Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies

References

• Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814–3826.
   PubMed Web of Science ®Google Scholar
• Salazar EL, Calzada L. The role of progesterone in endometrial estradiol- and progesterone-receptor synthesis in women with menstrual disorders and habitual abortion. Gynecol Endocrinol. 2007;23:222–225.
   PubMed Web of Science ®Google Scholar
• Maybin JA, Critchley HO. Progesterone: a pivotal hormone at menstruation. Ann NY Acad Sci. 2011;1221:88–97.
   PubMed Web of Science ®Google Scholar
• Bulun SE. Uterine fibroids. N Engl J Med. 2013;369:1344–1355.
   PubMed Web of Science ®Google Scholar
• Li X, O’Malley BW. Unfolding the action of progesterone receptors. J Biol Chem. 2003;278:39261–39264.
   PubMed Web of Science ®Google Scholar
• Patel B, Elguero S, Thakore S, et al. Role of nuclear progesterone receptor isoforms in uterine pathophysiology. Hum Reprod Update. 2015;21:155–173.
   PubMed Web of Science ®Google Scholar
• Mani SK, Oyola MG. Progesterone signaling mechanisms in brain and behavior. Front Endocrinol (Lausanne). 2012;3:7.
   PubMedGoogle Scholar
• Obr AE, Edwards DP. The biology of progesterone receptor in the normal mammary gland and in breast cancer. Mol Cell Endocrinol. 2012;357:4–17.
   PubMed Web of Science ®Google Scholar
• Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21:748–761.
   PubMed Web of Science ®Google Scholar
• Brosens JJ, de Souza NM, Barker FG. Uterine junctional zone: function and disease. Lancet. 1995;346:558–560.
   PubMed Web of Science ®Google Scholar
• Fusi L, Cloke B, Brosens JJ. The uterine junctional zone. Best Pract Res Clin Obstet Gynaecol. 2006;20:479–491.
   PubMed Web of Science ®Google Scholar
• Mote PA, Balleine RL, McGowan EM, et al. Heterogeneity of progesterone receptors A and B expression in human endometrial glands and stroma. Hum Reprod. 2000;15(Suppl 3):48–56.
   PubMed Web of Science ®Google Scholar
• Critchley HO, Saunders PT. Hormone receptor dynamics in a receptive human endometrium. Reprod Sci. 2009;16:191–199.
   PubMed Web of Science ®Google Scholar
• Mesiano S. Myometrial progesterone responsiveness. Semin Reprod Med. 2007;25:5–13.
   PubMed Web of Science ®Google Scholar
• Lessey BA, Killam AP, Metzger DA, et al. Immunohistochemical analysis of human uterine estrogen and progesterone receptors throughout the menstrual cycle. J Clin Endocrinol Metab. 1988;67:334–340.
   PubMed Web of Science ®Google Scholar
• Ingamells S, Campbell IG, Anthony FW, et al. Endometrial progesterone receptor expression during the human menstrual cycle. J Reprod Fertil. 1996;106:33–38.
   PubMedGoogle Scholar
• Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25:445–453.
   PubMed Web of Science ®Google Scholar
• Das SK. Cell cycle regulatory control for uterine stromal cell decidualization in implantation. Reproduction. 2009;137:889–899.
   PubMed Web of Science ®Google Scholar
• Goddard LM, Murphy TJ, Org T, et al. Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation. Cell. 2014;156:549–562.
   PubMed Web of Science ®Google Scholar
• Beato M, Herrlich P, Schutz G. Steroid hormone receptors: many actors in search of a plot. Cell. 1995;83:851–857.
   PubMed Web of Science ®Google Scholar
• Mangelsdorf DJ, Thummel C, Beato M, et al. The nuclear receptor superfamily: the second decade. Cell. 1995;83:835–839.
   PubMed Web of Science ®Google Scholar
• Burris TP, Solt LA, Wang Y, et al. Nuclear receptors and their selective pharmacologic modulators. Pharmacol Rev. 2013;65:710–778.
   PubMed Web of Science ®Google Scholar
• Pieber D, Allport VC, Bennett PR. Progesterone receptor isoform A inhibits isoform B-mediated transactivation in human amnion. Eur J Pharmacol. 2001;427:7–11.
   PubMed Web of Science ®Google Scholar
• Ellmann S, Sticht H, Thiel F, et al. Estrogen and progesterone receptors: from molecular structures to clinical targets. Cell Mol Life Sci. 2009;66:2405–2426.
