Selective progesterone receptor modulators in reproductive medicine: Pharmacology, clinical efficacy and safety

Fertility and Sterility

Volumn 96, Issue 5, 2011, Pages 1175-1189

  Bouchard, Philippe ^a,b   Chabbert Buffet, Nathalie ^b,c   Fauser, Bart C J M ^d  

^a HÔPITAL SAINT ANTOINE   (France)

^b SORBONNE UNIVERSITÉ   (France)

^c HÔPITAL TENON   (France)

^d UNIVERSITY MEDICAL CENTER UTRECHT   (Netherlands)

Author keywords

Amenorrhea; contraception; leiomyoma; progesterone receptor; selective progesterone receptor modulator; SPRM

Indexed keywords

11BETA [4 (DIMETHYLAMINO)PHENYL] 4',5' DIHYDRO 6BETA METHYLSPIRO[ESTRA 4,9 DIENE 17BETA,2'(3'H) FURAN] 3 ONE; ANTIGESTAGEN; ASOPRISNIL; CP 8816; CP 8863; DEXAMETHASONE; GESTAGEN; GESTRINONE; GLUCOCORTICOID RECEPTOR; GONADORELIN AGONIST; LEUPRORELIN; LEVONORGESTREL; LONAPRISAN; MIFEPRISTONE; ONAPRISTONE; ORAL CONTRACEPTIVE AGENT; ORG 31806; PF 2413873; PLACEBO; PROGESTERONE; PROGESTERONE RECEPTOR A; PROGESTERONE RECEPTOR B; PROGESTERONE RECEPTOR MODULATOR; PROSTAGLANDIN; TELAPRISTONE ACETATE; ULIPRISTAL; UNCLASSIFIED DRUG; WAY 255348; ZK 114043; ZK 136799; ZK 137316;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALZHEIMER DISEASE; ANEMIA; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; BONE DENSITY; BREAST CANCER; CANCER PREVENTION; CUSHING SYNDROME; DRUG EFFICACY; DRUG INDICATION; DRUG MECHANISM; DRUG RECEPTOR BINDING; DRUG SAFETY; DRUG STRUCTURE; EMERGENCY CONTRACEPTION; ENDOMETRIOSIS; ENDOMETRIUM CANCER; FEMALE GENITAL SYSTEM; GYNECOLOGIC CANCER; GYNECOLOGIC DISEASE; HUMAN; LEIOMYOMA; LIVER TOXICITY; NONHUMAN; OVARY CYST; PREGNANCY TERMINATION; PRIORITY JOURNAL; PROLACTIN BLOOD LEVEL; PSYCHOSIS; RECEPTOR AFFINITY; REPRODUCTION; REVIEW; SIDE EFFECT; SINGLE DRUG DOSE; UTERUS BLEEDING; UTERUS MYOMA;

EID: 80054979226     PISSN: 00150282     EISSN: 15565653     Source Type: Journal    
DOI: 10.1016/j.fertnstert.2011.08.021     Document Type: Article

References (155)

1. A. Rocha, and R. Soares Unraveling progesterone-induced molecular mechanisms in physiological and pathological conditions Curr Clin Pharmacol 4 2009 148 153
2. I.J. McEwan Nuclear receptors: one big family Methods Mol Biol 505 2009 3 18
3. D. Philibert RU 38486: an original multifaceted antihormone in vivo M. Agarwal, Adrenal steroid antagonism 1984 Walter de Gruyter Berlin 77 101
4. G.F. Allan, and Z. Sui Non-steroidal progesterone receptor specific ligands Mini Rev Med Chem 5 2005 701 708
5. N. Chabbert-Buffet, S. Ouzounian, A.P. Kairis, and P. Bouchard Contraceptive applications of progesterone receptor modulators Eur J Contracept Reprod Health Care 13 2008 222 230
6. N. Chabbert-Buffet, G. Meduri, P. Bouchard, and I.M. Spitz Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications Hum Reprod Update 11 2005 293 307
7. K. Chwalisz, M.C. Perez, D. Demanno, C. Winkel, G. Schubert, and W. Elger Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis Endocr Rev 26 2005 423 438
8. O.M. Conneely, B. Mulac-Jericevic, F. DeMayo, J.P. Lydon, and B.W. O'Malley Reproductive functions of progesterone receptors Recent Prog Horm Res 57 2002 339 355
9. S. Mesiano, and T.N. Welsh Steroid hormone control of myometrial contractility and parturition Semin Cell Dev Biol 18 2007 321 331
10. O.M. Conneely, B.M. Jericevic, and J.P. Lydon Progesterone receptors in mammary gland development and tumorigenesis J Mammary Gland Biol Neoplasia 8 2003 205 214
11. Q. Li, A. Kannan, F.J. DeMayo, J.P. Lydon, P.S. Cooke, and H. Yamagishi The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2 Science 331 2011 912 916
