GYNECOLOGY AND MENOPAUSE

Selective progesterone receptor modulators

in reproductive medicine: pharmacology, clinical
efficacy and safety
Philippe Bouchard, M.D.,a,b Nathalie Chabbert-Buffet, M.D., Ph.D.,b,c and Bart C. J. M. Fauser, M.D., Ph.D.d
a
Endocrinology Unit, AP-HP Hospital Saint-Antoine, Paris, France; b University Pierre and Marie Curie, Paris, France;
c
Department of Obstetrics and Gynecology, AP-HP Hospital Tenon, Paris, France; d Department of Reproductive Medicine
and Gynecology, University Medical Center Utrecht, Utrecht, the Netherlands

Objective: To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and sum-
marize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for
gynecologic indications.
Design: Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant
articles were identified from citations within these publications.
Setting: None.
Patient(s): None.
Intervention(s): None.
Main Outcome Measure(s): None.
Result(s): Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termi-
nation because of the unique property of this compound to terminate pregnancy when associated with prostaglandins.
Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because
SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests
a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-
controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate
in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids.
Conclusion(s): Mifepristone in combination with prostaglandins has been licensed for pregnancy termination
because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs
hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma. (Fer-
til Steril
2011;96:1175–89. 2011 by American Society for Reproductive Medicine.)
Key Words: Amenorrhea, contraception, leiomyoma, progesterone receptor, selective progesterone receptor
modulator, SPRM

Progesterone exerts biologic effects on a range of organ systems, in-
cluding the cardiovascular and central nervous systems, and bone.
However, it is probably best known for its pivotal role in the regula-
Received March 21, 2011; revised August 8, 2011; accepted August 12,
2011; published online September 22, 2011.
P.B. has received fees and grants from Ferring, HRA Pharma, Nordic
Pharma, Pierre Fabre, Schering Plough, Preglem, Pantarhei Bioscience,
Serono, and Wyeth, is a senior consultant at the Population Council
(New York), and is a member of the International Committee on Contra-
ceptive Research. N.C-B. has been investigator in studies funded by the
following companies: HRA Pharma, Organon, Theramex. B.C.J.M.F.
has received fees and grant support from the following companies:
Andromed, Ardana, Ferring, Genovum, Glycotope, Merck, Merck
Serono, Organon, Pantharei Bioscience, Philips, Preglem, Schering,
Schering Plough, Serono, and Wyeth.
Editorial assistance was provided by Adelphi Communications, supported
by PregLem SA.
Reprint requests: Philippe Bouchard, Service d’Endocrinologie, Ho ^ pital
Saint Antoine 184 rue du Faubourg Saint Antoine 75012 Paris, France
(E-mail: philippe.bouchard@sat.aphp.fr).
tion of the female reproductive system, including during pregnancy
and mammary gland development (1). Progesterone mediates its
function by interacting with the progesterone receptor (PR), a mem-
ber of a superfamily of almost 50 ligand-activated nuclear transcrip-
tion factors, which can be divided into six subfamilies (2). Other
members of this large family of receptors include the glucocorticoid,
androgen, estrogen, thyroid hormone, and retinoic acid receptors.
The profound importance of progesterone in the female reproduc-
tive system has led to the development of synthetic PR ligands with
both agonistic and antagonistic properties. The first PR antagonist to
be identified was RU486 (mifepristone), discovered in 1980 by
Teusch et al. at Roussel during their research on antiglucocorticoid
agents (3). This discovery was followed by the development of other
steroidal progesterone ligands, while nonsteroidal PR ligands have
been identified more recently (4). In general, PR ligands with mixed
activity act as agonists and/or antagonists in a tissue-specific man-
ner. These compounds therefore have great potential in a number
of gynecologic indications. This review will summarize what is cur-
rently known about the mechanism of action of such molecules, their

0015-0282/$36.00 Fertility and Sterility Vol. 96, No. 5, November 2011 1175
doi:10.1016/j.fertnstert.2011.08.021 Copyright ª2011 American Society for Reproductive Medicine, Published by Elsevier Inc.
effects on tissues of the reproductive system, and the data demon-
strating their potential efficacy for gynecologic indications.
MATERIALS AND METHODS
A PubMed search for relevant publications from 2005 onward was per-
formed, using the following search strategy: ‘‘sprm OR progesterone receptor
modulator OR asoprisnil OR J867 OR mifepristone OR onapristone OR
mixed profile progestagen OR ulipristal OR CDB-2914 OR VA2914 OR
CDB2914 OR CDB-4124 OR CDB4124.’’ The titles of the 1,548 articles
identified in this search were manually screened to identify those publica-
tions containing relevant information. Final searches using the following
search terms were performed without any date restrictions to ensure no rel-
evant publications had been missed (n denotes number of publications iden-
tified): ‘‘CDB-2914 OR VA2914 OR CDB2914’’ (n ¼ 46); ‘‘CDB-4124 OR
CDB4124’’ (n ¼ 11); ‘‘asoprisnil OR J867’’ (n ¼ 39); ‘‘sprm OR progester-
one receptor modulator’’ (n ¼ 298). Additional relevant articles were identi-
fied from citations within all publications identified. In addition, information
about selective progesterone receptor modulators (SPRMs) in clinical or pre-
clinical development was obtained using Citeline Pipeline (Informa Health-
care). This review focuses on articles published since 2005 because trials
before 2005 were previously reviewed elsewhere (5–7).
PROGESTERONE AND THE PROGESTERONE RECEPTOR
Within the female reproductive system, the key function of proges-
terone is to establish and maintain pregnancy (8, 9). Progesterone
plays a crucial role in breast differentiation and antagonizes the
proliferative effects of estradiol on the endometrium, while
allowing the expression of genes involved in embryo implantation
(8, 10, 11). During pregnancy, progesterone secretion is associated
with quiescence of the myometrium, and its decrease during labor
is one of the signals for delivery (9).
Progesterone has long been known to bind to the PR, inducing
conformational changes leading to binding of the progesterone–
PR protein complex to progesterone response elements in the pro-
moters of target genes. Once bound to the target genes, the proges-
terone–PR complex interacts with coactivators, leading to
transcription of the target genes (12, 13) (Fig. 1A). Confirmation
that progesterone mainly mediates reproductive functions via inter-
action with the PR has come from analysis of mice homozygous for
disruption of the PR gene (16). Adult female mice lacking the PR
demonstrate a complete absence of ovulation, uterine hyperplasia
and inflammation, a lack of mammary gland development, and an
inability to display appropriate sexual behavior (16). Two main
PR isoforms have been described, which have distinct biologic ac-
tivities and target genes. The PR-A isoform is similar to the PR-B
isoform except that the PR-A form lacks the 164 N-terminal amino
acids found in PR-B (17, 18). PR-A appears to be a dominant inhib-
itor of PR-B (19). Specific deletion of PR isoforms has provided ad-
ditional information on their roles in mice. While PR-A controls
estrogen induced endometrial proliferation, PR-B mediates mam-
mary gland epithelium proliferation and differentiation (20, 21).
Although it is clear that the tissue ratio of PR-A/PR-B is crucial
for the SPRM effect, it should be noted that the relevance of these
isoforms in terms of SPRM efficacy in vivo is still uncertain, partic-
ularly as all SPRMs bind to both isoforms, which share identical
ligand-binding domains. Therefore, the physiologic relevance of
these in vitro findings remains hypothetical. However, unbalanced
PR-A/PR-B ratios have been observed in breast and endometrial
cancer (22, 23). Progesterone is also thought to play
a reproductive role as a neuroendocrine switch in the brain by
attenuating the pulsatile release of gonadotropin-releasing hormone,
which plays a part in regulating the luteinizing hormone surge (24).
1176 Bouchard et al. SPRMs in reproductive medicine
Selective Progesterone Receptor Modulators
The PR ligands can possess activity ranging from pure agonist activ-
ity through mixed agonist/antagonist activity to pure antagonist ac-
tivity. The McPhail test, in which the progestational activity of
a substance is tested in estrogen-primed immature rabbits, remains
the standard test for determining the PR agonist/antagonist activity
of a compound (25, 26). However, while the McPhail test is
informative, it is apparently unable to distinguish between minor
differences in PR antagonistic activity. Using the McPhail test,
mifepristone is characterized as a ‘‘pure’’ antagonist (26). Current
distinctions, based on traditional model systems, between molecules
with apparently antagonistic functions and those with a mixed pro-
file may be somewhat imprecise. Indeed, all SPRMs potentially
block ovulation and have similar effects on leiomyoma growth
and endometrial changes. In addition, their effect on the uterus dif-
fers from those described in mice, where deletion of PR genes leads
to pure endometrial hyperplasia (16). However, subtle differences
have been described in terms of endometrial changes, which may re-
flect the relative influence of the agonist and antagonist actions.
These more subtle differences make it difficult to compare dose re-
sponse effects between different agents. A new classification ap-
proach based on transcriptional activity in vitro has recently been
suggested (27). This approach appears to refine the classification
of PR ligands, demonstrating the unique activity of each SPRM.
In this review, the term selective progesterone receptor modulator
(SPRM) will be used to describe all PR ligands that show some degree
of cell and tissue context-dependent agonistic and antagonistic activ-
ity (28). Among all SPRMs studied, mifepristone, the pioneer drug,
somehow remains a separate entity because its properties as an antag-
onist are unique and because mifepristone is the only SPRM that is
able to interrupt pregnancy in several species, including humans.
Molecular Mechanism of Action of SPRMs
Like progesterone, SPRM molecules interact with the PR, allowing
the binding of PR dimers to target gene promoters. However, the
conformation induced by each SPRM promotes interaction of the
PR with not only coactivators but also corepressors, leading to
mixed agonist/antagonist activity depending on their structure and
the relative tissue concentrations of these comodulators (29) (see
Fig. 1B). Limited information is available regarding the specific af-
finities of different SPRMs for the PR, and the differential interac-
tion of SPRMs with the PR-A and PR-B isoforms. However, it has
been demonstrated that activation of transcription induced by
a PR-B–bound SPRM may not involve binding to canonical hor-
mone responsive elements and can be inhibited by PR-A in HeLa
cells (31). Moreover, the activities of PR isoforms are differentially
modulated by SPRMs in breast cancer cell lines (32). In addition,
coregulator shuttling and degradation is a crucial step in PR-
mediated transcriptional activity; the PR agonist R5020 induces
this recycling phenomenon, but mifepristone does not, and even fur-
ther impairs the agonist-induced SRC1 degradation (33). Finally, PR
isoforms have also been shown to have distinct affinities for different
coregulators (19), a mechanism that may also be involved in the bi-
ologic action. However, the physiologic relevance of these different
regulatory mechanisms has not been confirmed in vivo thus far.
Several SPRMs developed to date can interact with steroid recep-
tors other than the PR to a greater or lesser extent (34). For example,
mifepristone binds to the glucocorticoid receptor (GR) with an affin-
ity three to four times higher than that of dexamethasone and conse-
quently may be of therapeutic value in the treatment of Cushing
syndrome (35). In contrast, most other SPRMs bind weakly to the
Vol. 96, No. 5, November 2011
 FIGURE 1
Mechanism of action of progesterone and selective progesterone receptor modulators (SPRMs). (A) After entering the cytoplasm of the target
cell, progesterone binds to the progesterone receptor (PR) which causes a conformational change in the PR, resulting in the dissociation of
chaperone proteins, PR dimerization, and binding of the progesterone–PR protein complex to progesterone response elements in the
promoters of target genes. Two major different isoforms of PR (PR-A and PR-B) exert different gene selective biological activities. This allows
the progesterone–PR protein complex to interact with coactivators, facilitating communication with the basal transcription apparatus and
ultimately leading to transcription of the target gene (12, 13). Steroid hormone receptors, including the PR, can also activate nongenomic
signaling pathways in the absence of steroid hormone (14, 15). (B) Interaction of SPRMs with the progesterone receptor isoforms (PR-A/B)
induces a conformational change in the PR, which allows a more potent recruitment of corepressors (such as nuclear receptor corepressor
(NCoR) and silencing mediator of retinoid and thyroid hormone receptor [SMRT]) to the PR than that induced by progesterone. However,
under these conditions the PR ligand-binding domain can also interact with the coactivators SRC-1 and AIB1 (29). As the precise
conformational change induced in the PR, and thus the balance of interaction with coactivators and corepressors depends upon the identity of
the individual SPRM molecule to which the PR is bound, each SPRM has a different and unique molecular signature (7, 28–30). Furthermore,
the precise activity of each SPRM will vary by tissue, depending on the relative levels of coactivators and corepressors in each cellular
environment.