   PubMed Web of Science ®Google Scholar
• Hagan CR, Knutson TP, Lange CA. A common docking domain in progesterone receptor-B links DUSP6 and CK2 signaling to proliferative transcriptional programs in breast cancer cells. Nucleic Acids Res. 2013;41:8926–8942.
   PubMed Web of Science ®Google Scholar
• O’Malley BW. Coregulators: from whence came these “master genes”. Mol Endocrinol. 2007;21:1009–1013.
   PubMed Web of Science ®Google Scholar
• Mangal RK, Wiehle RD, Poindexter AN 3rd, et al. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle. J Steroid Biochem Mol Biol. 1997;63:195–202.
   PubMed Web of Science ®Google Scholar
• Wang H, Critchley HO, Kelly RW, et al. Progesterone receptor subtype B is differentially regulated in human endometrial stroma. Mol Hum Reprod. 1998;4:407–412.
   PubMed Web of Science ®Google Scholar
• Kawaguchi K, Fujii S, Konishi I, et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy. Virchows Arch A Pathol Anat Histopathol. 1991;419:309–315.
   PubMedGoogle Scholar
• Viville B, Charnock-Jones DS, Sharkey AM, et al. Distribution of the A and B forms of the progesterone receptor messenger ribonucleic acid and protein in uterine leiomyomata and adjacent myometrium. Hum Reprod. 1997;12:815–822.
   PubMed Web of Science ®Google Scholar
• Fujimoto J, Hirose R, Ichigo S, et al. Expression of progesterone receptor form A and B mRNAs in uterine leiomyoma. Tumour Biol. 1998;19:126–131.
   PubMed Web of Science ®Google Scholar
• Bombail V, MacPherson S, Critchley HO, et al. Estrogen receptor related beta is expressed in human endometrium throughout the normal menstrual cycle. Hum Reprod. 2008;23:2782–2790.
   PubMed Web of Science ®Google Scholar
• Mulac-Jericevic B, Mullinax RA, DeMayo FJ, et al. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. Science. 2000;289:1751–1754.
   PubMed Web of Science ®Google Scholar
• Conneely OM, Mulac-Jericevic B, Lydon JP, et al. Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice. Mol Cell Endocrinol. 2001;179:97–103.
   PubMed Web of Science ®Google Scholar
• Conneely OM, Mulac-Jericevic B, Lydon JP. Progesterone-dependent regulation of female reproductive activity by two distinct progesterone receptor isoforms. Steroids. 2003;68:771–778.
   PubMed Web of Science ®Google Scholar
• Conneely OM, Mulac-Jericevic B, DeMayo F, et al. Reproductive functions of progesterone receptors. Recent Prog Horm Res. 2002;57:339–355.
   PubMedGoogle Scholar
• Samalecos A, Gellersen B. Systematic expression analysis and antibody screening do not support the existence of naturally occurring progesterone receptor (PR)-C, PR-M, or other truncated PR isoforms. Endocrinology. 2008;149:5872–5887.
   PubMed Web of Science ®Google Scholar
• Thomas P, Zhu Y, Pace M. Progestin membrane receptors involved in the meiotic maturation of teleost oocytes: a review with some new findings. Steroids. 2002;67:511–517.
   PubMed Web of Science ®Google Scholar
• Thomas P. Characteristics of membrane progestin receptor alpha (mPRalpha) and progesterone membrane receptor component 1 (PGMRC1) and their roles in mediating rapid progestin actions. Front Neuroendocrinol. 2008;29:292–312.
   PubMed Web of Science ®Google Scholar
• Hanna R, Pang Y, Thomas P, et al. Cell-surface expression, progestin binding, and rapid nongenomic signaling of zebrafish membrane progestin receptors alpha and beta in transfected cells. J Endocrinol. 2006;190:247–260.
   PubMed Web of Science ®Google Scholar
• Krietsch T, Fernandes MS, Kero J, et al. Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. Mol Endocrinol. 2006;20:3146–3164.
   PubMed Web of Science ®Google Scholar
• Gellersen B, Fernandes MS, Brosens JJ. Non-genomic progesterone actions in female reproduction. Hum Reprod Update. 2009;15:119–138.
   PubMed Web of Science ®Google Scholar
• Scarpin KM, Graham JD, Mote PA, et al. Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal. 2009;7:e009.
   Google Scholar
• Liu Z, Auboeuf D, Wong J, et al. Coactivator/corepressor ratios modulate PR-mediated transcription by the selective receptor modulator RU486. Proc Natl Acad Sci U S A. 2002;99:7940–7944.
