Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology
Annie Im & Leonard J Appleman†
University of Pittsburgh, Division of Hematology/Oncology, Department of Medicine, 5150 Centre Avenue, Pittsburgh, PA 15232, USA
Importance of the field: Mifepristone is a synthetic selective progesterone- receptor modulator (SPRM) that is widely used around the globe in the field of reproductive medicine. At present mifepristone is approved in a number of countries for early termination of pregnancy (TOP), cervical dilatation before surgical TOP, and management of early embryonic loss or fetal death. A number of new clinical applications are being developed in gynecology, endocrinology and oncology. Mifepristone has also served as an invaluable tool in the study of steroid hormone biology.
Areas covered in this review: Current indications for mifepristone are reviewed. New applications for mifepristone under clinical investigation are discussed. In addition, the unique molecular and cellular effects of mifepristone are described.
What the reader will gain: The reader will understand the mechanisms of action of mifepristone and the underlying steroid hormone biology. The reader will know the approved clinical indications for mifepristone and appreciate the ongoing basic and clinical research into new applications.
Take home message: Mifepristone is the first-discovered and still most widely used antiprogestin. It has several indications in reproductive medicine and is under investigation for a variety of potential applications in other fields of medicine. The molecular and cellular effects of mifepristone illuminate important aspects of steroid hormone biology.
Keywords: mifepristone, misoprostol, progesterone, termination of pregnancy
1. Introduction
Progesterone is a steroid hormone that is critical for the orchestration of multiple reproductive processes including ovulation and the establishment and maintenance of pregnancy. The progesterone receptor mediates its effects through ligand- dependent transcription of specific genes. The physiologic effects of progesterone include transformation of endometrium from proliferative to secretory state, inhibition of myometrial contractility, and facilitation of the luteinizing hormone (LH) surge. Mifepristone (RU 486; Box 1) is a synthetic steroid compound that acts primarily as a potent antagonist of progesterone and cortisol. By disrupting biologic processes necessary for the maintenance of pregnancy, mifepristone was developed as a drug for the termination of pregnancy. However, owing to the intricate effects of mifepristone in many receptors in the body, there has been evidence for potential use in many additional clinical applications.
2. Overview: unmet needs of current therapies
More than 26 million pregnancies are legally terminated across the globe each year, and another 20 million may be terminated illegally. Moreover, unregulated surgical abortions are common in developing countries and are estimated to be associated with more than 200,000 deaths worldwide each year [1]. There is a need for well-tolerated, medical methods for termination of pregnancies that are safe and readily available worldwide. In addition, there are several gynecologic, onco- logic and endocrine conditions in which hormones, particu- larly progesterone, have been identified in the pathophysiology of disease. For example, hormonal therapies have provided an effective and well-tolerated alternative to chemotherapeutic agents in the treatment of hormone-responsive malignancies, and there is a continuing need for therapeutic options. Discovery of new approaches and well-tolerated agents is needed in many of the aforementioned fields.
3. Introduction to mifepristone
Mifepristone is the first anti-progestin to be developed, having been initially described in 1981 as an antagonist of the glucocorticoid receptor (GR) and later the progesterone receptor (PR) [2] and androgen receptor (AR) [3]. Despite the development of newer agents, mifepristone remains by far the most widely used anti-progestin in clinical practice. This is due to its unique pharmacologic properties as well as to its relative safety and tolerability. Mifepristone is now approved for use in the USA for termination of intrauterine pregnancy
of up to 49 days gestation (up to 63 days in Britain and Sweden), preparation of the cervix before mechanical cervical dilation for pregnancy termination, and for labor induction in the case of fetal death. It is known to be more effective for termination of pregnancy (TOP) when combined with a prostaglandin such as misoprostol, to increase myometrial contractions and subsequent expulsion of the embryo. Mife- pristone has also been studied in clinical trials for use as continuous oral contraception, emergency contraception and treatment of uterine fibroids and endometriosis. Mifepristone has been studied as a potential therapeutic agent in breast, cervical, endometrial, ovarian and prostate cancers and meningiomas, and for use in endocrine disorders with hypercortisol states.