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

GR (26, 36, 37). Nonsteroidal SPRMs, which may be more selective
for the PR, are also in development (34, 38, 39). More recently,
a class of SPRMs, called mixed-profile progestogens, has been de-
scribed. These compounds are reported to have more agonistic activ-
ity than the currently described SPRMs (40).
Major SPRMs Currently Available and Currently in
Development
The properties of selected SPRMs in clinical development and those
that have shown promise in preclinical or clinical research studies
are summarized in Table 1. The chemical structures are shown in
Figure 2. Although a large number of SPRMs have been identified,
only a few are being pursued for clinical use at present, and only two
are currently licensed for gynecologic use. Mifepristone has been
approved in more than 30 countries for the termination of pregnancy,
cervical dilation, medical termination of pregnancy during the sec-
ond trimester, and fetal death in utero (41, 42), and a single dose of
ulipristal acetate (30 mg) has been launched in Europe and the
United States as an emergency contraceptive.
SPRMS AS CONTRACEPTIVES
The critical role of progesterone in ovulation and preparing the en-
dometrium for implantation suggests that SPRMs may have poten-
tial for use as contraceptives.

Fertility and Sterility 1177

 TABLE 1
Selected major selective progesterone receptor modulators (SPRMs) with current or past development noted in the literature.

Compound Therapeutic applicationa Current status

Mifepristone (RU-486) Termination of pregnancy Launched

Emergency contraception Phase III
Psychosisb Phase III
Cushing diseaseb Phase III
Long-term contraception Phase II
Uterine fibroids Phase II
Endometriosis Phase II
Alzheimer diseaseb Phase II
Endometrial cancer Phase I
Ulipristal acetate (CDB-2914; VA2914) Emergency contraception Launched
Uterine fibroids Phase III
Long-term contraceptionc Phase II
Asoprisnil (J-867) Uterine fibroids Withdrawn
Endometriosis Withdrawn
Long-term contraception Withdrawn
Telapristone acetate (CDB-4124) Uterine fibroids Phase III trials terminated; phase I/II trial initiated
Anemia Phase III trials terminated; phase I/II trial initiated
Endometriosis Phase II trials terminated; phase I/II trial initiated
Lonaprisan (ZK230211) Cancer Phase II
CP8816 and CP8863 Gynecologic disorders Preclinical
WAY-255348 Contraception Preclinical
Onapristone (ZK98299) Endometriosis No development since the 1990s
Cancer No development since the 1990s
ORG-31710 and ORG-31806 Contraception Preclinical; no development since the 1990s
Cancer Preclinical; no development since the 1990s
PF-2413873 Endometriosis Discontinued
ZK137316 Contraception Discontinued
a
Including licensed uses and those for which the drug has undergone trials or for which it has or had been marked for development.
b
Indications in development due to antiglucocorticoid activity of mifepristone.
c
Using a vaginal ring formulation.

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

Rationale interfere with blastocyst attachment (59). The short-term adminis-

Ovulation is blocked in women receiving mifepristone continu-
ously at daily doses of 2 mg or more (43), and high rates of an-
ovulation are observed in women treated with daily ulipristal
acetate, 5 mg or 10 mg (44). In contrast, although asoprisnil pro-
longs the menstrual cycle in a dose-dependent manner, its effect
on ovulation is inconsistent and does not show dose dependency
(45). At high doses, continuous administration of mifepristone
can suppress follicular development in addition to preventing
ovulation (46, 47).
It is important, however, that despite their effects on ovula-
tion, SPRMs do not result in the down-regulation of ovarian es-
trogen levels, allowing estrogen concentrations to remain within
physiologic levels (43–51). Administration of a single dose of
mifepristone or ulipristal acetate also delays ovulation (52–56),
a property that allows the use of these compounds for
emergency contraception.
Studies in baboons and humans have demonstrated that single
doses of CDB 2914 or ZK 137-316 also alter endometrial develop-
ment (49, 57). Moreover, short treatment of the endometrium with
mifepristone or ORG-31710 can inhibit blastocyst attachment
(58, 59) in ex vivo endometrial culture models. This may be
related to the down-regulation of endometrial receptivity markers
(60). Longer term treatment with ORG-31710 in the ex vivo baboon
endometrial culture model did not induce modifications that could
tration of SPRMs for emergency contraception may induce a specific
endometrial effect as compared with a progestin used for the same
purpose (58). This effect has not been documented during long-
term administration.
Clinical Studies
Emergency contraception Many clinical data exist to support the
use of SPRMs as contraceptives. Key trials in this area from 2005
onward are summarized in Table 2; trials before 2005 have been
reviewed previously elsewhere (5, 6). A number of large studies
have demonstrated the efficacy of mifepristone for emergency
contraception (see Table 2), and a recent meta-analysis encompass-
ing 45,842 women has confirmed that middle- or low-dose
mifepristone is more effective for emergency contraception than lev-
onorgestrel (81). A single 30-mg dose of ulipristal acetate is also
very effective as an emergency contraceptive, with a longer duration
of effect (120 hours) than levonorgestrel (61, 63). Ulipristal acetate
has been approved for emergency contraception in 29 countries thus
far, and is commercially available in 25 of them.
Long-term contraception Development of SPRMs for long-term
contraception is less advanced, but several trials have shown that
mifepristone administered either daily or weekly can be an effective
contraceptive, while ulipristal acetate (5 mg or 10 mg daily) induces