   PubMed Web of Science ®Google Scholar
• Han SJ, DeMayo FJ, Xu J, et al. Steroid receptor coactivator (SRC)-1 and SRC-3 differentially modulate tissue-specific activation functions of the progesterone receptor. Mol Endocrinol. 2006;20:45–55.
   PubMed Web of Science ®Google Scholar
• Simmen RC, Heard ME, Simmen AM, et al. The Kruppel-like factors in female reproductive system pathologies. J Mol Endocrinol. 2015;54:R89–R101.
   PubMedGoogle Scholar
• Madauss KP, Grygielko ET, Deng SJ, et al. A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Mol Endocrinol. 2007;21:1066–1081.
   PubMed Web of Science ®Google Scholar
• Wilkens J, Male V, Ghazal P, et al. Uterine NK cells regulate endometrial bleeding in women and are suppressed by the progesterone receptor modulator asoprisnil. J Immunol. 2013;191:2226–2235.
   PubMed Web of Science ®Google Scholar
• Gregory CW, Wilson EM, Apparao KB, et al. Steroid receptor coactivator expression throughout the menstrual cycle in normal and abnormal endometrium. J Clin Endocrinol Metab. 2002;87:2960–2966.
   PubMed Web of Science ®Google Scholar
• Gellersen B, Brosens J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J Endocrinol. 2003;178:357–372.
   PubMed Web of Science ®Google Scholar
• Kalkhoven E, Wissink S, van der Saag PT, et al. Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor. J Biol Chem. 1996;271:6217–6224.
   PubMed Web of Science ®Google Scholar
• Shatnawi A, Tran T, Ratnam M. R5020 and RU486 act as progesterone receptor agonists to enhance Sp1/Sp4-dependent gene transcription by an indirect mechanism. Mol Endocrinol. 2007;21:635–650.
   PubMed Web of Science ®Google Scholar
• Hagan CR, Lange CA. Molecular determinants of context-dependent progesterone receptor action in breast cancer. BMC Med. 2014;12:32.
   PubMed Web of Science ®Google Scholar
• Faus H, Haendler B. Post-translational modifications of steroid receptors. Biomed Pharmacother. 2006;60:520–528.
   PubMed Web of Science ®Google Scholar
• Abdel-Hafiz HA, Horwitz KB. Post-translational modifications of the progesterone receptors. J Steroid Biochem Mol Biol. 2014;140:80–89.
   PubMed Web of Science ®Google Scholar
• Lange CA, Shen T, Horwitz KB. Phosphorylation of human progesterone receptors at serine-294 by mitogen-activated protein kinase signals their degradation by the 26S proteasome. Proc Natl Acad Sci U S A. 2000;97:1032–1037.
   PubMed Web of Science ®Google Scholar
• Chabbert-Buffet N, Meduri G, Bouchard P, et al. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update. 2005;11:293–307.
   PubMed Web of Science ®Google Scholar
• Boonyaratanakornkit V, McGowan E, Sherman L, et al. The role of extranuclear signaling actions of progesterone receptor in mediating progesterone regulation of gene expression and the cell cycle. Mol Endocrinol. 2007;21:359–375.
   PubMed Web of Science ®Google Scholar
• Cai W, Zhu Y, Furuya K, et al. Two different molecular mechanisms underlying progesterone neuroprotection against ischemic brain damage. Neuropharmacology. 2008;55:127–138.
   PubMed Web of Science ®Google Scholar
• Ballare C, Vallejo G, Vicent GP, et al. Progesterone signaling in breast and endometrium. J Steroid Biochem Mol Biol. 2006;102:2–10.
   PubMed Web of Science ®Google Scholar
• Vares G, Sai S, Wang B, et al. Progesterone generates cancer stem cells through membrane progesterone receptor-triggered signaling in basal-like human mammary cells. Cancer Lett. 2015;362:167–173.
   PubMed Web of Science ®Google Scholar
• Lu J, Reese J, Zhou Y, et al. Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells. J Endocrinol. 2015;224:183–194.
   PubMed Web of Science ®Google Scholar
• Balasubramanian B, Portillo W, Reyna A, et al. Nonclassical mechanisms of progesterone action in the brain: I. Protein kinase C activation in the hypothalamus of female rats. Endocrinology. 2008;149:5509–5517.
   PubMed Web of Science ®Google Scholar
• Balasubramanian B, Portillo W, Reyna A, et al. Nonclassical mechanisms of progesterone action in the brain: II. Role of calmodulin-dependent protein kinase II in progesterone-mediated signaling in the hypothalamus of female rats. Endocrinology. 2008;149:5518–5526.