12. K.M. Scarpin, J.D. Graham, P.A. Mote, and C.L. Clarke Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression Nucl Recept Signal 7 2009 e009
13. S.A. Leonhardt, and D.P. Edwards Mechanism of action of progesterone antagonists Exp Biol Med (Maywood) 227 2002 969 980
14. V. Boonyaratanakornkit, and D.P. Edwards Receptor mechanisms mediating non-genomic actions of sex steroids Semin Reprod Med 25 2007 139 153
15. J.D. Blaustein Minireview: neuronal steroid hormone receptors: they're not just for hormones anymore Endocrinology 145 2004 1075 1081
16. J.P. Lydon, F.J. DeMayo, C.R. Funk, S.K. Mani, A.R. Hughes, and C.A. Montgomery Jr. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities Genes Dev 9 1995 2266 2278
17. P.H. Giangrande, G. Pollio, and D.P. McDonnell Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor J Biol Chem 272 1997 32889 32900
18. P.H. Giangrande, and D.P. McDonnell The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene Recent Prog Horm Res 54 1999 291 314
19. P.H. Giangrande, E.A. Kimbrel, D.P. Edwards, and D.P. McDonnell The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding Mol Cell Biol 20 2000 3102 3115
20. O.M. Conneely, B. Mulac-Jericevic, J.P. Lydon, and F.J. De Mayo Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice Mol Cell Endocrinol 179 2001 97 103
21. B. Mulac-Jericevic, J.P. Lydon, F.J. DeMayo, and O.M. Conneely Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform Proc Natl Acad Sci USA 100 2003 9744 9749
22. R.L. Arnett-Mansfield, A. DeFazio, P.A. Mote, and C.L. Clarke Subnuclear distribution of progesterone receptors A and B in normal and malignant endometrium J Clin Endocrinol Metab 89 2004 1429 1442
23. P.A. Mote, S. Bartow, N. Tran, and C.L. Clarke Loss of co-ordinate expression ofprogesterone receptors A and B is an early event in breast carcinogenesis Breast Cancer Res Treat 72 2002 163 172
24. N. Chabbert-Buffet, D.C. Skinner, A. Caraty, and P. Bouchard Neuroendocrine effects of progesterone Steroids 65 2000 613 620
25. M.K. McPhail The assay of progestin J Physiol 83 1934 145 156
26. W. Elger, J. Bartley, B. Schneider, G. Kaufmann, G. Schubert, and K. Chwalisz Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity Steroids 65 2000 713 723
27. W. Afhüppe, A. Sommer, J. Müller, W. Schwede, U. Fuhrmann, and C. Möller Global gene expression profiling of progesterone receptor modulators in T47D cells provides a new classification system J Steroid Biochem Mol Biol 113 2009 105 115
28. C.L. Smith, and B.W. O'Malley Coregulator function: a key to understanding tissue specificity of selective receptor modulators Endocr Rev 25 2004 45 71
29. K.P. Madauss, E.T. Grygielko, S.J. Deng, A.C. Sulpizio, T.B. Stanley, and C. Wu A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator Mol Endocrinol 21 2007 1066 1081
30. S.E. Wardell, and D.P. Edwards Mechanisms controlling agonist and antagonist potential of selective progesterone receptor modulators (SPRMs) Semin Reprod Med 23 2005 9 21
31. L. Tung, M.K. Mohamed, J.P. Hoeffler, G.S. Takimoto, and K.B. Horwitz Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors Mol Endocrinol 7 1993 1256 1265
32. J.C. Leo, and V.C. Lin The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner Int J Cancer 122 2008 230 243
33. L. Amazit, A. Roseau, J.A. Khan, A. Chauchereau, R.K. Tyagi, and H. Loosfelt Ligand-dependent degradation of SRC-1 is pivotal for progesterone receptor transcriptional activity Mol Endocrinol 25 2011 394 408
34. K.P. Madauss, E.L. Stewart, and S.P. Williams The evolution of progesterone receptor ligands Med Res Rev 27 2007 374 400