3.1 Chemistry
Mifepristone is a derivative of the synthetic progestin norethindrone, which is itself a 19-nor-testosterone progestin. Mife- pristone is chemically designated as 11b-[p-(dimethylamino) phenyl]-17b-hydroxyl-17-(1-propynyl)estra-4,9-dien-3-one. Its empirical formula is C29H35NO2. Its molecular weight is 429.6. Substitution at the 11 beta position is thought to confer the anti-progestin action, by analogy to known anti- estrogens [2]. Mifepristone is soluble in methanol, chloroform and acetone, and poorly soluble in water.
3.2 Mechanism of action
3.2.1 Molecular mechanisms of mifepristone
Mifepristone acts as an antagonist of progestins, glucocorticoids and androgens through the PR, GR and AR, respectively [2-4]. In the absence of ligand, PR exists primarily in the cytosol as monomeric protein bound to heat-shock proteins. Binding of progestins results in dimerization of receptor monomers, translocation to the nucleus, protein phosphorylation, binding to specific DNA sequences, and transcriptional activation of target genes. Mifepristone binds to PR at the ligand-binding site with five times the affinity of progesterone [4]. The biologic effects of mifepristone are antagonistic, resulting in down- regulation of progesterone-dependent genes. Mifepristone also has partial agonist activity at the PR: when added to cells in the absence of progesterone, there is weak agonist activity in activation of certain genes [5]. The mechanism of progesterone antagonism is incompletely understood: dissociation of PR from heat-shock proteins, dimerization and translocation of receptor/drug complexes to the nucleus are all equivalent for progesterone and mifepristone [6]. The DNA footprint of PR- ligand complexes at hormone response elements in promoter genes is identical for PR-progesterone and PR-mifepristone complexes [7]. Mifepristone forms contacts with amino acid residues within the ligand-binding pocket of PR that are unique from those contacted progesterone [8], and the C-terminal ligand-binding domain of PR assumes a different three-dimensional conformation when bound by mifepristone than when bound by progesterone [5]. This conformational difference abolishes transcriptional activation by the PR- ligand complex because mifepristone-PR complexes lack bind- ing to transcriptional coactivator proteins [9], and recruit co-repressor proteins such as NCorR and SMRT [10]. Exper- imental truncation of the extreme C-terminal 42 amino acids of PR abolishes binding to progesterone but preserves binding to mifepristone [11]. Mifepristone acts as an agonist in association with this truncated form, indicating that the C-terminal domain has an inhibitory function and is displaced by progesterone but not mifepristone. This C-terminal domain contains helix 12 of the secondary structure, which is displaced in several other examples of steroid hormone antagonism, such as raloxifene at the estrogen receptor alpha [12]. Mifepristone also binds to the GR with high affinity and has predominant antagonist activity [2] and to the AR with antagonist activity [13].
3.2.2 Physiologic effects of mifepristone
Treatment with mifepristone during pregnancy results in decidual necrosis and detachment of the products of con- ception. Endometrial capillaries also undergo necrosis and regression [14]. Myometrial contractions occur as a result of the loss of the normal inhibitory signal maintained by progester- one. Cervical softening and dilation also occurs. A direct inhibitory effect on endometrial cell proliferation has also been seen [15]. In non-pregnant women, the chronic use of mifepristone at lower doses often inhibits ovulation and induces amenorrhea. There is evidence of a direct inhibitory effect on endometrial cell proliferation as well [15].
Because of differing affinities for various nuclear hormone receptors and co-factors, the cellular effects of mifepristone may vary with the intracellular concentrations of the drug. Consequentially, the physiologic effects of mifepristone may vary with the dose administered. Similarly, the schedule of mifepristone administration (continuous daily dosing vs higher doses as lesser frequency) may lead to different biologic effects.
3.3 Pharmacokinetics and metabolism
Mifepristone is readily absorbed orally with an absolute bioavailability of 69% following administration of a 20-mg dose. Plasma drug concentrations increase following single oral dose escalations from 50 up to 100 mg. No further increase in the parent compound is observed as doses are increased from 100 to 800 mg. However, the concentration of pharmacologically active metabolites increases with this dose escalation. The half-life of mifepristone in humans is 20 – 40 h [16]. Mifepristone is 98% bound to plasma proteins, primarily albumin and a1-acid glycoprotein. Hepatic metabolism, enterohepatic circulation and subse- quent excretion in feces are the predominant mechanisms of elimination. Mono and di-demethylated products are generated by CYP3A4, and are thought to retain pharmacologic activity.
