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

Published:September 23, 2011DOI:https://doi.org/10.1016/j.fertnstert.2011.08.021

      Objective

      To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize 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 termination 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.

      Key Words

      Progesterone exerts biologic effects on a range of organ systems, including the cardiovascular and central nervous systems, and bone. However, it is probably best known for its pivotal role in the regulation of the female reproductive system, including during pregnancy and mammary gland development (
      • Rocha A.
      • Soares R.
      Unraveling progesterone-induced molecular mechanisms in physiological and pathological conditions.
      ). Progesterone mediates its function by interacting with the progesterone receptor (PR), a member of a superfamily of almost 50 ligand-activated nuclear transcription factors, which can be divided into six subfamilies (
      • McEwan I.J.
      Nuclear receptors: one big family.
      ). 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 reproductive 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 (
      • Philibert D.
      RU 38486: an original multifaceted antihormone in vivo.
      ). This discovery was followed by the development of other steroidal progesterone ligands, while nonsteroidal PR ligands have been identified more recently (
      • Allan G.F.
      • Sui Z.
      Non-steroidal progesterone receptor specific ligands.
      ). In general, PR ligands with mixed activity act as agonists and/or antagonists in a tissue-specific manner. These compounds therefore have great potential in a number of gynecologic indications. This review will summarize what is currently known about the mechanism of action of such molecules, their effects on tissues of the reproductive system, and the data demonstrating their potential efficacy for gynecologic indications.

      Materials and methods

      A PubMed search for relevant publications from 2005 onward was performed, 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 publications containing relevant information. Final searches using the following search terms were performed without any date restrictions to ensure no relevant publications had been missed (n denotes number of publications identified): “CDB-2914 OR VA2914 OR CDB2914” (n = 46); “CDB-4124 OR CDB4124” (n = 11); “asoprisnil OR J867” (n = 39); “sprm OR progesterone receptor modulator” (n = 298). Additional relevant articles were identified from citations within all publications identified. In addition, information about selective progesterone receptor modulators (SPRMs) in clinical or preclinical development was obtained using Citeline Pipeline (Informa Healthcare). This review focuses on articles published since 2005 because trials before 2005 were previously reviewed elsewhere (
      • Chabbert-Buffet N.
      • Ouzounian S.
      • Kairis A.P.
      • Bouchard P.
      Contraceptive applications of progesterone receptor modulators.
      ,
      • Chabbert-Buffet N.
      • Meduri G.
      • Bouchard P.
      • Spitz I.M.
      Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.
      ,
      • Chwalisz K.
      • Perez M.C.
      • Demanno D.
      • Winkel C.
      • Schubert G.
      • Elger W.
      Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
      ).