   PubMed Web of Science ®Google Scholar
• Bashour NM, Wray S. Progesterone directly and rapidly inhibits GnRH neuronal activity via progesterone receptor membrane component 1. Endocrinology. 2012;153:4457–4469.
   PubMed Web of Science ®Google Scholar
• Vicent GP, Ballare C, Nacht AS, et al. Induction of progesterone target genes requires activation of Erk and Msk kinases and phosphorylation of histone H3. Mol Cell. 2006;24:367–381.
   PubMed Web of Science ®Google Scholar
• Faivre E, Skildum A, Pierson-Mullany L, et al. Integration of progesterone receptor mediated rapid signaling and nuclear actions in breast cancer cell models: role of mitogen-activated protein kinases and cell cycle regulators. Steroids. 2005;70:418–426.
   PubMed Web of Science ®Google Scholar
• Madauss KP, Stewart EL, Williams SP. The evolution of progesterone receptor ligands. Med Res Rev. 2007;27:374–400.
   PubMed Web of Science ®Google Scholar
• Lusher SJ, Raaijmakers HC, Vu-Pham D, et al. Structural basis for agonism and antagonism for a set of chemically related progesterone receptor modulators. J Biol Chem. 2011;286:35079–35086.
   PubMed Web of Science ®Google Scholar
• Chabbert-Buffet N, Pintiaux A, Bouchard P. The immninent dawn of SPRMs in obstetrics and gynecology. Mol Cell Endocrinol. 2012;358:232–243.
   PubMed Web of Science ®Google Scholar
• Berrodin TJ, Jelinsky SA, Graciani N, et al. Novel progesterone receptor modulators with gene selective and context-dependent partial agonism. Biochem Pharmacol. 2009;77:204–215.
   PubMed Web of Science ®Google Scholar
• Wardell SE, Narayanan R, Weigel NL, et al. Partial agonist activity of the progesterone receptor antagonist RU486 mediated by an amino-terminal domain coactivator and phosphorylation of serine400. Mol Endocrinol. 2010;24:335–345.
   PubMed Web of Science ®Google Scholar
• Afhuppe W, Sommer A, Muller J, et al. Global gene expression profiling of progesterone receptor modulators in T47D cells provides a new classification system. J Steroid Biochem Mol Biol. 2009;113:105–115.
   PubMed Web of Science ®Google Scholar
• Giangrande PH, Kimbrel EA, Edwards DP, et al. The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding. Mol Cell Biol. 2000;20:3102–3115.
   PubMed Web of Science ®Google Scholar
• Im A, Appleman LJ. Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology. Expert Opin Pharmacother. 2010;11:481–488.
   PubMed Web of Science ®Google Scholar
• Hoellen F, Griesinger G, Bohlmann MK. Therapeutic drugs in the treatment of symptomatic uterine fibroids. Expert Opin Pharmacother. 2013;14:2079–2085.
   PubMed Web of Science ®Google Scholar
• Benagiano G, Bastianelli C, Farris M, et al. Selective progesterone receptor modulators: an update. Expert Opin Pharmacother. 2014;15:1403–1415.
   PubMed Web of Science ®Google Scholar
• Yoshida S, Ohara N, Xu Q, et al. Cell-type specific actions of progesterone receptor modulators in the regulation of uterine leiomyoma growth. Semin Reprod Med. 2010;28:260–273.
   PubMed Web of Science ®Google Scholar
• Horak P, Mara M, Dundr P, et al. Effect of a selective progesterone receptor modulator on induction of apoptosis in uterine fibroids in vivo. Int J Endocrinol. 2012;2012:436174.
   PubMed Web of Science ®Google Scholar
• Xu Q, Ohara N, Liu J, et al. Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. Mol Hum Reprod. 2008;14:181–191.
   PubMed Web of Science ®Google Scholar
• Bulun SE, Moravek MB, Yin P, et al. Uterine leiomyoma stem cells: linking progesterone to growth. Semin Reprod Med. 2015;33:357–365.
   PubMed Web of Science ®Google Scholar
• Tanwar PS, Lee HJ, Zhang L, et al. Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod. 2009;81:545–552.
   PubMed Web of Science ®Google Scholar
• Mäkinen N, Mehine M, Tolvanen J, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011;334:252–255.
   PubMed Web of Science ®Google Scholar
• Mutter GL, Bergeron C, Deligdisch L, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol. 2008;21:591–598.
   PubMed Web of Science ®Google Scholar
• Donnez J, Vazquez F, Tomaszewski J, et al. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril. 2014;101:1565–1573.e18.