4. Clinical efficacy
Mifepristone has been studied as new therapy for a variety of diseases and clinical conditions, some of which are discussed below.
4.1 Termination of pregnancy (TOP), and obstetrics Mifepristone has been most extensively studied when admin- istered as a single 600-mg dose, followed by administration of the prostaglandin misoprostol 24 – 48 h later. An office visit with confirmation of TOP is performed on day 15. Large trials were conducted in France and the USA to assess this regimen, and success rates ranged from 92 to 98% in women with
pregnancies of less than 49 days gestation. These rates are higher after vaginal administration of misoprostol compared with oral misoprostol. In one study, TOP was successful in 92% of the patients who received the mifepristone and misoprostol regimen within 49 days, 83% in those who received mifepristone between 50 and 56 days, and 77% of those who received mifepristone between 57 and 63 days [17], supporting the fact that risk of failed medical termination of pregnancy increases as gestational age increases. Excessive vaginal bleeding is the most severe side effect, and in this study necessitated hospitalization, surgical interventions and fluid administration in 2% of patients who received mifep- ristone before 49 days, and 4% in those who received the drug between 50 and 63 days. Mifepristone is used in the medical management of early pregnancy failure or fetal death. Mifepristone 200 mg fol- lowed by misoprostol 800 µg can be given to induce expulsion of products of conception, as an alternative to either surgical or expectant management. Success rates from this regimen have been looked at in observational studies, showing rates of 52 – 84%, with the wide range related to variable does and routes of administration of misoprostol [18]. One randomized control trial found a success rate of 90%, with equal efficacy compared to surgical curettage using updated ultrasound criteria to determine success rates [19], while another study showed a success rate of 90% for this regimen using similarly updated criteria [20].
Based on the same mechanisms of action, mifepristone can be used in the induction of labor in late pregnancy. A recent Cochrane Systematic Review looked at 10 studies comparing mifepristone versus placebo or no treatment in third trimester cervical ripening or labor induction [21]. Women treated with mifepristone were significantly less likely to have caesarean sections performed for failure to induce labor, though there was not enough evidence supporting an ideal dose or on neonatal outcomes.
4.2 Emergency contraception
Mifepristone has been studied in several trials as an emergency contraceptive agent at doses ranging from 10 to 600 mg as a single dose [22-26]. A single dose of 10 mg has been shown to be as effective as higher doses, and shows equal efficacy compared with the levonorgestrel regimens used at present [27]. In addition, a recent review showed that mifepristone at doses of 25 – 50 mg was superior to levonorgestrel for emergency contraception, with the main side effect being delayed onset of subsequent menses [28]. Mifepristone is effective up to 120 h after coitus, whereas other methods of emergency contracep- tion must be given within 72 h. This is due to the unique mechanism of action of mifepristone, whereby it acts by blocking tubal transport as well as blocking blastocyst attach- ment. China is the only country in which mifepristone is approved for emergency contraception.
4.3 Long-term contraception
Existing contraceptive formulations include preparations of estrogen plus progestins, which have been associated with increased risk of venous thrombosis, and progesterone-only preparations, which have been associated with high failure rate, unpredictable menstrual bleeding and functional cysts. Mifepristone at low doses inhibits ovulation and prevents the formation of a secretory endometrium. A study of
98 patients randomized to receive either 2 or 5 mg of mifepristone daily was conducted to assess efficacy and safety in contraception [29]. Both doses were well tolerated, and no pregnancies were reported. However, a majority of women in both groups experienced amenorrhea. Another early study showed the use of a monthly dose of 200 mg of mifepristone given immediately after ovulation is sufficient to prevent pregnancy, owing to secretory impairment of the endometrium [30]. However, it is likely that the difficulty of determining the precise time of ovulation limits the efficacy of this method.
4.4 Endometriosis and uterine fibroids
One of the goals in the treatment of endometriosis is to prevent estrogenic stimulation of the ectopic endometrium, thereby preventing symptomatic pain and bleeding. Mife- pristone can selectively inhibit proliferation of endometrial tissue and suppress endometrial bleeding. Two small published series including 16 total patients showed that mifepristone at doses of 50 mg/day improved pelvic pain and resulted in objective regression of endometriosis [31,32]. These benefits were not associated with any significant side effects.