1178 Bouchard et al. SPRMs in reproductive medicine Vol. 96, No. 5, November 2011

FIGURE 2
Chemical structures of progesterone, norethindrone, and selected
selective progesterone receptor modulators.
Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.
anovulation in most women. The potential of asoprisnil for
long-term contraception is less clear (see Table 2). The use of
SPRMs for long-term contraception is of great interest as it would
provide an estrogen-free method. However, the use of SPRMs for
this indication cannot progress until the long-term effects of SPRMs
on the endometrium have been clarified.
Mifepristone for termination of pregnancy Mifepristone is the only
SPRM used for pregnancy termination because of its unique ability
to terminate pregnancy in women. Other SPRMs have not been stud-
ied for this indication (26). A wealth of published data describes the
efficacy of mifepristone at doses between 200 mg and 600 mg, fol-
lowed by a prostaglandin, for the medical termination of pregnancy.
Fertility and Sterility
These reports include a number of review articles (41, 82–84), which
will not be duplicated here. It should also be noted that mifepristone
is not effective for the termination of pregnancy alone, but only in
combination with a prostaglandin (82).
SPRMS FOR THE TREATMENT OF ENDOMETRIOSIS
Endometriosis—the growth of endometrial glands and stroma out-
side of the uterus (85, 86)—has been estimated to be present in up
to 10% of women of reproductive age and represents a significant
cause of pelvic pain and infertility (87, 88). The only definitive,
long-term treatment for endometriosis is abdominal hysterectomy
with removal of ovaries and all visible endometriosis (85). Such
radical therapy is clearly not appropriate for women who have
not completed their families. Medical treatments usually include
oral contraceptives, progestins, or gonadotropin-releasing hor-
mone (GnRH) agonists. However, these two latter therapies
suppress estrogen secretion and therefore induce a significant de-
crease in bone mass in addition to hot flushes and vaginal dryness,
which impair the quality of life of those women receiving the
treatments (88).
Rationale
An ideal medical therapy for endometriosis should be able to ame-
liorate pain and suppress endometrial proliferation while avoiding
a hypoestrogenic state. A wealth of data has demonstrated that
SPRMs inhibit endometrial proliferation. In nonhuman primates,
a number of SPRMs, including ulipristal acetate, asoprisnil, PRA-
910, and onapristone suppress endometrial proliferation, resulting
in endometrial atrophy (48, 89–91). Similar suppression has been
described in human cell lines after treatment with ulipristal
acetate or mifepristone (92, 93), and in subjects treated with
SPRMs including asoprisnil, lonaprisan, mifepristone, or
telapristone acetate (50, 94, 95, 96–98). Further evidence for the
potential of SPRMs in endometriosis comes from the suppression
of endometriotic lesions in animal models by mifepristone,
onapristone, and ZK136799 (99, 100). Moreover, some SPRMs
can suppress endometrial prostaglandin production in mammalian
model systems (26, 101, 102), potentially reducing endometrial-
associated pain. The relevance of these nonhuman models remains
uncertain because SPRMs do not behave similarly in terms of endo-
metrial effects in nonhuman primates and in women (7).
Clinical Studies
A small number of clinical studies have demonstrated that SPRMs
and PR antagonists have potential for the treatment of endometri-
osis. Mifepristone at 50 mg daily has been shown to improve pain
and cause regression of endometriosis (103), although a lower
dose of 5 mg daily is unable to control the growth of endometriotic
lesions (104). Mifepristone-loaded subcutaneous implants may also
be an effective treatment for endometriosis (105). Asoprisnil and te-
lapristone acetate have also been reported to relieve pain associated
with endometriosis (7, 106, 107). These beneficial effects of SPRM
treatment may reflect changes in the endometrial morphology and/or
the absence of bleeding. However, the potential consequences of
progesterone receptor modulator-associated endometrial change
(PAEC) formation on endometriotic lesions remain unknown, and
long-term treatment of endometriosis with SPRMs will have to
wait until the long-term effect of SPRMs on the endometrium are de-
termined. In the future, intermittent treatment regimens with SPRMs
might be appropriate (107).
1179
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TABLE 2
Key clinical trials since 2005 describing the use of selective progesterone receptor modulators (SPRMs) for contraception and uterine leiomyomata.
Bouchard et al.

Treatment Treatment
Study Design and dose n duration/timing Key results

Contraception
Ulipristal acetate
Emergency contraception
Creinin et al., 2006 (61) R, DB %72 h after unprotected Pregnancy rate, %
intercourse
Ulipristal acetate (1  50 mg) 775 0.9
SPRMs in reproductive medicine

Levonorgestrel (2  0.75 mg) 774 1.7

Arms had similar side
effect profiles
Fine et al., 2010 (62) OL Ulipristal acetate (1  30 mg) 1,241 48–120 h after unprotected 2.1% pregnancy rate (satisfies
intercourse the protocol-defined statistical
criteria for success)
Mainly mild or moderate AEs
Glasier et al., 2010 (63) R, SB %120 h after unprotected Pregnancy rate, %
intercourse
Ulipristal acetate (1  30 mg) 1,104 1.8
Levonorgestrel (1  1.5 mg) 1,117 2.6
Arms had similar AE frequency
Two serious AEs were judged
possibly treatment-related;
dizziness (ulipristal acetate)
and a molar pregnancy
(levonorgestrel)
Long-term contraception (ovulation)
Chabbert-Buffet R, PC, DB 84 d Anovulation rate, % (P value
et al., 2007 (44) vs. placebo)
Placebo 11 0
Ulipristal acetate (2.5 mg daily) 11 9.1 (P¼NS)
Ulipristal acetate (5 mg daily) 11 81.8 (P< .001)
Ulipristal acetate (10 mg daily) 10 80.0 (P< .001)
General and gynecologic
safety data were
satisfactory
Vol. 96, No. 5, November 2011

Mifepristone
Emergency contraception
Jin et al., 2005 (64) R, DB %120 h after unprotected Pregnancy rate, %
intercourse
Mifepristone (1  10 mg) 49 2.0
Mifepristone (1  50 mg) 47 2.1
Mifepristone (1  600 mg) 48 2.1

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

Fertility and Sterility

TABLE 2
Continued.

Treatment Treatment
Study Design and dose n duration/timing Key results

Esteve et al., 2007 (65) OL Mifepristone (1  10 mg) 635 %144 h after unprotected 1.1% pregnancy rate
intercourse Acceptable profile of side effects
Taneepanichskul, 2009 (66) OL Mifepristone (1  10 mg) 120 %120 h after unprotected 0 pregnancy rate
intercourse Few side effects
Wu et al., 2010 (67) R, DB %72 h after unprotected Pregnancy rate, %
intercourse
Mifepristone (1  10 mg) 499 1.8
Gestrinone (1  10 mg) 499 2.4
No difference in side effects
between arms
Long-term contraception
Lakha et al., 2007 (68) R, DB 24 wk Pregnancy rate, %
Mifepristone (5 mg daily) 73 0.6
Levonorgestrel (0.03 mg daily) 23 1.2
There were no major AEs
in either group
Pei et al., 2007 (69) R, DB 24 wk Pregnancy rate, %
Mifepristone (25 mg weekly) 39 0
Mifepristone (50 mg weekly) 37 0
83 Side effects were uncommon
and mild
Agarwal et al., 2009 (70) OL 2–12 mo Pregnancy rate, %
Mifepristone (200 mg monthly) 80 0.2
Combined oral contraceptive 83 1.0
(COC) daily
Significantly fewer side
effects in the mifepristone
vs COC group (P¼ .001)

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

1181
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TABLE 2
Continued.
Bouchard et al.

Treatment Treatment
Study Design and dose n duration/timing Key results

Asoprisnil
Long-term contraception
Chwalisz K et al., 2005 (45) DB, PC 28 d Anovulation rate, % (measured by
progesterone levels <3.5 ng/mL
during treatment)
Placebo 12 8.3
SPRMs in reproductive medicine

Asoprisnil (5 mg daily) 8 12.5

Asoprisnil (5 mg twice daily)
Asoprisnil (10 mg daily)
Asoprisnil (25 mg daily)
Asoprisnil (25 mg twice daily)
Asoprisnil (50 mg daily)
8 62.5
8 50.0
8 37.5
8 37.5
8 87.5
Asoprisnil was well tolerated

Treatment Treatment
Study Design and dose n duration/timing Key results

Uterine leiomyomata
Ulipristal acetate
Levens et al., 2008 (51) R, DB, PC 3 cycles or Change in leiomyoma Amenorrhea during cycle
90–102 d volume (%) 3 (% women)
Placebo 8 þ6 0
Ulipristal acetate (10 mg daily) 8 36 87.5
Ulipristal acetate (20 mg daily) 6 21 100.0
Ulipristal acetate was well tolerated
Nieman et al., 2011 (71) R, DB, PC 3 cycles or Change in leiomyoma Amenorrhea during
90–102 d volume (%) treatment (% women)
Placebo 12 þ7 0
Ulipristal acetate (10 mg daily) 13 17 61.5
Ulipristal acetate (20 mg daily) 13 24 92.0
Ulipristal acetate was well tolerated
Asoprisnil
Chwalisz et al., 2007 (50) R, DB, PC 12 wk Median change in uterine Amenorrhea (% women)
volume (%)
Vol. 96, No. 5, November 2011

Placebo 31 þ1 0
Asoprisnil (5 mg daily) 33 14 16
Asoprisnil (10 mg daily) 29 9 36
Asoprisnil (25 mg daily) 36 17 70
Asoprisnil was well tolerated

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

Fertility and Sterility

TABLE 2
Continued.

Treatment Treatment
Study Design and dose n duration/timing Key results

Wilkens et al., 2008 (72) R, DB, PC 12 wk Median change in largest Average number of
leiomyoma volume, % bleeding days
in cycle 3
Placebo 10 þ4.9 7.3
Asoprisnil (10 mg daily) 12 0.4 1.2
Asoprisnil (25 mg daily) 11 25.8 0.2
Asoprisnil was well tolerated
Telapristone acetate
Wiehle et al., 2008 (73) R, DB, PC 3 mo Mean change in leiomyoma volume, %
Placebo 10.6
Telapristone acetate (12.5 mg daily) 17.9
Telapristone acetate (25 mg daily) 40.3
Telapristone acetate (50 mg daily) 40.3
Lupron (3.75 mg monthly) 32.6
Mifepristone
Eisinger et al., 2005 (74) R, OL 1y Change in mean uterine Amenorrhea at 1 y
volume at 1 y, % (% women)
Mifepristone (5 mg daily) 52 75
Mifepristone (10 mg daily) 53 40
1 patient in the mifepristone 10 mg group showed simple
hyperplasia at 1 y
Fiscella et al., 2006 (75) R, PC 26 wk Mean change in uterine volume, % Amenorrhea at 26 wk
(% women)
Placebo 20 þ10 0
Mifepristone (5 mg daily) 22 47 41
No statistically significant differences in adverse events
between treatment groups
Carbonell Esteve et al., R 3 mo Change in leiomyoma volume, % Amenorrhea during
2008 (76) cycle 3 (% women)
Mifepristone (5 mg daily) 50 57 90.0
Mifepristone (10 mg daily) 49 45 89.8
1 patient in the mifepristone 10 mg group showed simple
hyperplasia
Bagaria et al., 2009 (77) R, DB, PC 3 mo Median change in leiomyoma Amenorrhea during cycle
volume, % 3 (% women)
Placebo 20 þ0.5 0
Mifepristone (10 mg daily) 20 30.2 84.2
63.1% of mifepristone-treated patients with endometrial
hyperplasia without atypia diagnosis

Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

1183
 SPRMS FOR THE TREATMENT OF DYSFUNCTIONAL
UTERINE BLEEDING

Amenorrhea during months

Change in health-related
Some studies have suggested that SPRMs may be able to control

Cystic glandular dilation, but no endometrial hyperplasia or atypia

3 and 6, respectively
uterine bleeding via a direct effect on endometrial blood vessels

65 and 32

quality of life, %
(45, 72, 108, 109), as amenorrhea in patients receiving SPRMs

þ40.9
þ123.4
12
34
does not appear to depend on inhibition of ovulation in all cases

(% women)
(45, 72). The mechanism of the amenorrhea observed after SPRM
treatment is still poorly understood (110). Suppression of bleeding

No premalignant changes
in women with uterine fibroids treated with SPRMs has been shown
to be associated with a moderate reduction in uterine artery blood
flow, without major changes in angiogenic factors and extracellular
Key results

Mean change in leiomyoma volume, %

matrix composition (72). This is a clear difference to the modifica-
tions observed after progestin administration (72, 110, 111).
Furthermore, intrauterine administration of the SPRM ZK230211
Change in uterine volume, %
in women scheduled for hysterectomy due to menorrhagia or

Note: AE ¼ adverse event; DB ¼ double-blind; NS ¼ not statistically significant; OL ¼ open label; PC ¼ placebo-controlled; R ¼ randomized; SB ¼ single-blind.
dysmenorrhea resulted in a reduced number of days with bleeding
Mean change in uterine

þ17.7
17.6
and spotting compared with intrauterine administration of
volume (%) at 6 mo

11

28
þ6

levonorgestrel (96). Finally, women experiencing breakthrough

bleeding during progestin treatment show a clear improvement in
bleeding pattern following SPRM administration (112, 113).

SPRMS FOR THE TREATMENT OF UTERINE FIBROIDS

Uterine leiomyomata arise from the smooth muscle cells of the
myometrium (114, 115). Despite their benign status, uterine
leiomyomata can cause debilitating symptoms, including
duration/timing
Treatment

menorrhagia, abdominal pain, and infertility (114–116). There is

6 mo

3 mo

6 mo

still much debate regarding the etiology of uterine leiomyomata,

with genetics, hormones, and growth factors all thought to play
a part (114). It is, however, likely that progesterone and the PR
have key roles in their development (117–125), and it has been
shown that PR–ligand complexes reduce apoptosis and increase
23

16
14

19
43
n

proliferation of leiomyoma cells (116). Traditionally, the favored

treatment for uterine leiomyoma has been hysterectomy or myomec-
tomy, with more modern, less invasive therapies including uterine
Mifepristone (2.5 or 5 mg daily)

artery embolization, high-intensity focused ultrasound, and uterine

artery ligation. Available pharmacologic therapies are limited but in-
Mifepristone (2.5 mg daily)

clude GnRH agonists and antagonists, oral contraceptives, and pro-

Treatment
and dose

gestins (115, 126).

Mifepristone (50 mg
every other day)

Rationale
The apparent importance of progesterone for the growth and devel-
Placebo

Placebo

opment of uterine leiomyoma suggests that SPRMs may be an effec-

tive treatment. Accordingly, treatment of cultured leiomyoma cells
with ulipristal acetate, telapristone acetate, or asoprisnil results in
Bouchard. SPRMs in reproductive medicine. Fertil Steril 2011.

inhibition of proliferation (120, 127–129) and induction of the

Partially R, PC

endoplasmic reticulum stress-induced (130), intrinsic (120, 127,

Design

129), or extrinsic (131) apoptosis pathways. In contrast, these agents

have no effect on the proliferation or apoptosis of normal myome-
R, PC

trial cells (120, 127–129, 131). Asoprisnil and ulipristal acetate

OL

have also been shown to down-regulate a number of growth factors

and their receptors in cultured leiomyoma cells (132, 133). In
Engman et al., 2009 (79)
Eisinger et al., 2009 (78)

addition, both asoprisnil and ulipristal acetate can reduce collagen

Feng et al., 2010 (80)

synthesis in cultured leiomyoma cells through up-regulation of the

extracellular matrix metalloproteinase inducer (134, 135).

Clinical Studies
Continued.

A number of clinical trials have investigated the efficacy and safety of

TABLE 2

SPRMs as a treatment for uterine leiomyoma. Trials before 2005 have

Study

been reviewed previously elsewhere (6, 7, 107), and key trials from
2005 onward are summarized in Table 2. Studies have demonstrated
that mifepristone, ulipristal acetate, asoprisnil, and telapristone acetate