35. S. Johanssen, and B. Allolio Mifepristone (RU 486) in Cushing's syndrome Eur J Endocrinol 157 2007 561 569
36. G. Schubert, W. Elger, G. Kaufmann, B. Schneider, G. Reddersen, and K. Chwalisz Discovery, chemistry, and reproductive pharmacology of asoprisnil and related 11β-benzaldoxime substituted selective progesterone receptor modulators (SPRMs) Semin Reprod Med 23 2005 58 73
37. B.J. Attardi, J. Burgenson, S.A. Hild, and J.R. Reel In vitro antiprogestational/antiglucocorticoid activity and progestin and glucocorticoid receptor binding of the putative metabolites and synthetic derivatives of CDB-2914, CDB-4124, and mifepristone J Steroid Biochem Mol Biol 88 2004 277 288
38. R.C. Winneker, A. Fensome, P. Zhang, M.R. Yudt, C.C. McComas, and R.J. Unwalla A new generation of progesterone receptor modulators Steroids 73 2008 689 701
39. L. Zhi Discovery of structurally diverse nonsteroidal SPRMs based on a screening hit, 1,2-dihydro-2,2,4-trimethyl-6-phenylquinolinone Curr Top Med Chem 8 2008 766 780
40. J. Rewinkel, M. Enthoven, I. Golstein, R.M. van der, A. Scholten, and M. van Tilborg 11-(pyridinylphenyl)steroids - a new class of mixed-profile progesterone agonists/antagonists Bioorg Med Chem 16 2008 2753 2763
41. E.A. Schaff Mifepristone: ten years later Contraception 81 2010 1 7
42. A. Im, and L.J. Appleman Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology Expert Opin Pharmacother 11 2010 481 488
43. D.T. Baird, K.J. Thong, C. Hall, and S.T. Cameron Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days Hum Reprod 10 1995 2270 2276
44. N. Chabbert-Buffet, A. Pintiaux-Kairis, and P. Bouchard Effects of the progesterone receptor modulator VA2914 in a continuous low dose on the hypothalamic-pituitary-ovarian axis and endometrium in normal women: a prospective, randomized, placebo-controlled trial J Clin Endocrinol Metab 92 2007 3582 3589
45. K. Chwalisz, W. Elger, T. Stickler, C. Mattia-Goldberg, and L. Larsen The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women Hum Reprod 20 2005 1090 1099
46. H.B. Croxatto, A.M. Salvatierra, H.D. Croxatto, and B. Fuentealba Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle Hum Reprod 8 1993 201 207
47. J.H. Liu, G. Garzo, S. Morris, C. Stuenkel, A. Ulmann, and S.S. Yen Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486 J Clin Endocrinol Metab 65 1987 1135 1140
48. K. Chwalisz, R. Garg, R. Brenner, O. Slayden, C. Winkel, and W. Elger Role of nonhuman primate models in the discovery and clinical development of selective progesterone receptor modulators (SPRMs) Reprod Biol Endocrinol 4 Suppl 1 2006 S8
49. P. Stratton, E.D. Levens, B. Hartog, J. Piquion, Q. Wei, and M. Merino Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914 Fertil Steril 93 2009 2035 2041
50. K. Chwalisz, L. Larsen, C. Mattia-Goldberg, A. Edmonds, W. Elger, and C.A. Winkel A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata Fertil Steril 87 2007 1399 1412
51. E.D. Levens, C. Potlog-Nahari, A.Y. Armstrong, R. Wesley, A. Premkumar, and D.L. Blithe CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial Obstet Gynecol 111 2008 1129 1136
52. J.G. van der Stege, E.H. Pahl-van Beest, R.J. Beerthuizen, R.H. van Lunsen, P.C. Scholten, and D.H. Bogchelman Effects of a preovulatory single low dose of mifepristone on ovarian function Eur J Contracept Reprod Health Care 11 2006 104 108
53. R. Leminen, T. Raivio, S. Ranta, J. Oehler, H. von Hertzen, and O.A. Jänne Late follicular phase administration of mifepristone suppresses circulating leptin and FSH - mechanism(s) of action in emergency contraception? Eur J Endocrinol 152 2005 411 418