      Progesterone and the progesterone receptor

      Within the female reproductive system, the key function of progesterone is to establish and maintain pregnancy (
      • Conneely O.M.
      • Mulac-Jericevic B.
      • DeMayo F.
      • Lydon J.P.
      • O’Malley B.W.
      Reproductive functions of progesterone receptors.
      ,
      • Mesiano S.
      • Welsh T.N.
      Steroid hormone control of myometrial contractility and parturition.
      ). 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 (
      • Conneely O.M.
      • Mulac-Jericevic B.
      • DeMayo F.
      • Lydon J.P.
      • O’Malley B.W.
      Reproductive functions of progesterone receptors.
      ,
      • Conneely O.M.
      • Jericevic B.M.
      • Lydon J.P.
      Progesterone receptors in mammary gland development and tumorigenesis.
      ,
      • Li Q.
      • Kannan A.
      • DeMayo F.J.
      • Lydon J.P.
      • Cooke P.S.
      • Yamagishi H.
      • et al.
      The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2.
      ). During pregnancy, progesterone secretion is associated with quiescence of the myometrium, and its decrease during labor is one of the signals for delivery (
      • Mesiano S.
      • Welsh T.N.
      Steroid hormone control of myometrial contractility and parturition.
      ).
      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 promoters of target genes. Once bound to the target genes, the progesterone–PR complex interacts with coactivators, leading to transcription of the target genes (
      • Scarpin K.M.
      • Graham J.D.
      • Mote P.A.
      • Clarke C.L.
      Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression.
      ,
      • Leonhardt S.A.
      • Edwards D.P.
      Mechanism of action of progesterone antagonists.
      ) (Fig. 1A). Confirmation that progesterone mainly mediates reproductive functions via interaction with the PR has come from analysis of mice homozygous for disruption of the PR gene (
      • Lydon J.P.
      • DeMayo F.J.
      • Funk C.R.
      • Mani S.K.
      • Hughes A.R.
      • Montgomery Jr., C.A.
      • et al.
      Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
      ). 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 (
      • Lydon J.P.
      • DeMayo F.J.
      • Funk C.R.
      • Mani S.K.
      • Hughes A.R.
      • Montgomery Jr., C.A.
      • et al.
      Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
      ). Two main PR isoforms have been described, which have distinct biologic activities 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 (
      • Giangrande P.H.
      • Pollio G.
      • McDonnell D.P.
      Mapping and characterization of the functional domains responsible for the differential activity of the A and B isoforms of the human progesterone receptor.
      ,
      • Giangrande P.H.
      • McDonnell D.P.
      The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.
      ). PR-A appears to be a dominant inhibitor of PR-B (
      • Giangrande P.H.
      • Kimbrel E.A.
      • Edwards D.P.
      • McDonnell D.P.
      The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.
      ). Specific deletion of PR isoforms has provided additional information on their roles in mice. While PR-A controls estrogen induced endometrial proliferation, PR-B mediates mammary gland epithelium proliferation and differentiation (
      • Conneely O.M.
      • Mulac-Jericevic B.
      • Lydon J.P.
      • De Mayo F.J.
      Reproductive functions of the progesterone receptor isoforms: lessons from knock-out mice.
      ,
      • Mulac-Jericevic B.
      • Lydon J.P.
      • DeMayo F.J.
      • Conneely O.M.
      Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform.
      ). 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, particularly 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 (
      • Arnett-Mansfield R.L.
      • DeFazio A.
      • Mote P.A.
      • Clarke C.L.
      Subnuclear distribution of progesterone receptors A and B in normal and malignant endometrium.
      ,
      • Mote P.A.
      • Bartow S.
      • Tran N.
      • Clarke C.L.
      Loss of co-ordinate expression ofprogesterone receptors A and B is an early event in breast carcinogenesis.
      ). 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 (
      • Chabbert-Buffet N.
      • Skinner D.C.
      • Caraty A.
      • Bouchard P.
      Neuroendocrine effects of progesterone.
      ).
      Figure thumbnail gr1
      Figure 1Mechanism 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 (
      • Scarpin K.M.
      • Graham J.D.
      • Mote P.A.
      • Clarke C.L.
      Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression.
      ,
      • Leonhardt S.A.
      • Edwards D.P.
      Mechanism of action of progesterone antagonists.
      ). Steroid hormone receptors, including the PR, can also activate nongenomic signaling pathways in the absence of steroid hormone (
      • Boonyaratanakornkit V.
      • Edwards D.P.
      Receptor mechanisms mediating non-genomic actions of sex steroids.
      ,
      • Blaustein J.D.
      Minireview: neuronal steroid hormone receptors: they’re not just for hormones anymore.
      ). (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
      (
      • Madauss K.P.
      • Grygielko E.T.
      • Deng S.J.
      • Sulpizio A.C.
      • Stanley T.B.
      • Wu C.
      • et al.
      A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.
      )
      . 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 (
      • Chwalisz K.
      • Perez M.C.
      • Demanno D.
      • Winkel C.
      • Schubert G.
      • Elger W.
      Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
      ,
      • Smith C.L.
      • O’Malley B.W.
      Coregulator function: a key to understanding tissue specificity of selective receptor modulators.
      ,
      • Madauss K.P.
      • Grygielko E.T.
      • Deng S.J.
      • Sulpizio A.C.
      • Stanley T.B.
      • Wu C.
      • et al.
      A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.
      ,
      • Wardell S.E.
      • Edwards D.P.
      Mechanisms controlling agonist and antagonist potential of selective progesterone receptor modulators (SPRMs).
      ). Furthermore, the precise activity of each SPRM will vary by tissue, depending on the relative levels of coactivators and corepressors in each cellular environment.

