, Ulmann A, et al. 1987. The antiprogestin RU486 in advanced breast cancer: preliminary clinical trial. Bull. Cancer 74:455-61
135. Blankenstein MA, Blaauw G, Lamberts SWJ. 1984. Progestin and estrogen receptors in human meningioma. Clin. Neuropharmacol. 7:363-67
136. Magdelenat H, Pertuiset BP, Poisson M, et al. 1982. Progestin and oestrogen receptors in meningiomas: biochemical characterization clinical and pathological correlations in 42 cases. Acta Neurochir. 64: 199-213
137. Olson JJ, Beck DW, Schlechte JA, et al. 1987. Effect of the antiprogesterone RU-38486 on meningioma implanted into nude mice. J. Neurosurg. 66:584-87
138. Grunberg SM, Weiss MH, Spitz JM, et al. 1991. Treatment of unresectable meningiomas with the antiprogesteorne agent mifepristone. J. Neurosurg. 74:861-66
139. Haak HR, de Keizer RJW, Hagenouw-Taal JCW, et al. 1990. Successful mifepristone treatment of recurrent, inoperable meningioma. Lancet 2:124-25
140. Lamberts SWJ, Tanghe HLJ, Avezaat CJJ, et al. 1992. Mifepristone (RU486) treatment of meningiomas. J. Neurol Neurosurg. Psy. 55:486-90
141. Matsuda Y, Kawamoto K, Kiya K, et al. 1994. Antitumor effects of antiprogesterones in human meningioma cells in vitro and in vivo. J. Neurosurg. 80:527-34
142. Halbreich U. 1990. Treatment of premenstrual syndromes with progesterone antagonists (e.g. RU486): political and methodological issues. Psychiatry 53:407-9
143. Lamberts SWJ, Koper JW, de Jong JH. 1991. The endocrine effects of long-term treatment with mifepristone (RU486). J. Clin. Endocrinol. Metab. 73:187-91
144. Laue L, Lotze MT, Chrousos GT, et al. 1990. Effect of chronic treatment with the glucocorticoid antagonist RU486 in man: toxicity, immunological and hormonal aspects. J. Clin. Endocrinol. Metab. 71: 1474-80
145. Hermus ARMM, Pieters GFFM, Pesman GJ, et al. 1987. Enhancement of the ACTH response to human CRH by pretreatment with the antiglucocorticoid RU486. Eur. J. Pharmacol 31:609-11
146. Gaillard RC, Poffet D, Riondel AM, Saurat JH. 1985. RU486 inhibits peripheral effects of glucocorticoids in humans. J. Clin. Endocrinol. Metab. 61:1009-11
147. Bertagna X, Basin C, Picard F, et al. 1988. Peripheral antiglucocorticoid action of RU486 in man. Clin. Endocrinol. 28: 537-41
148. Nieman LK, Chrousos GP, Kelluer C, et al. 1985. Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU486. J. Clin. Endocrinol. Metab. 61:536-40
149. Van der Lely AJ, Foeken K, Van der Mast RC, et al. 1991. Rapid reversal of acute psychosis in the Cushing syndrome with the cortisol-receptor antagonist mifepristone (RU486). Ann. Intern. Med. 114: 143-44
150. Beaufrère B, de Parscau L, Chatelain P, et al. 1987. RU486 administration in a child with Cushing's syndrome. Lancet 2:217
151. Bertagna X, Bertagna C, Laudat MH, et al. 1986. Pituitary-adrenal response to the antiglucocorticoid action of RU486 in Cushing's syndrome. J. Clin. Endocrinol. Metab. 63:639-43
152. Spitz IM, Bardin CW. 1993. Mifepristone (RU486) - a modulator of progestin and glucocorticoid action. N. Engl. J. Med. 329: 404-12
153. Garrel DR, Moussali R, de Oliveira A, et al. 1995. RU486 prevents the acute effects of cortisol on glucose and leucine metabolism. J. Clin. Endocrinol. Metab. 80: 379-85
154. Raux-Demay MC, Pierret T, Bouvier d'Yvoire M, et al. 1990. Transient inhibition of RU486 antiglucocorticoid action by dexamethasone. J. Clin. Endocrinol. Metab. 70:230-33
155. Refaeli Y, Levy DN, Weiner DB. 1995. The glucocorticoid receptor type II complex is a target of the HIV-1 vpr gene product. Proc. Natl. Acad. Sci. USA 92:3621-25
156. Roberts CP, Parthasarathy S, Gulati R, et al. Effect of RU486 and related compounds on the proliferation of cultured macrophages. Am. J. Reprod. Immunol. 34: 248-56
157. Parthasarathy S, Morales AJ, Murphy AA. 1994. Antioxidant: a new role for RU486 and related compounds. J. Clin. Invest. 94: 1990-95
158. Norman LE, Thong KJ, Baird DT. 1991. Uterine contractility and induction of abortion in early pregnancy by misoprostol and mifepristone. Lancet 338:1233-36
159. Thong KJ, Baird DT. 1992. A study of gemeprost alone, dilapan or mifepristone in combination with gemeprost for the termination of the second trinmester pregnancy. Contraception 46:11-17