Progesterone plays an important role in the pathogenesis of symptomatic uterine leiomyomatas (fibroids). Although treat- ment of fibroids is mainly surgical, medical treatments have been studied for both adjuvant therapy and as an alternative to surgery. A number of clinical trials have established the effect of mifepristone in reducing the size of uterine fibroids and improving quality of life in women with symptomatic dis- ease [33,34]. A number of clinical trials have established the effect of mifepristone in reducing the size of uterine fibroids, reducing mean blood loss and increasing hemoglobin, reduc- ing the number of bleeding days and improving quality of life in women with symptomatic disease [33-35]. One of the benefits of mifepristone as an option for medical treatment of fibroids is in its lack of hypo-estrogenic effects, and therefore could be used for more long-term therapy. Studies of mifepristone in the treatment of uterine fibroids have provided insight into the role of progesterone in the complex pathophysiology of the disease, contributing to the body of knowledge that has only recently been uncovered.Other potential gynecologic uses for mifepristone include preventing the LH surge in ovarian hyperstimulatin in in vitro fertilization [36] and controlling vaginal bleeding in women using progestin-only contraceptives [37].
4.5 Oncology
Mifepristone has been studied in several malignancies in which steroid receptor signaling is important for cancer cell growth and survival [38]. Malignancies known to be influenced by steroid sex hormones include breast, ovarian, prostate, cervical and endometrial cancers, and meningiomas.
Mifepristone has been studied in breast cancer, a malig- nancy in which hormonal therapies, including selective estro- gen receptor modulators (SERMs), are widely used. In one study looking at the effect of a SERM and mifepristone on MCF-7 breast cancer cells in vitro, the use of a combination of both drugs was shown to be more cytostatic and cytotoxic than either therapy alone [39]. Several Phase II studies of mifepristone in patients with metastatic breast cancer have demonstrated disease response with tolerable side effects, including nausea, lethargy, anorexia and hot flashes [40]. The studies included a small number of subjects, but showed an objective response rate of 10 – 12% in previously treated patients and an objective response rate of 11% (CI 2 – 28%) when used as first-line, single-agent therapy [41].
Prostate cancer cells are highly dependent on androgens for growth and survival, and abrogation of androgen signal- ing is the most active systemic approach known for prostate cancer. Surgical castration, pharmacologic suppression of testicular androgen production, inhibition of androgen syn- thesis and competitive inhibition of androgen-receptor inter- action are all effective methods of hormonal treatment of prostate cancer. In addition to its antagonist activity at the PR and GR, mifepristone is also a potent AR antagonist. Mifepristone has been shown to have a higher binding affinity to androgen receptors than other nonsteroidal AR antagonists that are now in routine clinical use (flutamide, bicalutamide), and is more effective at mediating recruitment of corepressor proteins [3]. In one Phase II study of mife- pristone in advanced castration-refractory prostate cancer, where it is known that androgens continue to play a role in disease progression, patients had a significant increase in serum androgen concentrations after treatment with mife- pristone [42]. No clinical responses were seen. The authors hypothesized that the inhibition of the GR by mifepristone resulted in an increase in adrenocorticotropic hormone (ACTH) by feedback mechanisms, with subsequent increase in androgen production, thereby overwhelming the effect of AR antagonism. Although these results do not indicate clinical efficacy of mifepristone in the treatment of hor- mone-refractory prostate cancer, they offer insight into the mechanisms of action of mifepristone and the ultimate physiologic translation of these effects.
Mifepristone has also been studied in the treatment of other neoplastic diseases. A Phase II study of mifepristone in 34 patients with advanced, chemotherapy-refractory ovarian carcinoma documented a 26% response rate including three complete responses [43]. In addition, mifepristone has been shown to have a synergistic effect with cisplatin in cytotoxic effects on cervical cancer cells [44]. A recently published Phase II study of 200 mg daily in 12 patients with advanced endometrial cancer found no objective responses [45]. There have been mixed results in studies looking at the treatment of unresectable meningiomas, but one study showed minimal regression of meningioma in 8 of 26 patients, with only mild side effects [46]. It is clear that additional research needs to be done to delineate further the effects of this drug in oncologic diseases. Combination therapy with cytotoxic, hormonal or targeted agents may hold more promise than single-agent treatment of malignancies with mifepristone.