54. J. Sengupta, L. Dhawan, P.G. Lalitkumar, and D. Ghosh A multiparametric study of the action of mifepristone used in emergency contraception using the Rhesus monkey as a primate model Contraception 68 2003 453 469
55. P. Stratton, B. Hartog, N. Hajizadeh, J. Piquion, D. Sutherland, and M. Merino A single mid-follicular dose of CDB-2914, a new antiprogestin, inhibits folliculogenesis and endometrial differentiation in normally cycling women Hum Reprod 15 2000 1092 1099
56. J.R. Reel, S. Hild-Petito, and R.P. Blye Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats Contraception 58 1998 129 136
57. S. Banaszak, A. Brudney, K. Donnelly, D. Chai, K. Chwalisz, and A.T. Fazleabas Modulation of the action of chorionic gonadotropin in the baboon (Papio anubis) uterus by a progesterone receptor antagonist (ZK 137.316) Biol Reprod 63 2000 820 825
58. P.G. Lalitkumar, S. Lalitkumar, C.X. Meng, A. Stavreus-Evers, F. Hambiliki, and U. Bentin-Ley Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model Hum Reprod 22 2007 3031 3037
59. A. Petersen, U. Bentin-Ley, V. Ravn, K. Qvortrup, S. Sorensen, and H. Islin The antiprogesterone Org 31710 inhibits human blastocyst-endometrial interactions in vitro Fertil Steril 83 Suppl 1 2005 1255 1263
60. C.X. Meng, K.L. Andersson, U. Bentin-Ley, K. Gemzell-Danielsson, and P.G. Lalitkumar Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model Fertil Steril 91 2009 256 264
61. M.D. Creinin, W. Schlaff, D.F. Archer, L. Wan, R. Frezieres, and M. Thomas Progesterone receptor modulator for emergency contraception: a randomized controlled trial Obstet Gynecol 108 2006 1089 1097
62. P. Fine, H. Mathé, S. Ginde, V. Cullins, J. Morfesis, and E. Gainer Ulipristal acetate taken 48-120 hours after intercourse for emergency contraception Obstet Gynecol 115 2010 257 263
63. A.F. Glasier, S.T. Cameron, P.M. Fine, S.J. Logan, W. Casale, and J. Van Horn Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis Lancet 375 2010 555 562
64. J. Jin, E. Weisberg, and I.S. Fraser Comparison of three single doses of mifepristone as emergency contraception: a randomised controlled trial Aust NZ J Obstet Gynaecol 45 2005 489 494
65. J.L. Esteve, R. García, A. Breto, and M. Llorente Emergency contraception in Cuba with 10 mg of mifepristone Eur J Contracept Reprod Health Care 12 2007 162 167
66. S. Taneepanichskul Emergency contraception with mifepristone 10 mg in Thai women J Med Assoc Thai 92 2009 999 1002
67. S. Wu, J. Dong, J. Cong, C. Wang, H. VonHertzen, and E.M. Godfrey Gestrinone compared with mifepristone for emergency contraception: a randomized controlled trial Obstet Gynecol 115 2010 740 744
68. F. Lakha, P.C. Ho, Z.M. Van der Spuy, K. Dada, R. Elton, and A.F. Glasier A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel) Hum Reprod 22 2007 2428 2436
69. K. Pei, B. Xiao, X. Jing, S. Lu, L. Wei, and H. Zhao Weekly contraception with mifepristone Contraception 75 2007 40 44
70. M. Agarwal, V. Das, A. Agarwal, A. Pandey, and D. Srivastava Evaluation of mifepristone as a once a month contraceptive pill Am J Obstet Gynecol 200 2009 e27 e29
71. L.K. Nieman, W. Blocker, T. Nansel, S. Mahoney, J. Reynolds, and D. Blithe Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study Fertil Steril 95 2011 767 772 e1-2
72. J. Wilkens, K. Chwalisz, C. Han, J. Walker, I.T. Cameron, and S. Ingamells Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy J Clin Endocrinol Metab 93 2008 4664 4671
73. R. Wiehle, J. Goldberg, T. Brodniewicz, K. Jarus-Dziedzic, and Z. Jabiry-Zieniewicz Effects of a new progesterone receptor modulator, CDB-4124, on fibroid size and uterine bleeding US Obstetr Gynaecol 3 2008 17 20