       Selective Progesterone Receptor Modulators

      The PR ligands can possess activity ranging from pure agonist activity through mixed agonist/antagonist activity to pure antagonist activity. 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 (
      • McPhail M.K.
      The assay of progestin.
      ,
      • Elger W.
      • Bartley J.
      • Schneider B.
      • Kaufmann G.
      • Schubert G.
      • Chwalisz K.
      Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
      ). 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 (
      • Elger W.
      • Bartley J.
      • Schneider B.
      • Kaufmann G.
      • Schubert G.
      • Chwalisz K.
      Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
      ). Current distinctions, based on traditional model systems, between molecules with apparently antagonistic functions and those with a mixed profile 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 differs from those described in mice, where deletion of PR genes leads to pure endometrial hyperplasia (
      • Lydon J.P.
      • DeMayo F.J.
      • Funk C.R.
      • Mani S.K.
      • Hughes A.R.
      • Montgomery Jr., C.A.
      • et al.
      Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
      ). However, subtle differences have been described in terms of endometrial changes, which may reflect the relative influence of the agonist and antagonist actions. These more subtle differences make it difficult to compare dose response effects between different agents. A new classification approach based on transcriptional activity in vitro has recently been suggested (
      • Afhüppe W.
      • Sommer A.
      • Müller J.
      • Schwede W.
      • Fuhrmann U.
      • Möller C.
      Global gene expression profiling of progesterone receptor modulators in T47D cells provides a new classification system.
      ). 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 activity (
      • Smith C.L.
      • O’Malley B.W.
      Coregulator function: a key to understanding tissue specificity of selective receptor modulators.
      ). Among all SPRMs studied, mifepristone, the pioneer drug, somehow remains a separate entity because its properties as an antagonist 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 (
      • Madauss K.P.
      • Grygielko E.T.
      • Deng S.J.
      • Sulpizio A.C.
      • Stanley T.B.
      • Wu C.
      • et al.
      A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator.
      ) (see Fig. 1B). Limited information is available regarding the specific affinities of different SPRMs for the PR, and the differential interaction 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 hormone responsive elements and can be inhibited by PR-A in HeLa cells (
      • Tung L.
      • Mohamed M.K.
      • Hoeffler J.P.
      • Takimoto G.S.
      • Horwitz K.B.
      Antagonist-occupied human progesterone B-receptors activate transcription without binding to progesterone response elements and are dominantly inhibited by A-receptors.
      ). Moreover, the activities of PR isoforms are differentially modulated by SPRMs in breast cancer cell lines (
      • Leo J.C.
      • Lin V.C.
      The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner.
      ). 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 further impairs the agonist-induced SRC1 degradation (
      • Amazit L.
      • Roseau A.
      • Khan J.A.
      • Chauchereau A.
      • Tyagi R.K.
      • Loosfelt H.
      • et al.
      Ligand-dependent degradation of SRC-1 is pivotal for progesterone receptor transcriptional activity.
      ). Finally, PR isoforms have also been shown to have distinct affinities for different coregulators (
      • Giangrande P.H.
      • Kimbrel E.A.
      • Edwards D.P.
      • McDonnell D.P.
      The opposing transcriptional activities of the two isoforms of the human progesterone receptor are due to differential cofactor binding.
      ), a mechanism that may also be involved in the biologic 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 receptors other than the PR to a greater or lesser extent (
      • Madauss K.P.
      • Stewart E.L.
      • Williams S.P.
      The evolution of progesterone receptor ligands.
      ). For example, mifepristone binds to the glucocorticoid receptor (GR) with an affinity three to four times higher than that of dexamethasone and consequently may be of therapeutic value in the treatment of Cushing syndrome (
      • Johanssen S.
      • Allolio B.
      Mifepristone (RU 486) in Cushing’s syndrome.
      ). In contrast, most other SPRMs bind weakly to the GR (
      • Elger W.
      • Bartley J.
      • Schneider B.
      • Kaufmann G.
      • Schubert G.
      • Chwalisz K.
      Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
      ,
      • Schubert G.
      • Elger W.
      • Kaufmann G.
      • Schneider B.
      • Reddersen G.
      • Chwalisz K.
      Discovery, chemistry, and reproductive pharmacology of asoprisnil and related 11β-benzaldoxime substituted selective progesterone receptor modulators (SPRMs).
      ,
      • Attardi B.J.
      • Burgenson J.
      • Hild S.A.
      • Reel J.R.
      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.
      ). Nonsteroidal SPRMs, which may be more selective for the PR, are also in development (
      • Madauss K.P.
      • Stewart E.L.
      • Williams S.P.
      The evolution of progesterone receptor ligands.
      ,
      • Winneker R.C.
      • Fensome A.
      • Zhang P.
      • Yudt M.R.
      • McComas C.C.
      • Unwalla R.J.
      A new generation of progesterone receptor modulators.
      ,
      • Zhi L.
      Discovery of structurally diverse nonsteroidal SPRMs based on a screening hit, 1,2-dihydro-2,2,4-trimethyl-6-phenylquinolinone.
      ). More recently, a class of SPRMs, called mixed-profile progestogens, has been described. These compounds are reported to have more agonistic activity than the currently described SPRMs (
      • Rewinkel J.
      • Enthoven M.
      • Golstein I.
      • van der R.M.
      • Scholten A.
      • van Tilborg M.
      • et al.
      11-(pyridinylphenyl)steroids—a new class of mixed-profile progesterone agonists/antagonists.
      ).