4.6 Endocrinology
Mifepristone has antagonist activity at the GR, which has led to investigation of its use in various disorders of hypercortisolism, including Cushing’s syndrome. The anti- glucocorticoid effects have also led to suggestion of its inves- tigation in psychiatric diseases such as psychotic depression [47] and Alzheimer’s disease [48], where mechanisms involving cortisol are thought to be related to the pathophysiology of those disorders. Mifepristone eye drops lower intraocular pressure in a rabbit model, and thus mifepristone has been proposed as a treatment for glaucoma [49].
5. Safety and tolerability
The most common side effects of mifepristone given in combination with misoprostol for TOP are abdominal pain/cramping, vaginal bleeding and gastrointestinal symp- toms including nausea, vomiting and diarrhea. Vaginal bleed- ing is expected with terminations of pregnancy, and overall blood loss is small, with a mean fall in hemoglobin of 0.7 g/dl and mean volume loss of 80 – 101 ml. In data collected from several large studies, only 38 out of 25,907 women (0.1%) were given blood transfusions [50]. The duration of bleeding related to medical TOP is greater than with surgical methods, with a median ranging from 8 to 17 days. Severe vaginal bleeding can require treatment with uterotonics, vasoconstric- tor drugs, curettage, intravenous fluids or transfusion of red blood cells.
Fatal toxic shock syndrome due to the organism Clostridium sordellii has been reported after TOP with mifepristone and misoprostol [51]. The clinical presentation is characterized by absence of fever as well as profound leukocytosis, hypotension, edema and hemoconcentration. According to observations from a recent retrospective study of infections in medical abortions, the rate of serious infections has declined from 0.93 out of 1000 abortions to 0.06 out of 1000 abortions with the following procedural changes: buccal, rather than vaginal, administration of misoprostol; routine use of prophylactic antibiotics; and routine testing for sexually transmitted diseases [52].
Moreover, the risk of complications during subsequent pregnancy following medical TOP with mifepristone is not increased [53]. Studies for the use of mifepristone in clinical applications aside from TOP, as referenced above, have shown good tolerability, with the main side effects being delayed onset of menses, amenorrhea, nausea, lethargy, anorexia and fatigue.
5.1 Contraindications
Mifepristone is contraindicated in patients with any one of the following conditions: confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass; placement of an intrauterine device; adrenal failure; concurrent long-term corticosteroid therapy; allergy to mifepristone; hemorrhagic disorders of concurrent anticoagulant therapy; and inherited porphyrias (due to risk of exacerbations).
5.2 Drug interactions
The metabolism of mifepristone is mediated by CYP 3A4, and it is therefore recommended that potent inhibitors or inducers of this enzyme be avoided. Mifepristone has been shown to inhibit CYP 3A4 enzymatic activity in vitro. Given the long half-life of mifepristone, drugs that are 3A4 substrates and have a narrow therapeutic range, such as general anesthetic agents, should be used with caution.
6. Regulatory affairs
Mifepristone was developed by the French company Roussel Uclaf. It was approved in France in 1988 and marketed the following year. Approval was granted in the UK in 1991, in Sweden in 1992, and in several other European countries over the ensuing decade. Mifepristone is now registered for the termination of pregnancy in more than 20 countries, includ- ing China, Taiwan, Vietnam, India, South Africa and several Eastern European counties. In September 2000, the FDA approved mifepristone for the termination of early pregnancy, defined as up to 49 days from the beginning of the last menstrual period. The US patent rights were donated to the Populations Council, Inc., a non-profit organization, in 1994.
In order to prescribe mifepristone in the USA, the provider must be qualified to date pregnancies and diagnose ectopics, and provide surgical intervention in cases of incomplete abortions or severe bleeding, or have in place arrangements for patients to obtain such services from other physicians who can perform these procedures. An FDA prescriber agreement is required, which is a signed document that indicates that the prescriber meets the above qualifications and understands the drug’s clinical pharmacology, the indications and contraindi- cations, and relevant warnings and precautions. Any hospi- talizations, transfusions, or other serious events related to the administration of mifepristone are required to be reported to Danco Laboratories, the supplier.