1184 Bouchard et al. SPRMs in reproductive medicine Vol. 96, No. 5, November 2011
are all effective at reducing leiomyoma and uterine volume. Leio-
myoma volumes are reduced by 17% to 57% and uterine volume by
9% to 53% during treatment with SPRMs, compared with general in-
creases in volume in patients receiving placebo (see Table 2). In
contrast to GnRH agonist therapy, these SPRMS are also able to sup-
press bleeding rapidly in women with uterine leiomyomata, without
suppressing estrogen secretion, with the majority of women experi-
encing amenorrhea during treatment with ulipristal acetate, asoprisnil,
or mifepristone (see Table 2). Moreover, a number of trials reported an
improvement in quality of life measures for women receiving
ulipristal acetate, asoprisnil, or mifepristone (51, 71, 72, 75, 78, 80).
EFFECT OF SPRMS ON BREAST TISSUE
It is thought that progesterone drives mitotic activity—which peaks
during the luteal phase—in normal, adult breast tissue, with proges-
tins able to stimulate proliferation of breast cancer cells and enhance
their invasiveness (136, 137). Importantly, treatment of Brca1/p53 –/–
deficient mice with mifepristone prevents mammary tumorigenesis
(138). The potential role that SPRMs may play in preventing or
treating breast cancer has been reviewed previously elsewhere
(139) and lies outside the scope of this article. However, it is also im-
portant to understand the effect that SPRMs may have on normal
breast tissue.
Although limited data describing the activity of SPRMs in normal
breast tissue are available, it appears that SPRMs have an antiproli-
ferative effect in a number of systems. Exposure of mammary glands
from progesterone-primed virgin mice to ZK114043 led to a reduc-
tion in epithelial cell proliferation and differentiation of alveolar
cells (140). In primates, too, treatment with asoprisnil or mifepris-
tone results in antiproliferative effects in breast tissue (48, 141),
and the antiproliferative effects of mifepristone have been
described in the normal human breast (141). These data suggest
that treatment with SPRMs may lower the risk for breast cancer, al-
though further studies are necessary to investigate this potentially
beneficial effect.
PROGESTERONE RECEPTOR MODULATOR-ASSOCIATED
ENDOMETRIAL CHANGES
Previously, there was some concern regarding the endometrial
changes induced by medium- to long-term (3 to 6 months) continuous
daily dosing of mifepristone (2 to 200 mg daily) and asoprisnil
(142–144). These unusual changes are characterized by dilated,
weakly secretory endometrial glands with few mitotic figures, and
stromal effects ranging from compaction to nonuniform edema (45,
50, 74, 78). However, a panel of expert pathologists—convened
to examine these novel changes—concluded that the changes
revealed nothing that should be considered a safety concern (145).
It is clear that modifications to the diagnostic criteria are required
to describe these unusual changes, which have been termed proges-
terone receptor modulator-associated endometrial changes (PAECs)
(146). Short-term studies of asoprisnil, ulipristal acetate, and telapri-
stone acetate have confirmed the absence of endometrial hyperplasia
in all subjects when pathologic review encompasses the spectrum of
PAECs (72, 94, 95, 147). However, long-term studies are needed,
especially if SPRMs are to be used for more than 3 months.
SAFETY OF LONG-TERM TREATMENT WITH SPRMS
Liver Toxicity
The most concerning side effect reported in patients treated with
SPRMs is the elevation of liver enzymes in patients receiving telap-
ristone acetate (50 mg), which led to suspension of the phase 3 trials
Fertility and Sterility
of this drug in patients with uterine fibroids (148, 149). Clinical trials
with this drug have restarted employing lower doses (150). The de-
velopment of another SPRM, onapristone, was also halted due to
liver toxicity (151). For other SPRMs, only mild and transient eleva-
tion of transaminases has been reported (50, 51, 71, 76, 79). Because
liver toxicity has not been reported as a feature of mifepristone,
asoprisnil, or ulipristal acetate, it may be that the liver toxicity of
telapristone acetate and onapristone is specific to their structure,
and/or the pathways by which telapristone acetate and onapristone
are metabolized, rather than being a class effect. Possibly, the
ethanol-like 1-hydroxyalkyl moiety present in onapristone—and
likely to be formed during metabolic degradation of telapristone—
will be further transformed into hydroxyl alkyl radical-forming
adducts (152).
Ovarian Cysts
There have been a number of reports suggesting that ovarian cysts
are more common in women treated with SPRMs. However, the
cysts—which probably arise from abnormal ovulation—are gener-
ally small, asymptomatic, and resolve without treatment (44, 45,
49, 50, 68, 153).
Prolactin Levels
Two studies of ulipristal acetate in women with uterine fibroids have
shown prolactin levels to be mildly elevated during treatment in
some women; elevations were transient in most cases, and none
was considered a serious adverse event (51, 71). Another study of
ulipristal acetate (44) and studies of mifepristone and asoprisnil
(45, 79) reported no effect of SPRM treatment on prolactin levels.
Bone Mineral Density
Other hormonal therapies, such as GnRH agonists, cause loss of
bone mineral density due to hypoestrogenic effects. In contrast,
SPRMs maintain physiologic levels of estrogen (43–51) and thus
maintain bone mineral density (99, 103).
CONCLUSION
The SPRMs are PR ligands that display molecule- and tissue-
specific interactions with coactivators and corepressors, leading to
mixed agonist and antagonist activity. Although each SPRM has
a different molecular signature, SPRMs all have very similar effects
on the reproductive system, blocking ovulation, inducing nonphy-
siologic endometrial changes, suppressing bleeding, and reducing
the size of uterine leiomyoma. Nonetheless, differences are also ap-
parent, with mifepristone being the only SPRM to carry significant
abortifacient activity and a far higher affinity for the GR than other
SPRM molecules.
Expectations for the Future
The SPRMs are presently approved for emergency contraception
(ulipristal acetate) and for termination of pregnancy (mifepristone,
in association with prostaglandins). They are currently in develop-
ment for a number of different gynecologic applications, including
estrogen-free contraception, uterine leiomyoma, and eventually
treatment of endometriosis. There is also the prospect that SPRMs
could be used before surgery to facilitate leiomyoma surgery and im-
prove surgical outcomes. Currently, GnRH agonists are often used in
this capacity and have been shown to improve preoperative and post-
operative hemoglobin levels and hematocrit, reduce the proportion
of hysterectomies with difficult surgery, reduce the invasiveness of
1185
the surgical technique used, and reduce the duration of hospital stay
(154, 155). However, this treatment takes several weeks to become
effective and induces low estrogen levels and hot flushes.
The next step on the path to enabling SPRMs to achieve their
full potential as a novel and much-needed therapy is to demon-
REFERENCES
1. Rocha A, Soares R. Unraveling progesterone-
induced molecular mechanisms in physiological
and pathological conditions. Curr Clin Pharmacol
2009;4:148–53. 18.
2. McEwan IJ. Nuclear receptors: one big family.
Methods Mol Biol 2009;505:3–18.
3. Philibert D. RU 38486: an original multifaceted
antihormone in vivo. In: Agarwal M, ed. Adrenal
steroid antagonism. Berlin: Walter de Gruyter; 19.
1984;77–101.
4. Allan GF, Sui Z. Non-steroidal progesterone recep-
tor specific ligands. Mini Rev Med Chem 2005;5:
701–8.
5. Chabbert-Buffet N, Ouzounian S, Kairis AP, 20.
Bouchard P. Contraceptive applications of proges-
terone receptor modulators. Eur J Contracept Re-
prod Health Care 2008;13:222–30.
6. Chabbert-Buffet N, Meduri G, Bouchard P, 21.
Spitz IM. Selective progesterone receptor modula-
tors and progesterone antagonists: mechanisms of
action and clinical applications. Hum Reprod Up-
date 2005;11:293–307.
7. Chwalisz K, Perez MC, Demanno D, Winkel C, 22.
Schubert G, Elger W. Selective progesterone recep-
tor modulator development and use in the treatment
of leiomyomata and endometriosis. Endocr Rev
2005;26:423–38.
8. Conneely OM, Mulac-Jericevic B, DeMayo F, 23.
Lydon JP, O’Malley BW. Reproductive functions
of progesterone receptors. Recent Prog Horm Res
2002;57:339–55.
9. Mesiano S, Welsh TN. Steroid hormone control of 24.
myometrial contractility and parturition. Semin
Cell Dev Biol 2007;18:321–31.
10. Conneely OM, Jericevic BM, Lydon JP. Progester- 25.
one receptors in mammary gland development and
tumorigenesis. J Mammary Gland Biol Neoplasia 26.
2003;8:205–14.
11. Li Q, Kannan A, DeMayo FJ, Lydon JP, Cooke PS,
Yamagishi H, et al. The antiproliferative action of
progesterone in uterine epithelium is mediated by
Hand2. Science 2011;331:912–6.
12. Scarpin KM, Graham JD, Mote PA, Clarke CL. Pro- 27.
gesterone action in human tissues: regulation by
progesterone receptor (PR) isoform expression, nu-
clear positioning and coregulator expression. Nucl
Recept Signal 2009;7:e009.
13. Leonhardt SA, Edwards DP. Mechanism of action of 28.
progesterone antagonists. Exp Biol Med (May-
wood) 2002;227:969–80.
14. Boonyaratanakornkit V, Edwards DP. Receptor
mechanisms mediating non-genomic actions of 29.
sex steroids. Semin Reprod Med 2007;25:
139–53.
15. Blaustein JD. Minireview: neuronal steroid hor-
mone receptors: they’re not just for hormones any-
more. Endocrinology 2004;145:1075–81. 30.
16. Lydon JP, DeMayo FJ, Funk CR, Mani SK,
Hughes AR, Montgomery CA Jr, et al. Mice lacking
progesterone receptor exhibit pleiotropic reproduc-
tive abnormalities. Genes Dev 1995;9:2266–78. 31.
17. Giangrande PH, Pollio G, McDonnell DP. Mapping
and characterization of the functional domains re-
1186 Bouchard et al. SPRMs in reproductive medicine
strate the efficacy and safety of SPRMs both for use presurgically
and for long-term, chronic use. For long-term use, intermittent
treatment regimens may reduce or avoid the need to monitor
for PAECs by ensuring regular and predictable withdrawal
bleeding (107).
sponsible for the differential activity of the A and
B isoforms of the human progesterone receptor. J
Biol Chem 1997;272:32889–900.
Giangrande PH, McDonnell DP. The A and B iso-
forms of the human progesterone receptor: two
functionally different transcription factors encoded
by a single gene. Recent Prog Horm Res 1999;54:
291–314.
Giangrande PH, Kimbrel EA, Edwards DP,
McDonnell DP. The opposing transcriptional activ-
ities of the two isoforms of the human progesterone
receptor are due to differential cofactor binding.
Mol Cell Biol 2000;20:3102–15.
Conneely OM, Mulac-Jericevic B, Lydon JP, De
Mayo FJ. Reproductive functions of the progester-
one receptor isoforms: lessons from knock-out
mice. Mol Cell Endocrinol 2001;179:97–103.
Mulac-Jericevic B, Lydon JP, DeMayo FJ,
Conneely OM. Defective mammary gland
morphogenesis in mice lacking the progesterone
receptor B isoform. Proc Natl Acad Sci USA
2003;100:9744–9.
Arnett-Mansfield RL, DeFazio A, Mote PA,
Clarke CL. Subnuclear distribution of progester-
one receptors A and B in normal and malignant
endometrium. J Clin Endocrinol Metab
2004;89:1429–42.
Mote PA, Bartow S, Tran N, Clarke CL. Loss of co-
ordinate expression ofprogesterone receptors A and
B is an early event in breast carcinogenesis. Breast
Cancer Res Treat 2002;72:163–72.
Chabbert-Buffet N, Skinner DC, Caraty A,
Bouchard P. Neuroendocrine effects of progester-
one. Steroids 2000;65:613–20.
McPhail MK. The assay of progestin. J Physiol
1934;83:145–56.
Elger W, Bartley J, Schneider B, Kaufmann G,