160. Kling MA, Demitrak MA, Whitfield HU, et al. 1993. Effects of the glucocorticoid antagonist RU486 on pituitary-adrenal function in patients with anorexia nervosa and healthy volunteers: enhancement of plasma ACTH and cortisol secretion in underweight patients. Neuroendocrinology 57:1082-91
161. Laue L, Chrousos GP, Loriaux DL, et al. 1988. The antiglucocorticoid and antiprogestin steroid RU486 suppresses the adreno-corticotropin response to ovine corticotropin-releasing hormone in man. J. Clin. Endocrinol. Metab. 66:290-93
162. Ammar S, Allilaire JF, Lecrubier Y, et al. 1986. Afternoon increase in plasma cortisol in depressed patients receiving an antiglucocorticosteroid in the morning. Am. J. Psychiatr. 143: 129-30
163. Kling MA, Whitfield JW, Brandt HA, et al. 1989. Effects of glucocorticoid antagonism with RU486 on pituitatry adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion. Psychopharmacol. Bull. 25: 466-72
164. De Kloet ER. 1988. Antiglucocorticoid RU 39486 attenuates retention of a behaviour and disinhibits the hypothalamic-pituitary axis at different brain sites. Neuroendocrinology 47:109-15
165. Papolos DF. 1993. Effects of the antiglucocorticoid RU 38486 on the induction of learned behaviour helpless behaviour in Sprague-Dawley rats. Brain Res. 615: 304-9
166. Krishnan KRR, Reed D, Wilson WH, et al. 1992. RU486 in depression. Prog. Neuro-Psychopharmacol. Biol. Psychiatr. 16: 913-20
167. Kling MA, Whitfield HJ, Brandt HA, et al. 1989. Effects of glucocorticoid antagonism with RU486 on pituitary-adrenal function in patients with major depression: time-dependent enhancement of plasma ACTH secretion. Psychopharmacol. Bull. 25: 466-72
168. Opoku J, Kalimi M. 1992. Role of the antiglucocorticoid RU486 in the prevention of steroid-induced hypertension. Acta Endocrinol. 127:258-61
169. Grünfeld JP, Eloy L, Ramos-Frendo B, et al. 1987. Do glucocorticosteroids play a role in the regulation of blood pressure? A study performed with a glucocorticosteroid antagonist. Adv. Nephrol. 16:53-68
170. Grünfeld JP, Eloy L. 1988. Glucocorticoid antagonists as probes to study the vascular effects of glucocorticoids. Kidney Int. 34(Suppl. 26):24-26
171. Van Buren M, Boer P, Koomans HA. 1993. Effects of acute mineralocorticoid and glucocorticoid receptor blockade on the excretion of an acute potassium load in healthy humans. J. Clin. Endocrinol. Metab. 77: 902-9
172. Okada S, York DA, Bray GA. 1992. Mifepristone (RU486), a blocker of type II glucocorticoid and progestin receptors, reverses a dietary form of obesity. Am. Physiol. Soc. 262:51106-10
173. Hardwick AJ, Linton EA, Rothwell NJ. 1989. Thermogenic effects of the antiglucocorticoid RU486 in the rat: involvement of corticotropin-releasing factor and sympathetic activation of brown adipose tissue. Endocrinology 124:1684-88
174. Perronne C, Cohen Y, Truffot-Pernot C, et al. 1992. Sparfloxacin, ethambutol, and cortisol receptor inhibitor RU 40555 treatment for disseminated Mycobacterium avium complex infection of normal C57BL/6 mice. Antimicrob. Ag. Chemother. 36:2408-12
175. Green K, Cheeks L, Slagle T, et al. 1989. Interaction between progesterone and mifepristone on intraocular pressure in rabbits. Curr. Eye Res. 8:317-320
176. Munden PM, Schmidt TJ. 1992. Mifepristone blocks specific glucocorticoid receptor binding in rabbit iris-cilliary body. Arch. Ophtalmol. 110:703-5
177. Pinski J, Halmos G, Shirahige Y, et al. 1993. Inhibition of growth of the human malignant glioma cell line (U87MG) by the steroid hormone antagonist RU486. J. Clin. Endocrinol. Metab. 77:1388-92
178. Gaillard RC, Poffet D, Riondel AM, et al. 1985. RU486 inhibits peripheral effects of glucocorticoids in humans. J. Clin. Endocrinol. Metab. 61:1009-11
179. Lecureur V, Fardel O, Guillouzo A. 1994. The antiprogestatin drug RU486 potentiates doxorubucin cytotoxicity in multidrug resistant cells through inhibition of P-glycoprotein function. FEBS Lett. 355: 187-191
180. Gruol DJ, Zee MC, Trotter J, et al. 1994. Reversal of multidrug resistance by RU486. Cancer Res. 54:3088-91
181. Hospital M, Busetta B, Bucourt R, et al. 1972. X-ray crystallography of estrogens and their binding to receptor sites. Mol. Pharmacol 8:438-45