7. Conclusions
Mifepristone was the first anti-progestin to be developed, and its use continues to surpass those of newer agents. This is probably due to its diverse range of clinical uses based on its unique effects. In this way, mifepristone serves as paradigm in its molecular mechanisms of action. At present it serves as a safe and effective method for medical TOP. Early evidence shows its potential as a well-tolerated treatment of hormone- responsive malignancies such as breast cancer. Recent evidence even supports its use as a first-line option for emergency contraception. Additional benefit is in the safety and overall tolerability of mifepristone. With these promising results, it is likely that future research will uncover potential uses of mifepristone across many fields of medicine.
8. Expert opinion
As demonstrated through the evidence outlined above, mifepristone has clinical potential in a wide variety of fields including gynecology and reproductive medicine, oncology, and endocrinology. Moreover, it is a well-tolerated and safe drug, making its potential uses even more promising. Despite this knowledge, mifepristone is FDA approved in the USA only for medical termination of pregnancy. Following the first use of mifepristone as an abortifacient, it has been perma- nently linked to controversies surrounding TOP, despite its potential uses in many other non-related clinical applications. It is likely that this association has limited both its use and the investment in further research. While the development and study of other drugs are limited by obstacles such as financial issues, the development and study of mifepristone must additionally overcome political and social barriers as well. Our opinion is that there is evidence to support the further investigation of mifepristone in several clinical fields as a new approach to therapy.
Regarding termination of pregnancy, mifepristone in con- junction with misoprostol has a role as a safe and effective medical alternative to surgical abortion that can be readily available to women worldwide, especially given the morbidity and mortality that continues to be attributed to lack of available resources for TOP. Mifepristone has great potential as a resource for women in developing countries where surgical alternatives may be limited.
The application of mifepristone in other clinical venues deserves more investigation. Given that studies have already shown clinical superiority of mifepristone over current hor- monal preparations for emergency contraception with only mild side effects, investment into this use needs to continue. This may require another large-scale study to confirm previ- ous results that have been shown so far. At the present time, China is the only country where mifepristone is approved for emergency contraception.
The study of mifepristone in oncology remains in its early stages, and there needs to be more research to study potential options for hormonal therapies. This is especially the case in breast cancer where hormonal therapies have an essential role in treatment, and studies have indicated the promising effects of mifepristone. Moreover, though the study of mifepristone in other hormone responsive malignancies have shown mixed results, they provide insight into the mechanisms of both the drug and of the pathophysiology of the diseases themselves.
Another area that deserves more investment is development of next-generation selective progesterone receptor modulators (SPRMs). Though other progesterone antagonists exist, none has surpassed mifepristone in clinical use. However, as evi- denced throughout this review, there are limitations in the use of mifepristone owing to some of the mechanisms of action. For example, an SPRM that had less activity at the GR may be potentially effective in the treatment of prostate cancer, where feedback mechanisms involving cortisol may be increasing testosterone levels and negating the anti-androgen effect in patients treated with mifepristone.
Use of mifepristone should not be limited to termination of early pregnancy, and there needs to be investment in research for its use in different fields. Despite all that is known about this unique drug, there is still much to be discovered to enhance our knowledge about molecular mechanisms of this class of drugs, physiologic effects and clinical applications of mifepristone as new therapies for common diseases and clinical conditions.
Declaration of interest
The authors state no conflict of interest and have received no payment in preparation of this manuscript.