Schubert G, Chwalisz K. Endocrine pharmacologi-
cal characterization of progesterone antagonists
and progesterone receptor modulators with respect
to PR-agonistic and antagonistic activity. Steroids
2000;65:713–23.
Afh€uppe W, Sommer A, M€uller J, Schwede W,
Fuhrmann U, M€oller C. Global gene expression pro-
filing of progesterone receptor modulators in T47D
cells provides a new classification system. J Steroid
Biochem Mol Biol 2009;113:105–15.
Smith CL, O’Malley BW. Coregulator function:
a key to understanding tissue specificity of selec-
tive receptor modulators. Endocr Rev 2004;25:
45–71.
Madauss KP, Grygielko ET, Deng SJ, Sulpizio AC,
Stanley TB, Wu C, et al. A structural and in vitro
characterization of asoprisnil: a selective progester-
one receptor modulator. Mol Endocrinol 2007;21:
1066–81.
Wardell SE, Edwards DP. Mechanisms controlling
agonist and antagonist potential of selective proges-
terone receptor modulators (SPRMs). Semin Reprod
Med 2005;23:9–21.
Tung L, Mohamed MK, Hoeffler JP, Takimoto GS,
Horwitz KB. Antagonist-occupied human proges-
terone B-receptors activate transcription without
binding to progesterone response elements and are
dominantly inhibited by A-receptors. Mol Endocri-
nol 1993;7:1256–65.
32. Leo JC, Lin VC. The activities of progesterone re-
ceptor isoform A and B are differentially modulated
by their ligands in a gene-selective manner. Int J
Cancer 2008;122:230–43.
33. Amazit L, Roseau A, Khan JA, Chauchereau A,
Tyagi RK, Loosfelt H, et al. Ligand-dependent deg-
radation of SRC-1 is pivotal for progesterone recep-
tor transcriptional activity. Mol Endocrinol
2011;25:394–408.
34. Madauss KP, Stewart EL, Williams SP. The evolu-
tion of progesterone receptor ligands. Med Res
Rev 2007;27:374–400.
35. Johanssen S, Allolio B. Mifepristone (RU 486) in
Cushing’s syndrome. Eur J Endocrinol 2007;157:
561–9.
36. Schubert G, Elger W, Kaufmann G, Schneider B,
Reddersen G, Chwalisz K. Discovery, chemistry,
and reproductive pharmacology of asoprisnil and re-
lated 11b-benzaldoxime substituted selective pro-
gesterone receptor modulators (SPRMs). Semin
Reprod Med 2005;23:58–73.
37. Attardi BJ, Burgenson J, Hild SA, Reel JR. 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 Ste-
roid Biochem Mol Biol 2004;88:277–88.
38. Winneker RC, Fensome A, Zhang P, Yudt MR,
McComas CC, Unwalla RJ. A new generation of
progesterone receptor modulators. Steroids
2008;73:689–701.
39. Zhi L. Discovery of structurally diverse nonsteroidal
SPRMs based on a screening hit, 1,2-dihydro-
2,2,4-trimethyl-6-phenylquinolinone. Curr Top
Med Chem 2008;8:766–80.
40. Rewinkel J, Enthoven M, Golstein I, van der RM,
Scholten A, van Tilborg M, et al. 11-(pyridinyl-
phenyl)steroids—a new class of mixed-profile pro-
gesterone agonists/antagonists. Bioorg Med Chem
2008;16:2753–63.
41. Schaff EA. Mifepristone: ten years later. Contracep-
tion 2010;81:1–7.
42. Im A, Appleman LJ. Mifepristone: pharmacology
and clinical impact in reproductive medicine, endo-
crinology and oncology. Expert Opin Pharmacother
2010;11:481–8.
43. Baird DT, Thong KJ, Hall C, Cameron ST. Failure of
oestrogen induced luteinizing hormone surge in
women treated with mifepristone (RU 486) every
day for 30 days. Hum Reprod 1995;10:2270–6.
44. Chabbert-Buffet N, Pintiaux-Kairis A, Bouchard P.
Effects of the progesterone receptor modulator
VA2914 in a continuous low dose on the
hypothalamic-pituitary-ovarian axis and endome-
trium in normal women: a prospective, randomized,
placebo-controlled trial. J Clin Endocrinol Metab
2007;92:3582–9.
45. Chwalisz K, Elger W, Stickler T,
Mattia-Goldberg C, Larsen L. The effects of
1-month administration of asoprisnil (J867), a selec-
Vol. 96, No. 5, November 2011
 tive progesterone receptor modulator, in healthy
premenopausal women. Hum Reprod 2005;20:
1090–9.
46. Croxatto HB, Salvatierra AM, Croxatto HD,
Fuentealba B. Effects of continuous treatment with
low dose mifepristone throughout one menstrual cy-
cle. Hum Reprod 1993;8:201–7.
47. Liu JH, Garzo G, Morris S, Stuenkel C, Ulmann A,
Yen SS. Disruption of follicular maturation and de-
lay of ovulation after administration of the antipro-
gesterone RU486. J Clin Endocrinol Metab
1987;65:1135–40.
48. Chwalisz K, Garg R, Brenner R, Slayden O,
Winkel C, Elger W. Role of nonhuman primate
models in the discovery and clinical development of
selective progesterone receptor modulators (SPRMs).
Reprod Biol Endocrinol 2006;4(Suppl 1):S8.
49. Stratton P, Levens ED, Hartog B, Piquion J, Wei Q,
Merino M, et al. Endometrial effects of a single
early luteal dose of the selective progesterone recep-
tor modulator CDB-2914. Fertil Steril 2009;93:
2035–41.
50. Chwalisz K, Larsen L, Mattia-Goldberg C,
Edmonds A, Elger W, Winkel CA. A randomized,
controlled trial of asoprisnil, a novel selective pro-
gesterone receptor modulator, in women with uter-
ine leiomyomata. Fertil Steril 2007;87:1399–412.
51. Levens ED, Potlog-Nahari C, Armstrong AY,
Wesley R, Premkumar A, Blithe DL, et al.
CDB-2914 for uterine leiomyomata treatment: a ran-
domized controlled trial. Obstet Gynecol 2008;111:
1129–36.
52. van der Stege JG, Pahl-van Beest EH,
Beerthuizen RJ, van Lunsen RH, Scholten PC,
Bogchelman DH. Effects of a preovulatory single
low dose of mifepristone on ovarian function. Eur
J Contracept Reprod Health Care 2006;11:104–8.
53. Leminen R, Raivio T, Ranta S, Oehler J, von
Hertzen H, J€anne OA, et al. Late follicular phase ad-
ministration of mifepristone suppresses circulating
leptin and FSH—mechanism(s) of action in emer-
gency contraception? Eur J Endocrinol 2005;152:
411–8.
54. Sengupta J, Dhawan L, Lalitkumar PG, Ghosh D. A
multiparametric study of the action of mifepristone
used in emergency contraception using the Rhesus
monkey as a primate model. Contraception
2003;68:453–69.
55. Stratton P, Hartog B, Hajizadeh N, Piquion J,
Sutherland D, Merino M, et al. A single mid-
follicular dose of CDB-2914, a new antiprogestin,
inhibits folliculogenesis and endometrial differenti-
ation in normally cycling women. Hum Reprod
2000;15:1092–9.
56. Reel JR, Hild-Petito S, Blye RP. Antiovulatory and
postcoital antifertility activity of the antiprogestin
CDB-2914 when administered as single, multiple,
or continuous doses to rats. Contraception
1998;58:129–36.
57. Banaszak S, Brudney A, Donnelly K, Chai D,
Chwalisz K, Fazleabas AT. Modulation of the action
of chorionic gonadotropin in the baboon (Papio anu-
bis) uterus by a progesterone receptor antagonist
(ZK 137.316). Biol Reprod 2000;63:820–5.
58. Lalitkumar PG, Lalitkumar S, Meng CX, Stavreus-
Evers A, Hambiliki F, Bentin-Ley U, et al. Mifepris-
tone, but not levonorgestrel, inhibits human
blastocyst attachment to an in vitro endometrial
three-dimensional cell culture model. Hum Reprod
2007;22:3031–7.
59. Petersen A, Bentin-Ley U, Ravn V, Qvortrup K,
Sorensen S, Islin H, et al. The antiprogesterone
Org 31710 inhibits human blastocyst-endometrial
interactions in vitro. Fertil Steril 2005;83(Suppl 1):
1255–63.
Fertility and Sterility
60. Meng CX, Andersson KL, Bentin-Ley U,
Gemzell-Danielsson K, Lalitkumar PG. Effect of
levonorgestrel and mifepristone on endometrial re-
ceptivity markers in a three-dimensional human
endometrial cell culture model. Fertil Steril 2009;
91:256–64.
61. Creinin MD, Schlaff W, Archer DF, Wan L,
Frezieres R, Thomas M, et al. Progesterone receptor
modulator for emergency contraception: a random-
ized controlled trial. Obstet Gynecol 2006;108:
1089–97.
62. Fine P, Mathe H, Ginde S, Cullins V, Morfesis J,
Gainer E. Ulipristal acetate taken 48–120 hours after
intercourse for emergency contraception. Obstet
Gynecol 2010;115:257–63.
63. Glasier AF, Cameron ST, Fine PM, Logan SJ,
Casale W, Van Horn J, et al. Ulipristal acetate versus
levonorgestrel for emergency contraception: a rand-
omised non-inferiority trial and meta-analysis. Lan-
cet 2010;375:555–62.
64. Jin J, Weisberg E, Fraser IS. Comparison of three
single doses of mifepristone as emergency contra-
ception: a randomised controlled trial. Aust NZ
J Obstet Gynaecol 2005;45:489–94.
65. Esteve JL, Garcıa R, Breto A, Llorente M. Emer-
gency contraception in Cuba with 10 mg of mife-
pristone. Eur J Contracept Reprod Health Care
2007;12:162–7.
66. Taneepanichskul S. Emergency contraception with
mifepristone 10 mg in Thai women. J Med Assoc
Thai 2009;92:999–1002.
67. Wu S, Dong J, Cong J, Wang C, VonHertzen H,
Godfrey EM. Gestrinone compared with mifepris-
tone for emergency contraception: a randomized
controlled trial. Obstet Gynecol 2010;115:740–4.
68. Lakha F, Ho PC, Van der Spuy ZM, Dada K,
Elton R, Glasier AF, et al. A novel estrogen-free
oral contraceptive pill for women: multicentre,
double-blind, randomized controlled trial of mife-
pristone and progestogen-only pill (levonorgestrel).
Hum Reprod 2007;22:2428–36.
69. Pei K, Xiao B, Jing X, Lu S, Wei L, Zhao H. Weekly
contraception with mifepristone. Contraception
2007;75:40–4.
70. Agarwal M, Das V, Agarwal A, Pandey A,
Srivastava D. Evaluation of mifepristone as a once
a month contraceptive pill. Am J Obstet Gynecol
2009;200:e27–9.
71. Nieman LK, Blocker W, Nansel T, Mahoney S,
Reynolds J, Blithe D, et al. Efficacy and tolerability
of CDB-2914 treatment for symptomatic uterine
fibroids: a randomized, double-blind, placebo-
controlled, phase IIb study. Fertil Steril
2011;95:767–72.e1–2.
72. Wilkens J, Chwalisz K, Han C, Walker J,
Cameron IT, Ingamells S, et al. Effects of the selec-
tive progesterone receptor modulator asoprisnil on
uterine artery blood flow, ovarian activity, and clin-
ical symptoms in patients with uterine leiomyomata
scheduled for hysterectomy. J Clin Endocrinol
Metab 2008;93:4664–71.
73. Wiehle R, Goldberg J, Brodniewicz T, Jarus-
Dziedzic K, Jabiry-Zieniewicz Z. Effects of a new
progesterone receptor modulator, CDB-4124, on fi-
broid size and uterine bleeding. US Obstetr Gynae-
col 2008;3:17–20.
74. Eisinger SH, Bonfiglio T, Fiscella K, Meldrum S,
Guzick DS. Twelve-month safety and efficacy of
low-dose mifepristone for uterine myomas. J Minim
Invasive Gynecol 2005;12:227–33.
75. Fiscella K, Eisinger SH, Meldrum S, Feng C,
Fisher SG, Guzick DS. Effect of mifepristone for
symptomatic leiomyomata on quality of life and
uterine size: a randomized controlled trial. Obstet
Gynecol 2006;108:1381–7.
76. Carbonell Esteve JL, Acosta R, Heredia B, Perez Y,
Castaneda MC, Hernandez AV. Mifepristone for the
treatment of uterine leiomyomas: a randomized con-
trolled trial. Obstet Gynecol 2008;112:1029–36.
77. Bagaria M, Suneja A, Vaid NB, Guleria K,
Mishra K. Low-dose mifepristone in treatment of
uterine leiomyoma: a randomised double-blind pla-
cebo-controlled clinical trial. Aust NZ J Obstet Gy-
naecol 2009;49:77–83.
78. Eisinger SH, Fiscella J, Bonfiglio T, Meldrum S,
Fiscella K. Open-label study of ultra low-dose mif-
epristone for the treatment of uterine leiomyomata.
Eur J Obstet Gynecol Reprod Biol 2009;146:215–8.
79. Engman M, Granberg S, Williams AR, Meng CX,
Lalitkumar PG, Gemzell-Danielsson K. Mifepris-
tone for treatment of uterine leiomyoma: a prospec-
tive randomized placebo controlled trial. Hum
Reprod 2009;24:1870–9.
80. Feng C, Meldrum S, Fiscella K. Improved quality of
life is partly explained by fewer symptoms after
treatment of fibroids with mifepristone. Int J Gynae-
col Obstet 2010;109:121–4.
81. Cheng L, Gulmezoglu AM, Piaggio G, Ezcurra E,
Van Look PF. Interventions for emergency contra-
ception. Cochrane Database Syst Rev 2008;2:
CD001324.
82. Fiala C, Gemzel-Danielsson K. Review of medical
abortion using mifepristone in combination with
a prostaglandin analogue. Contraception 2006;74:
66–86.
83. Marions L. Mifepristone dose in the regimen with
misoprostol for medical abortion. Contraception
2006;74:21–5.
84. Schreiber C, Creinin M. Mifepristone in abortion
care. Semin Reprod Med 2005;23:82–91.