74. S.H. Eisinger, T. Bonfiglio, K. Fiscella, S. Meldrum, and D.S. Guzick Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas J Minim Invasive Gynecol 12 2005 227 233
75. K. Fiscella, S.H. Eisinger, S. Meldrum, C. Feng, S.G. Fisher, and D.S. Guzick Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial Obstet Gynecol 108 2006 1381 1387
76. J.L. Carbonell Esteve, R. Acosta, B. Heredia, Y. Perez, M.C. Castaneda, and A.V. Hernandez Mifepristone for the treatment of uterine leiomyomas: a randomized controlled trial Obstet Gynecol 112 2008 1029 1036
77. M. Bagaria, A. Suneja, N.B. Vaid, K. Guleria, and K. Mishra Low-dose mifepristone in treatment of uterine leiomyoma: a randomised double-blind placebo-controlled clinical trial Aust NZ J Obstet Gynaecol 49 2009 77 83
78. S.H. Eisinger, J. Fiscella, T. Bonfiglio, S. Meldrum, and K. Fiscella Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata Eur J Obstet Gynecol Reprod Biol 146 2009 215 218
79. M. Engman, S. Granberg, A.R. Williams, C.X. Meng, P.G. Lalitkumar, and K. Gemzell-Danielsson Mifepristone for treatment of uterine leiomyoma: a prospective randomized placebo controlled trial Hum Reprod 24 2009 1870 1879
80. C. Feng, S. Meldrum, and K. Fiscella Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone Int J Gynaecol Obstet 109 2010 121 124
81. L. Cheng, A.M. Gulmezoglu, G. Piaggio, E. Ezcurra, and P.F. Van Look Interventions for emergency contraception Cochrane Database Syst Rev 2 2008 CD001324
82. C. Fiala, and K. Gemzel-Danielsson Review of medical abortion using mifepristone in combination with a prostaglandin analogue Contraception 74 2006 66 86
83. L. Marions Mifepristone dose in the regimen with misoprostol for medical abortion Contraception 74 2006 21 25
84. C. Schreiber, and M. Creinin Mifepristone in abortion care Semin Reprod Med 23 2005 82 91
85. M.A. Bedaiwy, M.A. Abdel-Aleem, A. Miketa, and T. Falcone Endometriosis: a critical appraisal of the advances and the controversies of a challenging health problem Minerva Ginecol 61 2009 285 298
86. P.G. Signorile, and A. Baldi Endometriosis: new concepts in the pathogenesis Int J Biochem Cell Biol 42 2010 778 780
87. B. Eskenazi, and M.L. Warner Epidemiology of endometriosis Obstet Gynecol Clin North Am 24 1997 235 258
88. P. Crosignani, D. Olive, A. Bergqvist, and A. Luciano Advances in the management of endometriosis: an update for clinicians Hum Reprod Update 12 2006 179 189
89. R.M. Brenner, O.D. Slayden, A. Nath, Y.Y. Tsong, and R. Sitruk-Ware Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques Contraception 81 2010 336 342
90. K. Gopalkrishnan, R.R. Katkam, G. Sachdeva, S.D. Kholkute, V. Padwal, and C.P. Puri Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies Biol Reprod 68 2003 1959 1967
91. Z. Zhang, S.G. Lundeen, O. Slayden, Y. Zhu, J. Cohen, and T.J. Berrodin In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910 Ernst Schering Found Symp Proc 2007 171 197
92. Y. Wu, and S.W. Guo Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780 Gynecol Obstet Invest 62 2006 193 205
93. B.G. Moe, A.B. Vereide, A. Orbo, and G. Sager High concentrations of progesterone and mifepristone mutually reinforce cell cycle retardation and induction of apoptosis Anticancer Res 29 2009 1053 1058
94. O.B. Ioffe, R.J. Zaino, and G.L. Mutter Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator Mod Pathol 22 2009 450 459
95. J. Wilkens, A.R. Williams, K. Chwalisz, C. Han, I.T. Cameron, and H.O. Critchley Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN Hum Reprod 24 2009 1036 1044