       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 second trimester, and fetal death in utero (
      • Schaff E.A.
      Mifepristone: ten years later.
      ,
      • Im A.
      • Appleman L.J.
      Mifepristone: pharmacology and clinical impact in reproductive medicine, endocrinology and oncology.
      ), and a single dose of ulipristal acetate (30 mg) has been launched in Europe and the United States as an emergency contraceptive.
      Table 1Selected major selective progesterone receptor modulators (SPRMs) with current or past development noted in the literature.
      CompoundTherapeutic application
      Including licensed uses and those for which the drug has undergone trials or for which it has or had been marked for development.
      Current status
      Mifepristone (RU-486)Termination of pregnancyLaunched
      Emergency contraceptionPhase III
      Psychosis
      Indications in development due to antiglucocorticoid activity of mifepristone.
      Phase III
      Cushing disease
      Indications in development due to antiglucocorticoid activity of mifepristone.
      Phase III
      Long-term contraceptionPhase II
      Uterine fibroidsPhase II
      EndometriosisPhase II
      Alzheimer disease
      Indications in development due to antiglucocorticoid activity of mifepristone.
      Phase II
      Endometrial cancerPhase I
      Ulipristal acetate (CDB-2914; VA2914)Emergency contraceptionLaunched
      Uterine fibroidsPhase III
      Long-term contraception
      Using a vaginal ring formulation.
      Phase II
      Asoprisnil (J-867)Uterine fibroidsWithdrawn
      EndometriosisWithdrawn
      Long-term contraceptionWithdrawn
      Telapristone acetate (CDB-4124)Uterine fibroidsPhase III trials terminated; phase I/II trial initiated
      AnemiaPhase III trials terminated; phase I/II trial initiated
      EndometriosisPhase II trials terminated; phase I/II trial initiated
      Lonaprisan (ZK230211)CancerPhase II
      CP8816 and CP8863Gynecologic disordersPreclinical
      WAY-255348ContraceptionPreclinical
      Onapristone (ZK98299)EndometriosisNo development since the 1990s
      CancerNo development since the 1990s
      ORG-31710 and ORG-31806ContraceptionPreclinical; no development since the 1990s
      CancerPreclinical; no development since the 1990s
      PF-2413873EndometriosisDiscontinued
      ZK137316ContraceptionDiscontinued
      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.
      Figure thumbnail gr2
      Figure 2Chemical structures of progesterone, norethindrone, and selected selective progesterone receptor modulators.