   PubMed Web of Science ®Google Scholar
• Esmya EMC 5 mg Tablets (ulipristal acetate). [cited 2016 Feb 2]. Available from: http://www.medicines.org.uk/emc/medicine/26068
   Google Scholar
• Donnez J, Tatarchuk TF, Bouchard P, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366:409–420.
   PubMed Web of Science ®Google Scholar
• Donnez J, Tomaszewski J, Vazquez F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012;366:421–432.
   PubMed Web of Science ®Google Scholar
• Williams AR, Bergeron C, Barlow DH, et al. Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. Int J Gynecol Pathol. 2012;31:556–569.
   PubMed Web of Science ®Google Scholar
• Attardi BJ, Burgenson J, Hild SA, et al. 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. 2004;88:277–288.
   PubMed Web of Science ®Google Scholar
• Brenner RM, Slayden OD, Nath A, et al. Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques. Contraception. 2010;81:336–342.
   PubMed Web of Science ®Google Scholar
• Pohl O, Williams AR, Bergeron C, et al. A 39-week oral toxicity study of ulipristal acetate in cynomolgus monkeys. Regul Toxicol Pharmacol. 2013;66:6–12.
   PubMed Web of Science ®Google Scholar
• Baird DT, Brown A, Critchley HO, et al. Effect of long-term treatment with low-dose mifepristone on the endometrium. Hum Reprod. 2003;18:61–68.
   PubMed Web of Science ®Google Scholar
• Slayden OD, Brenner RM. Hormonal regulation and localization of estrogen, progestin and androgen receptors in the endometrium of nonhuman primates: effects of progesterone receptor antagonists. Arch Histol Cytol. 2004;67:393–409.
   PubMedGoogle Scholar
• Brenner RM, Slayden OD. Progesterone receptor antagonists and the endometrial antiproliferative effect. Semin Reprod Med. 2005;23:74–81.
   PubMed Web of Science ®Google Scholar
• Williams AR, Critchley HO, Osei J, et al. 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. 2007;22:1696–1704.
   PubMed Web of Science ®Google Scholar
• Mutter GL, Lin MC, Fitzgerald JT, et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst. 2000;92:924–930.
   PubMed Web of Science ®Google Scholar
• Wilkens J, Williams AR, Chwalisz K, et al. Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN. Hum Reprod. 2009;24:1036–1044.
   PubMed Web of Science ®Google Scholar
• NICE. Clinical Guideline 44; Heavy menstrual bleeding 2007; [cited 2016 Feb 2]. Available from: http://www.nice.org.uk/nicemedia/pdf/CG44FullGuideline.pdf
   Google Scholar
• Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24:235–258.
   PubMed Web of Science ®Google Scholar
• Munro MG, Critchley HO, Broder MS, et al. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;113:3–13.
   PubMed Web of Science ®Google Scholar
• Stewart EA. Uterine fibroids. Lancet. 2001;357:293–298.
   PubMed Web of Science ®Google Scholar
• Merrill RM. Hysterectomy surveillance in the United States, 1997 through 2005. Med Sci Monit. 2008;14:CR24–CR31.
   PubMed Web of Science ®Google Scholar
• Cardozo ER, Clark AD, Banks NK, et al. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206:211.e1–211.e9.
   PubMed Web of Science ®Google Scholar
• ONS. Who is having babies? 2009; [cited 2016 Feb 2]. Available from: http://webarchive.nationalarchives.gov.uk/20140721132900/http://www.statistics.gov.uk/pdfdir/births1209.pdf
   Google Scholar
• RCOG. National heavy menstrual bleeding audit final report. London: RCOG; 2014.
   Google Scholar
• Engman M, Granberg S, Williams AR, et al. Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial. Hum Reprod. 2009;24:1870–1879.
   PubMed Web of Science ®Google Scholar
• Wilkens J, Chwalisz K, Han C, et al. 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. 2008;93:4664–4671.
   PubMed Web of Science ®Google Scholar
• Chwalisz K, Garg R, Brenner RM, et al. Selective progesterone receptor modulators (SPRMs): a novel therapeutic concept in endometriosis. Ann N Y Acad Sci. 2002;955:373–388.
   PubMed Web of Science ®Google Scholar
• Kettel LM, Murphy AA, Morales AJ, et al. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril. 1996;65:23–28.
   PubMed Web of Science ®Google Scholar
• Chwalisz K, Perez MC, Demanno D, et al. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev. 2005;26:423–438.
   PubMed Web of Science ®Google Scholar