96. O. Heikinheimo, S. Vani, O. Carpen, A. Tapper, P. Harkki, and E.M. Rutanen Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study Hum Reprod 22 2007 2515 2522
97. A.R. Williams, H.O. Critchley, J. Osei, S. Ingamells, I.T. Cameron, and C. Han The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata Hum Reprod 22 2007 1696 1704
98. D.T. Baird, A. Brown, H.O. Critchley, A.R. Williams, S. Lin, and L. Cheng Effect of long-term treatment with low-dose mifepristone on the endometrium Hum Reprod 18 2003 61 68
99. D.R. Grow, R.F. Williams, J.G. Hsiu, and G.D. Hodgen Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study J Clin Endocrinol Metab 81 1996 1933 1939
100. K. Stoeckemann, C. Hegele-Hartung, and K. Chwalisz Effects of the progesterone antagonists onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis in intact rats Hum Reprod 10 1995 3264 3271
101. W. Elger, R. Ivell, A. Nandy, A. Rasch, A. Triller, and K. Chwalisz Modulation of uterine prostaglandin secretion by the selective progesterone receptor modulator (SPRM) asoprisnil, progestins, and antiprogestins in cycling and ovariectomized guinea pigs Fertil Steril 82 Suppl 2004 S316
102. K. Gemzell-Danielsson, and M. Hamberg The effect of antiprogestin (RU 486) and prostaglandin biosynthesis inhibitor (naproxen) on uterine fluid prostaglandin F2 alpha concentrations Hum Reprod 9 1994 1626 1630
103. L.M. Kettel, A.A. Murphy, A.J. Morales, A. Ulmann, E.E. Baulieu, and S.S. Yen Treatment of endometriosis with the antiprogesterone mifepristone (RU486) Fertil Steril 65 1996 23 28
104. L.M. Kettel, A.A. Murphy, A.J. Morales, and S.S. Yen Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486) Am J Obstet Gynecol 178 1998 1151 1156
105. L. Mei, J. Bao, L. Tang, C. Zhang, H. Wang, and L. Sun A novel mifepristone-loaded implant for long-term treatment of endometriosis: in vitro and in vivo studies Eur J Pharm Sci 39 2010 421 427
106. K. Chwalisz, C. Mattia-Goldberg, W. Elger, and A. Edmonds Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) asoprisnil Fertil Steril 82 2004 S83 S84
107. I.M. Spitz Clinical utility of progesterone receptor modulators and their effect on the endometrium Curr Opin Obstet Gynecol 21 2009 318 324
108. K. Chwalisz, R.M. Brenner, U.U. Fuhrmann, H. Hess-Stumpp, and W. Elger Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium Steroids 65 2000 741 751
109. N.R. Nayak, O.D. Slayden, K. Mah, K. Chwalisz, and R.M. Brenner Antiprogestin-releasing intrauterine devices: a novel approach to endometrial contraception Contraception 75 2007 S104 S111
110. S. Ravet, C. Munaut, S. Blacher, G. Brichant, S. Labied, and A. Beliard Persistence of an intact endometrial matrix and vessels structure in women exposed to VA-2914, a selective progesterone receptor modulator J Clin Endocrinol Metab 93 2008 4525 4531
111. R. Stephanie, S. Labied, S. Blacher, F. Frankenne, C. Munaut, and V. Fridman Endometrial vessel maturation in women exposed to levonorgestrel- releasing intrauterine system for a short or prolonged period of time Hum Reprod 22 2007 3084 3091
112. K. Gemzell-Danielsson, A.M. van Heusden, S.R. Killick, H.B. Croxatto, P. Bouchard, and S. Cameron Improving cycle control in progestogen-only contraceptive pill users by intermittent treatment with a new anti-progestogen Hum Reprod 17 2002 2588 2593
113. M.R. Massai, M. Pavez, B. Fuentealba, H.B. Croxatto, and C. d'Arcangues Effect of intermittent treatment with mifepristone on bleeding patterns in Norplant implant users Contraception 70 2004 47 54
114. W.H. Parker Etiology, symptomatology, and diagnosis of uterine myomas Fertil Steril 87 2007 725 736