Bibliography
1. Henshaw SK. Induced abortion: a world review, 1990. Fam Plann Perspect 1990;22:76-89
2. Philibert D, Deraedt R, Teutsch G. RU 38486: a potent antiglucocorticoid in vivo. VII International Congress of Pharmacology. Tokyo, Japan; 1981
3. Song LN, Coghlan M, Gelmann EP. Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor.
Mol Endocrinol 2004;18:70-85
4. Schreiber JR, Hsueh AJ, Baulieu EE. Binding of the anti-progestin RU-486 to rat ovary steroid receptors. Contraception 1983;28:77-85
5. el-Ashry D, Onate SA, Nordeen SK, Edwards DP. Human progesterone receptor complexed with the antagonist RU 486 binds to hormone response elements in a structurally altered form. Mol Endocrinol 1989;3:1545-58
6. DeMarzo AM, Onate SA, Nordeen SK, Edwards DP. Effects of the steroid antagonist RU486 on dimerization of the human progesterone receptor. Biochemistry 1992;31:10491-501
7. Chalepakis G, Arnemann J, Slater E, et al. Differential gene activation by glucocorticoids and progestins through the hormone regulatory element of mouse mammary tumor virus. Cell 1988;53:371-82
8. Benhamou B, Garcia T, Lerouge T, et al. A single amino acid that determines the sensitivity of progesterone receptors to RU486. Science 1992;255:206-9
9. Onate SA, Tsai SY, Tsai MJ, O’Malley BW. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 1995;270:1354-7
10. Wagner BL, Norris JD, Knotts TA, et al. The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor. Mol Cell Biol 1998;18:1369-78
11. Vegeto E, Allan GF, Schrader WT, et al. The mechanism of RU486 antagonism is dependent on the conformation of the carboxy-terminal tail of the human progesterone receptor. Cell
1992;69:703-13
12. Kong EH, Pike AC, Hubbard RE. Structure and mechanism of the oestrogen receptor. Biochem Soc Trans
2003;31:56-9
13. Shang Y, Myers M, Brown M. Formation of the androgen receptor transcription complex. Mol Cell 2002;9:601-10
14. Johannisson E, Oberholzer M, Swahn ML, Bygdeman M. Vascular changes in the human endometrium following the administration of the progesterone antagonist RU 486. Contraception 1989;39:103-17
15. Baird DT, Brown A, Critchley HO, et al.
Effect of long-term treatment with low-dose mifepristone on the
endometrium. Hum Reprod 2003;18:61-8
16. Loose DS, Stancel GM. Estrogens and progestins. In: Burton LL, Lazo JS, Parker KL, editors, Chapter 57.
The phamacological basis of therapeutics. 11th edition. Goodman & Gilman’s: McGraw-Hill, New York. Available from: http://www.accessmedicine.com/content. aspx?aID=953503
17. Spitz IM, Bardin CW, Benton L, Robbins A. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 1998;338:1241-7
18. Chen BA, Creinin MD. Medical management of early pregnancy failure: efficacy. Semin Reprod Med 2008;26:411-22
19. Niinimaki M, Jouppila P, Martikainen H, Talvensaari-Mattila A. A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. Fertil Steril 2006;86:367-72
20. Schreiber CA, Creinin MD, Reeves MF, Harwood BJ. Mifepristone and misoprostol for the treatment of early pregnancy failure: a pilot clinical trial. Contraception 2006;74:458-62
21. Hapangama D, Neilson JP. Mifepristone for induction of labour.
Cochrane Database Syst Rev 2009;3:CD002865.
22. Comparison of three single doses of mifepristone as emergency contraception: a randomised trial. Task force on postovulatory methods of fertility regulation. Lancet 1999;353:697-702
23. von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. Lancet
2002;360:1803-10
24. Glasier A, Thong KJ, Dewar M, et al. Mifepristone (RU 486) compared with high-dose estrogen and progestogen for emergency postcoital contraception.
N Engl J Med 1992;327:1041-4
25. Glasier A, Thong KJ, Dewar M, et al. Postcoital contraception with mifepristone. Lancet 1991;337:1414-15
26. Hamoda H, Ashok PW, Stalder C, et al. A randomized trial of mifepristone (10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol 2004;104:1307-13
27. von Hertzen H, Piaggio G. Levonorgestrel and mifepristone in emergency contraception. Steroids 2003;68:1107-13
28. Cheng L, Gu¨lmezoglu AM, Piaggio G, et al. Interventions for emergency contraception. Cochrane Database
Syst Rev 2008;2:CD001324
29. Brown A, Cheng L, Lin S, Baird DT. Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double-blind randomized control trial of 2 and 5 mg per day for 120 days. J Clin Endocrinol Metab 2002;87:63-70
30. Gemzell-Danielsson K, Swahn ML, Svalander P, Bygdeman M. Early luteal phase treatment with mifepristone
(RU 486) for fertility regulation. Hum Reprod 1993;8:870-3
31. Kettel LM, Murphy AA, Morales AJ, et al. Treatment of endometriosis with the antiprogesterone mifepristone (RU486). Fertil Steril 1996;65:23-8
32. Kettel LM, Murphy AA, Morales AJ, Yen SS. Preliminary report on the treatment of endometriosis with
low-dose mifepristone (RU 486).