      SPRMs as contraceptives

      The critical role of progesterone in ovulation and preparing the endometrium for implantation suggests that SPRMs may have potential for use as contraceptives.

       Rationale

      Ovulation is blocked in women receiving mifepristone continuously at daily doses of 2 mg or more (
      • Baird D.T.
      • Thong K.J.
      • Hall C.
      • Cameron S.T.
      Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days.
      ), and high rates of anovulation are observed in women treated with daily ulipristal acetate, 5 mg or 10 mg (
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      ). In contrast, although asoprisnil prolongs the menstrual cycle in a dose-dependent manner, its effect on ovulation is inconsistent and does not show dose dependency (
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ). At high doses, continuous administration of mifepristone can suppress follicular development in addition to preventing ovulation (
      • Croxatto H.B.
      • Salvatierra A.M.
      • Croxatto H.D.
      • Fuentealba B.
      Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle.
      ,
      • Liu J.H.
      • Garzo G.
      • Morris S.
      • Stuenkel C.
      • Ulmann A.
      • Yen S.S.
      Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486.
      ).
      It is important, however, that despite their effects on ovulation, SPRMs do not result in the down-regulation of ovarian estrogen levels, allowing estrogen concentrations to remain within physiologic levels (
      • Baird D.T.
      • Thong K.J.
      • Hall C.
      • Cameron S.T.
      Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days.
      ,
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      ,
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Croxatto H.B.
      • Salvatierra A.M.
      • Croxatto H.D.
      • Fuentealba B.
      Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle.
      ,
      • Liu J.H.
      • Garzo G.
      • Morris S.
      • Stuenkel C.
      • Ulmann A.
      • Yen S.S.
      Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486.
      ,
      • 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).
      ,
      • Stratton P.
      • Levens E.D.
      • Hartog B.
      • Piquion J.
      • Wei Q.
      • Merino M.
      • et al.
      Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914.
      ,
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      ). Administration of a single dose of mifepristone or ulipristal acetate also delays ovulation (
      • van der Stege J.G.
      • Pahl-van Beest E.H.
      • Beerthuizen R.J.
      • van Lunsen R.H.
      • Scholten P.C.
      • Bogchelman D.H.
      Effects of a preovulatory single low dose of mifepristone on ovarian function.
      ,
      • Leminen R.
      • Raivio T.
      • Ranta S.
      • Oehler J.
      • von Hertzen H.
      • Jänne O.A.
      • et al.
      Late follicular phase administration of mifepristone suppresses circulating leptin and FSH—mechanism(s) of action in emergency contraception?.
      ,
      • Sengupta J.
      • Dhawan L.
      • Lalitkumar P.G.
      • Ghosh D.
      A multiparametric study of the action of mifepristone used in emergency contraception using the Rhesus monkey as a primate model.
      ,
      • 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 differentiation in normally cycling women.
      ,
      • Reel J.R.
      • Hild-Petito S.
      • Blye R.P.
      Antiovulatory and postcoital antifertility activity of the antiprogestin CDB-2914 when administered as single, multiple, or continuous doses to rats.
      ), 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 development (
      • Stratton P.
      • Levens E.D.
      • Hartog B.
      • Piquion J.
      • Wei Q.
      • Merino M.
      • et al.
      Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914.
      ,
      • Banaszak S.
      • Brudney A.
      • Donnelly K.
      • Chai D.
      • Chwalisz K.
      • Fazleabas A.T.
      Modulation of the action of chorionic gonadotropin in the baboon (Papio anubis) uterus by a progesterone receptor antagonist (ZK 137.316).