85. Bedaiwy MA, Abdel-Aleem MA, Miketa A,
Falcone T. Endometriosis: a critical appraisal of
the advances and the controversies of a challenging
health problem. Minerva Ginecol 2009;61:285–98.
86. Signorile PG, Baldi A. Endometriosis: new concepts
in the pathogenesis. Int J Biochem Cell Biol
2010;42:778–80.
87. Eskenazi B, Warner ML. Epidemiology of endome-
triosis. Obstet Gynecol Clin North Am 1997;24:
235–58.
88. Crosignani P, Olive D, Bergqvist A, Luciano A. Ad-
vances in the management of endometriosis: an up-
date for clinicians. Hum Reprod Update 2006;12:
179–89.
89. Brenner RM, Slayden OD, Nath A, Tsong YY, Si-
truk-Ware R. Intrauterine administration of CDB-
2914 (Ulipristal) suppresses the endometrium of
rhesus macaques. Contraception 2010;81:336–42.
90. Gopalkrishnan K, Katkam RR, Sachdeva G,
Kholkute SD, Padwal V, Puri CP. Effects of an anti-
progestin onapristone on the endometrium of bonnet
monkeys: morphometric and ultrastructural studies.
Biol Reprod 2003;68:1959–67.
91. Zhang Z, Lundeen SG, Slayden O, Zhu Y, Cohen J,
Berrodin TJ, et al. In vitro and in vivo characteriza-
tion of a novel nonsteroidal, species-specific proges-
terone receptor modulator, PRA-910. Ernst
Schering Found Symp Proc 2007:171–97.
92. Wu Y, Guo SW. Inhibition of proliferation of endo-
metrial stromal cells by trichostatin A, RU486,
CDB-2914, N-acetylcysteine, and ICI 182780. Gy-
necol Obstet Invest 2006;62:193–205.
93. Moe BG, Vereide AB, Orbo A, Sager G. High con-
centrations of progesterone and mifepristone mutu-
ally reinforce cell cycle retardation and induction of
apoptosis. Anticancer Res 2009;29:1053–8.
94. Ioffe OB, Zaino RJ, Mutter GL. Endometrial
changes from short-term therapy with CDB-4124,
a selective progesterone receptor modulator. Mod
Pathol 2009;22:450–9.
1187
 95. Wilkens J, Williams AR, Chwalisz K, Han C,
Cameron IT, Critchley HO. Effect of asoprisnil on
uterine proliferation markers and endometrial ex-
pression of the tumour suppressor gene, PTEN.
Hum Reprod 2009;24:1036–44.
96. Heikinheimo O, Vani S, Carpen O, Tapper A,
Harkki P, Rutanen EM, et al. Intrauterine release
of progesterone antagonist ZK230211 is feasible
and results in novel endometrial effects: a pilot
study. Hum Reprod 2007;22:2515–22.
97. Williams AR, Critchley HO, Osei J, Ingamells S,
Cameron IT, Han C, et al. The effects of the selective
progesterone receptor modulator asoprisnil on the
morphology of uterine tissues after 3 months treat-
ment in patients with symptomatic uterine leiomyo-
mata. Hum Reprod 2007;22:1696–704.
98. Baird DT, Brown A, Critchley HO, Williams AR,
Lin S, Cheng L. Effect of long-term treatment
with low-dose mifepristone on the endometrium.
Hum Reprod 2003;18:61–8.
99. Grow DR, Williams RF, Hsiu JG, Hodgen GD. Anti-
progestin and/or gonadotropin-releasing hormone
agonist for endometriosis treatment and bone main-
tenance: a 1-year primate study. J Clin Endocrinol
Metab 1996;81:1933–9.
100. Stoeckemann K, Hegele-Hartung C, Chwalisz K.
Effects of the progesterone antagonists onapristone
(ZK 98 299) and ZK 136 799 on surgically induced
endometriosis in intact rats. Hum Reprod 1995;10:
3264–71.
101. Elger W, Ivell R, Nandy A, Rasch A, Triller A,
Chwalisz K. Modulation of uterine prostaglandin
secretion by the selective progesterone receptor
modulator (SPRM) asoprisnil, progestins, and anti-
progestins in cycling and ovariectomized guinea
pigs. Fertil Steril 2004;82(Suppl):S316.
102. Gemzell-Danielsson K, Hamberg M. The effect of
antiprogestin (RU 486) and prostaglandin biosyn-
thesis inhibitor (naproxen) on uterine fluid prosta-
glandin F2 alpha concentrations. Hum Reprod
1994;9:1626–30.
103. Kettel LM, Murphy AA, Morales AJ, Ulmann A,
Baulieu EE, Yen SS. Treatment of endometriosis
with the antiprogesterone mifepristone (RU486).
Fertil Steril 1996;65:23–8.
104. Kettel LM, Murphy AA, Morales AJ, Yen SS. Pre-
liminary report on the treatment of endometriosis
with low-dose mifepristone (RU 486). Am J Obstet
Gynecol 1998;178:1151–6.
105. Mei L, Bao J, Tang L, Zhang C, Wang H, Sun L,
et al. A novel mifepristone-loaded implant for
long-term treatment of endometriosis: in vitro and
in vivo studies. Eur J Pharm Sci 2010;39:421–7.
106. Chwalisz K, Mattia-Goldberg C, Elger W,
Edmonds A. Treatment of endometriosis with the
novel selective progesterone receptor modulator
(SPRM) asoprisnil. Fertil Steril 2004;82:S83–4.
107. Spitz IM. Clinical utility of progesterone receptor
modulators and their effect on the endometrium.
Curr Opin Obstet Gynecol 2009;21:318–24.
108. Chwalisz K, Brenner RM, Fuhrmann UU,
Hess-Stumpp H, Elger W. Antiproliferative effects
of progesterone antagonists and progesterone recep-
tor modulators on the endometrium. Steroids
2000;65:741–51.
109. Nayak NR, Slayden OD, Mah K, Chwalisz K,
Brenner RM. Antiprogestin-releasing intrauterine
devices: a novel approach to endometrial contracep-
tion. Contraception 2007;75:S104–11.
110. Ravet S, Munaut C, Blacher S, Brichant G,
Labied S, Beliard A, et al. Persistence of an intact
endometrial matrix and vessels structure in women
exposed to VA-2914, a selective progesterone re-
ceptor modulator. J Clin Endocrinol Metab
2008;93:4525–31.
111. Stephanie R, Labied S, Blacher S, Frankenne F,
Munaut C, Fridman V, et al. Endometrial vessel mat-
uration in women exposed to levonorgestrel-releasing
intrauterine system for a short or prolonged period of-
time. Hum Reprod 2007;22:3084–91.
112. Gemzell-Danielsson K, van Heusden AM,
Killick SR, Croxatto HB, Bouchard P, Cameron S,
et al. Improving cycle control in progestogen-only
contraceptive pill users by intermittent treatment
with a new anti-progestogen. Hum Reprod 2002;17:
2588–93.
113. Massai MR, Pavez M, Fuentealba B, Croxatto HB,
d’Arcangues C. Effect of intermittent treatment
with mifepristone on bleeding patterns in Norplant
implant users. Contraception 2004;70:47–54.
114. Parker WH. Etiology, symptomatology, and diagno-
sis of uterine myomas. Fertil Steril 2007;87:725–36.
115. Miller CE. Unmet therapeutic needs for uterine my-
omas. J Minim Invasive Gynecol 2009;16:11–21.
116. Catherino WH, Parrott E, Segars J. Proceedings
from the National Institute of Child Health and Hu-
man Development conference on the Uterine Fi-
broid Research Update Workshop. Fertil Steril
2011;95:9–12.
117. Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J,
Berliere M, Donnez J. 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 1999;14:2844–50.
118. Brandon DD, Bethea CL, Strawn EY, Novy MJ,
Burry KA, Harrington MS, et al. Progesterone re-
ceptor messenger ribonucleic acid and protein are
overexpressed in human uterine leiomyomas. Am J
Obstet Gynecol 1993;169:78–85.
119. Englund K, Blanck A, Gustavsson I, Lundkvist U,
Sj€oblom P, Norgren A, et al. Sex steroid receptors
in human myometrium and fibroids: changes during
the menstrual cycle and gonadotropin-releasing hor-
mone treatment. J Clin Endocrinol Metab 1998;83:
4092–6.
120. Chen W, Ohara N, Wang J, Xu Q, Liu J,
Morikawa A, et al. A novel selective progesterone
receptor modulator asoprisnil (J867) inhibits prolif-
eration and induces apoptosis in cultured human
uterine leiomyoma cells in the absence of compara-
ble effects on myometrial cells. J Clin Endocrinol
Metab 2006;91:1296–304.
121. Shimomura Y, Matsuo H, Samoto T, Maruo T. Up-
regulation by progesterone of proliferating cell
nuclear antigen and epidermal growth factor expres-
sion in human uterine leiomyoma. J Clin Endocrinol
Metab 1998;83:2192–8.
122. Matsuo H, Kurachi O, Shimomura Y, Samoto T,
Maruo T. Molecular bases for the actions of ovarian
sex steroids in the regulation of proliferation and ap-
optosis of human uterine leiomyoma. Oncology
1999;57(Suppl 2):49–58.
123. Maruo T, Matsuo H, Samoto T, Shimomura Y,
Kurachi O, Gao Z, et al. Effects of progesterone
on uterine leiomyoma growth and apoptosis.
Steroids 2000;65:585–92.
124. Matsuo H, Maruo T, Samoto T. Increased expression
of Bcl-2 protein in human uterine leiomyoma and its
up-regulation by progesterone. J Clin Endocrinol
Metab 1997;82:293–9.
125. Ishikawa H, Ishi K, Serna VA, Kakazu R, Bulun SE,
Kurita T. Progesterone is essential for maintenance
and growth of uterine leiomyoma. Endocrinology
2010;151:2433–42.
126. Lumsden MA. Modern management of fibroids. Ob-
stet Gynecol Reprod Med 2010;20:82–6.
127. Luo X, Yin P, Coon VJ, Cheng YH, Wiehle RD,
Bulun SE. The selective progesterone receptor mod-
ulator CDB4124 inhibits proliferation and induces
apoptosis in uterine leiomyoma cells. Fertil Steril
2010;93:2668–73.
128. Maruo T, Ohara N, Matsuo H, Xu Q, Chen W, Sitruk-
Ware R, et al. Effects of levonorgestrel-releasing IUS
and progesterone receptor modulator PRM CDB-
2914 on uterine leiomyomas. Contraception
2007;75(Suppl):S99–103.
129. Xu Q, Takekida S, Ohara N, Chen W, Sitruk-Ware R,
Johansson ED, et al. Progesterone receptor modula-
tor CDB-2914 down-regulates proliferative cell
nuclear antigen and Bcl-2 protein expression and
up-regulates caspase-3 and poly(adenosine 5’-di-
phosphate-ribose) polymerase expression in
cultured human uterine leiomyoma cells. J Clin En-
docrinol Metab 2005;90:953–61.
130. Xu Q, Ohara N, Liu J, Nakabayashi K, Demanno D,
Chwalisz K, et al. Selective progesterone receptor
modulator asoprisnil induces endoplasmic reticulum
stress in cultured human uterine leiomyoma cells.
Am J Physiol Endocrinol Metab 2007;293:
E1002–11.
131. Sasaki H, Ohara N, Xu Q, Wang J, DeManno DA,
Chwalisz K, et al. A novel selective progesterone re-
ceptor modulator asoprisnil activates tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL)-
mediated signaling pathway in cultured human uter-
ine leiomyoma cells in the absence of comparable
effects on myometrial cells. J Clin Endocrinol
Metab 2007;92:616–23.
132. Wang J, Ohara N, Wang Z, Chen W, Morikawa A,
Sasaki H, et al. A novel selective progesterone re-
ceptor modulator asoprisnil (J867) down-regulates
the expression of EGF, IGF-I, TGFb3 and their re-
ceptors in cultured uterine leiomyoma cells. Hum
Reprod 2006;21:1869–77.
133. Xu Q, Ohara N, Chen W, Liu J, Sasaki H,
Morikawa A, et al. Progesterone receptor modulator
CDB-2914 down-regulates vascular endothelial
growth factor, adrenomedullin and their receptors
and modulates progesterone receptor content in cul-
tured human uterine leiomyoma cells. Hum Reprod
2006;21:2408–16.
134. Xu Q, Ohara N, Liu J, Amano M, Sitruk-Ware R,
Yoshida S, et al. Progesterone receptor modulator
CDB-2914 induces extracellular matrix metallopro-
teinase inducer in cultured human uterine leio-
myoma cells. Mol Hum Reprod 2008;14:181–91.
135. Morikawa A, Ohara N, Xu Q, Nakabayashi K,
DeManno DA, Chwalisz K, et al. Selective progester-
one receptor modulator asoprisnil down-regulates col-
lagen synthesis in cultured human uterine leiomyoma
cells through up-regulating extracellular matrix met-
alloproteinase inducer. Hum Reprod 2008;23:944–51.
136. Gellersen B, Fernandes MS, Brosens JJ. Non-geno-
mic progesterone actions in female reproduction.
Hum Reprod Update 2009;15:119–38.
137. Ismail PM, Amato P, Soyal SM, DeMayo FJ,
Conneely OM, O’Malley BW, et al. Progesterone in-
volvement in breast development and tumorigene-
sis—as revealed by progesterone receptor
‘‘knockout’’ and ‘‘knockin’’ mouse models. Steroids
2003;68:779–87.
138. Poole AJ, Li Y, Kim Y, Lin SC, Lee WH, Lee EY.
Prevention of Brca1-mediated mammary tumori-
genesis in mice by a progesterone antagonist. Sci-
ence 2006;314:1467–70.
139. Benagiano G, Bastianelli C, Farris M. Selective pro-
gesterone receptor modulators 3: use in oncology,
endocrinology and psychiatry. Expert Opin Phar-
macother 2008;9:2487–96.
140. Li M, Spitzer E, Zschiesche W, Binas B, Parczyk K,
Grosse R. Antiprogestins inhibit growth and stimu-
late differentiation in the normal mammary gland.
J Cell Physiol 1995;164:1–8.