Am J Obstet Gynecol 1998;178:1151-6
33. Steinauer J, Pritts EA, Jackson R,
Jacoby AF. Systematic review of mifepristone for the treatment of uterine leiomyomata. Obstet Gynecol 2004;103:1331-6
34. Fiscella K, Eisinger SH, Meldrum S, et al. Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol 2006;108:1381-7
35. Engman M, Granberg S, Williams AR, et al. Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial. Hum Reprod 2009;24:1870-9
36. Escudero EL, Boerrigter PJ, Bennink HJ, et al. Mifepristone is an effective oral alternative for the prevention of premature luteinizing hormone surges and/or premature luteinization in women undergoing controlled ovarian hyperstimulation for in vitro fertilization. J Clin Endocrinol Metab 2005;90:2081-8
37. Abdel-Aleem H, d’Arcangues C, Vogelsong K, Gu¨lmezoglu AM. Treatment of vaginal bleeding irregularities induced by progestin only contraceptives. Cochrane Database Syst Rev 2007;4:CD003449
38. Benagiano G, Bastianelli C, Farris M. Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry. Expert Opin Pharmacother 2008;9:2487-96
39. Schoenlein PV, Hou M, Samaddar JS, et al. Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus
antiestrogen monotherapy of human breast cancer. Int J Oncol 2007;31:643-55
40. Klijn JG, de Jong FH, Bakker GH, et al. Antiprogestins, a new form of endocrine therapy for human breast cancer.
Cancer Res 1989;49:2851-6
41. Klijn JG, Setyono-Han B, Foekens JA. Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer. Steroids 2000;65:825-30
42. Taplin ME, Manola J, Oh WK, et al. A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones. BJU Int 2008;101:1084-9
43. Rocereto TF, Saul HM, Aikins JA Jr, Paulson J. Phase II study of mifepristone (RU486) in refractory ovarian cancer. Gynecol Oncol 2000;77:429-32
44. Jurado R, Lopez-Flores A, Alvarez A, Garcia-Lopez P. Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. Oncol Rep 2009;22:1237-45
45. Ramondetta LM, Johnson AJ, Sun CC, et al. Phase 2 trial of mifepristone
(RU-486) in advanced or recurrent endometrioid adenocarcinoma or
low-grade endometrial stromal sarcoma. Cancer 2009;115:1867-74
46. Grunberg SM, Weiss MH, Russell CA, et al. Long-term administration of mifepristone (RU486): clinical tolerance during extended treatment of meningioma. Cancer Invest 2006;24:727-33
47. Blasey CM, Debattista C, Roe R, et al. A multisite trial of mifepristone for the treatment of psychotic depression: a site-by-treatment interaction.
Contemp Clin Trials 2009;30:284-8
48. Belanoff JK, Jurik J, Schatzberg LD, et al. Slowing the progression of cognitive decline in Alzheimer’s disease using mifepristone. J Mol Neurosci 2002;19:201-6
49. Phillips CI, Green K, Gore SM, et al. Eye drops of RU 486-6, a peripheral steroid blocker, lower intraocular pressure in rabbits. Lancet 1984;1:767-8
50. Christin-Maitre S, Bouchard P, Spitz IM. Medical termination of pregnancy.
N Engl J Med 2000;342:946-56
51. Fischer M, Bhatnagar J, Guarner J, et al. Fatal toxic shock syndrome associated with Clostridium sordellii after medical abortion. N Engl J Med
2005;353:2352-60
52. Fjerstad M, Trussell J, Sivin I, et al. Rates of serious infection after changes in regimens for medical abortion.
N Engl J Med 2009;361:145-51
53. Virk J, Zhang J, Olsen J. Medical abortion and the risk of subsequent adverse pregnancy outcomes. N Engl J Med 2007;357:648-53.