115. C.E. Miller Unmet therapeutic needs for uterine myomas J Minim Invasive Gynecol 16 2009 11 21
116. W.H. Catherino, E. Parrott, and J. Segars Proceedings from the National Institute of Child Health and Human Development conference on the Uterine Fibroid Research Update Workshop Fertil Steril 95 2011 9 12
117. M. Nisolle, S. Gillerot, F. Casanas-Roux, J. Squifflet, M. Berliere, and J. Donnez Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy Hum Reprod 14 1999 2844 2850
118. D.D. Brandon, C.L. Bethea, E.Y. Strawn, M.J. Novy, K.A. Burry, and M.S. Harrington Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas Am J Obstet Gynecol 169 1993 78 85
119. K. Englund, A. Blanck, I. Gustavsson, U. Lundkvist, P. Sjöblom, and A. Norgren Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment J Clin Endocrinol Metab 83 1998 4092 4096
120. W. Chen, N. Ohara, J. Wang, Q. Xu, J. Liu, and A. Morikawa A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells J Clin Endocrinol Metab 91 2006 1296 1304
121. Y. Shimomura, H. Matsuo, T. Samoto, and T. Maruo Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma J Clin Endocrinol Metab 83 1998 2192 2198
122. H. Matsuo, O. Kurachi, Y. Shimomura, T. Samoto, and T. Maruo Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma Oncology 57 Suppl 2 1999 49 58
123. T. Maruo, H. Matsuo, T. Samoto, Y. Shimomura, O. Kurachi, and Z. Gao Effects of progesterone on uterine leiomyoma growth and apoptosis Steroids 65 2000 585 592
124. H. Matsuo, T. Maruo, and T. Samoto Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone J Clin Endocrinol Metab 82 1997 293 299
125. H. Ishikawa, K. Ishi, V.A. Serna, R. Kakazu, S.E. Bulun, and T. Kurita Progesterone is essential for maintenance and growth of uterine leiomyoma Endocrinology 151 2010 2433 2442
126. M.A. Lumsden Modern management of fibroids Obstet Gynecol Reprod Med 20 2010 82 86
127. X. Luo, P. Yin, V.J. Coon, Y.H. Cheng, R.D. Wiehle, and S.E. Bulun The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells Fertil Steril 93 2010 2668 2673
128. T. Maruo, N. Ohara, H. Matsuo, Q. Xu, W. Chen, and R. Sitruk-Ware Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas Contraception 75 Suppl 2007 S99 S103
129. Q. Xu, S. Takekida, N. Ohara, W. Chen, R. Sitruk-Ware, and E.D. Johansson Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5'-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells J Clin Endocrinol Metab 90 2005 953 961
130. Q. Xu, N. Ohara, J. Liu, K. Nakabayashi, D. Demanno, and K. Chwalisz Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells Am J Physiol Endocrinol Metab 293 2007 E1002 E1011
131. H. Sasaki, N. Ohara, Q. Xu, J. Wang, D.A. DeManno, and K. Chwalisz A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells J Clin Endocrinol Metab 92 2007 616 623
132. J. Wang, N. Ohara, Z. Wang, W. Chen, A. Morikawa, and H. Sasaki A novel selective progesterone receptor modulator asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGFβ3 and their receptors in cultured uterine leiomyoma cells Hum Reprod 21 2006 1869 1877
133. Q. Xu, N. Ohara, W. Chen, J. Liu, H. Sasaki, and A. Morikawa Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells Hum Reprod 21 2006 2408 2416
134. Q. Xu, N. Ohara, J. Liu, M. Amano, R. Sitruk-Ware, and S. Yoshida Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells Mol Hum Reprod 14 2008 181 191
135. A. Morikawa, N. Ohara, Q. Xu, K. Nakabayashi, D.A. DeManno, and K. Chwalisz Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer Hum Reprod 23 2008 944 951
136. B. Gellersen, M.S. Fernandes, and J.J. Brosens Non-genomic progesterone actions in female reproduction Hum Reprod Update 15 2009 119 138