1188 Bouchard et al. SPRMs in reproductive medicine Vol. 96, No. 5, November 2011
141. Engman M, Skoog L, S€oderqvist G, Gemzell-
Danielsson K. The effect of mifepristone on breast
cell proliferation in premenopausal women evalu-
ated through fine needle aspiration cytology. Hum
Reprod 2008;23:2072–9.
142. Safety of treatment of uterine fibroids with asopris-
nil. 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 Sep-
tember 14, 2011.
144. Eisinger SH, Meldrum S, Fiscella K, le Roux HD,
Guzick DS. Low-dose mifepristone for uterine leio-
myomata. Obstet Gynecol 2003;101:243–50.
145. Horne FM, Blithe DL. Progesterone receptor modu-
lators and the endometrium: changes and conse-
quences. Hum Reprod Update 2007;13:567–80.
146. Mutter GL, Bergeron C, Deligdisch L, Ferenczy A,
Glant M, Merino M, et al. The spectrum of endome-
trial pathology induced by progesterone receptor
modulators. Mod Pathol 2008;21:591–8.
147. Williams A, Bergeron C, Chabbert-Buffet N,
Ferenczy A. Progesterone receptor modulator-
Fertility and Sterility
associated endometrial changes (PAEC): a pilot his-
tological, dose-escalation study of ulipristal acetate.
Fact View Vision Obgyn 2010:2 [special issue,
May].
148. Repros Therapeutics. Repros Therapeutics Inc. pro-
vides clarification on increased liver enzymes at
highest dose in Proellex clinical program. July 23,
2009. News Blaze.com. Available at: http://newsbla
ze.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/200908033
992/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, Proel-
lex, in healthy women. Last updated June 28,
2011. Available at: http://clinicaltrials.gov/ct2/
show/NCT01187043. Accessed August 20, 2011.
151. Klijn JG, Setyono-Han B, Foekens JA. Progesterone
antagonists and progesterone receptor modulators in
the treatment of breast cancer. Steroids 2000;65:
825–30.
152. Repros Therapeutics. Repros requests lift of clinical
hold on Proellex. April 05, 2010. Available at: http://
www.businesswire.com/news/home/201004050050
89/en/Repros-Requests-Lift-Clinical-Hold-Proellex.
Accessed August 20, 2011.
153. Cameron ST, Thong KJ, Baird DT. Effect of daily
low dose mifepristone on the ovarian cycle and on
dynamics of follicle growth. Clin Endocrinol (Oxf)
1995;43:407–14.
154. Lethaby A, Vollenhoven B, Sowter M. Pre-operative
GnRH analogue therapy before hysterectomy or my-
omectomy for uterine fibroids. Cochrane Database
Syst Rev 2001;2:CD000547.
155. Lethaby A, Vollenhoven B, Sowter M. Efficacy of
pre-operative gonadotrophin hormone releasing an-
alogues for women with uterine fibroids undergoing
hysterectomy or myomectomy: a systematic review.
BJOG 2002;109:1097–108.
1189