137. P.M. Ismail, P. Amato, S.M. Soyal, F.J. DeMayo, O.M. Conneely, and B.W. O'Malley Progesterone involvement in breast development and tumorigenesis - as revealed by progesterone receptor "knockout" and "knockin" mouse models Steroids 68 2003 779 787
138. A.J. Poole, Y. Li, Y. Kim, S.C. Lin, W.H. Lee, and E.Y. Lee Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist Science 314 2006 1467 1470
139. G. Benagiano, C. Bastianelli, and M. Farris Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry Expert Opin Pharmacother 9 2008 2487 2496
140. M. Li, E. Spitzer, W. Zschiesche, B. Binas, K. Parczyk, and R. Grosse Antiprogestins inhibit growth and stimulate differentiation in the normal mammary gland J Cell Physiol 164 1995 1 8
141. M. Engman, L. Skoog, G. Söderqvist, and K. Gemzell-Danielsson The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology Hum Reprod 23 2008 2072 2079
142. Safety of treatment of uterine fibroids with asoprisnil. http://clinicaltrials gov/ct2/show/NCT00156208 2010.
143. Abbott CM-G. Study of asoprisnil in the treatment of uterine fibroid. Available at: http://clinicaltrials.gov/ct2/show/NCT00156156. Last accessed September 14, 2011.
144. S.H. Eisinger, S. Meldrum, K. Fiscella, H.D. le Roux, and D.S. Guzick Low-dose mifepristone for uterine leiomyomata Obstet Gynecol 101 2003 243 250
145. F.M. Horne, and D.L. Blithe Progesterone receptor modulators and the endometrium: changes and consequences Hum Reprod Update 13 2007 567 580
146. G.L. Mutter, C. Bergeron, L. Deligdisch, A. Ferenczy, M. Glant, and M. Merino The spectrum of endometrial pathology induced by progesterone receptor modulators Mod Pathol 21 2008 591 598
147. A. Williams, C. Bergeron, N. Chabbert-Buffet, and A. Ferenczy Progesterone receptor modulator-associated endometrial changes (PAEC): a pilot histological, dose-escalation study of ulipristal acetate Fact View Vision Obgyn 2010 2 [special issue, May].
148. Repros Therapeutics. Repros Therapeutics Inc. provides clarification on increased liver enzymes at highest dose in Proellex clinical program. July 23, 2009. News Blaze.com. Available at: http://newsblaze.com/story/ 2009072303060800003.bw/topstory.html. Accessed August 20, 2011.
149. BioMedReports.com/ Repros Therapeutics Inc. suspends dosing of Proellex and provides update on financial status. BioMedRports, August 3, 2009. Available at: http://biomedreports.com/200908033992/repros-therapeutics-inc-suspends- dosing-of-proellexr-and-provides-update-on-financial-status.html. Accessed August 20, 2011.
150. Repros Therapeutics. Determination of the lowest, safe and effective dose of the anti-progestin, Proellex, in healthy women. Last updated June 28, 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT01187043. Accessed August 20, 2011.
151. J.G. Klijn, B. Setyono-Han, and J.A. Foekens Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer Steroids 65 2000 825 830
152. Repros Therapeutics. Repros requests lift of clinical hold on Proellex. April 05, 2010. Available at: http://www.businesswire.com/news/home/ 20100405005089/en/Repros-Requests-Lift-Clinical-Hold-Proellex. Accessed August 20, 2011.
153. S.T. Cameron, K.J. Thong, and D.T. Baird Effect of daily low dose mifepristone on the ovarian cycle and on dynamics of follicle growth Clin Endocrinol (Oxf) 43 1995 407 414
154. A. Lethaby, B. Vollenhoven, and M. Sowter Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids Cochrane Database Syst Rev 2 2001 CD000547
155. A. Lethaby, B. Vollenhoven, and M. Sowter Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review BJOG 109 2002 1097 1108