      ). Moreover, short treatment of the endometrium with mifepristone or ORG-31710 can inhibit blastocyst attachment (
      • Lalitkumar P.G.
      • Lalitkumar S.
      • Meng C.X.
      • Stavreus-Evers A.
      • Hambiliki F.
      • Bentin-Ley U.
      • et al.
      Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model.
      ,
      • 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.
      ) in ex vivo endometrial culture models. This may be related to the down-regulation of endometrial receptivity markers (
      • Meng C.X.
      • Andersson K.L.
      • Bentin-Ley U.
      • Gemzell-Danielsson K.
      • Lalitkumar P.G.
      Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model.
      ). Longer term treatment with ORG-31710 in the ex vivo baboon endometrial culture model did not induce modifications that could interfere with blastocyst attachment (
      • 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.
      ). The short-term administration of SPRMs for emergency contraception may induce a specific endometrial effect as compared with a progestin used for the same purpose (
      • Lalitkumar P.G.
      • Lalitkumar S.
      • Meng C.X.
      • Stavreus-Evers A.
      • Hambiliki F.
      • Bentin-Ley U.
      • et al.
      Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model.
      ). 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 (
      • Chabbert-Buffet N.
      • Ouzounian S.
      • Kairis A.P.
      • Bouchard P.
      Contraceptive applications of progesterone receptor modulators.
      ,
      • Chabbert-Buffet N.
      • Meduri G.
      • Bouchard P.
      • Spitz I.M.
      Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.
      ). A number of large studies have demonstrated the efficacy of mifepristone for emergency contraception (see Table 2), and a recent meta-analysis encompassing 45,842 women has confirmed that middle- or low-dose mifepristone is more effective for emergency contraception than levonorgestrel (
      • Cheng L.
      • Gulmezoglu A.M.
      • Piaggio G.
      • Ezcurra E.
      • Van Look P.F.
      Interventions for emergency contraception.
      ). 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 (
      • Creinin M.D.
      • Schlaff W.
      • Archer D.F.
      • Wan L.
      • Frezieres R.
      • Thomas M.
      • et al.
      Progesterone receptor modulator for emergency contraception: a randomized controlled trial.
      ,
      • Glasier A.F.
      • Cameron S.T.
      • Fine P.M.
      • Logan S.J.
      • Casale W.
      • Van Horn J.
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      ). Ulipristal acetate has been approved for emergency contraception in 29 countries thus far, and is commercially available in 25 of them.
      Table 2Key clinical trials since 2005 describing the use of selective progesterone receptor modulators (SPRMs) for contraception and uterine leiomyomata.
      StudyDesignTreatment and dosenTreatment duration/timingKey results
      Contraception
       Ulipristal acetate
      Emergency contraception
      Creinin et al., 2006
      • Creinin M.D.
      • Schlaff W.
      • Archer D.F.
      • Wan L.
      • Frezieres R.
      • Thomas M.
      • et al.
      Progesterone receptor modulator for emergency contraception: a randomized controlled trial.
      R, DB≤72 h after unprotected intercoursePregnancy rate, %
      Ulipristal acetate (1 × 50 mg)7750.9
      Levonorgestrel (2 × 0.75 mg)7741.7
      Arms had similar side effect profiles
      Fine et al., 2010
      • Fine P.
      • Mathé H.
      • Ginde S.
      • Cullins V.
      • Morfesis J.
      • Gainer E.
      Ulipristal acetate taken 48–120 hours after intercourse for emergency contraception.
      OLUlipristal acetate (1 × 30 mg)1,24148–120 h after unprotected intercourse2.1% pregnancy rate (satisfies the protocol-defined statistical criteria for success)

      Mainly mild or moderate AEs
      Glasier et al., 2010
      • Glasier A.F.
      • Cameron S.T.
      • Fine P.M.
      • Logan S.J.
      • Casale W.
      • Van Horn J.
      • et al.
      Ulipristal acetate versus levonorgestrel for emergency contraception: a randomised non-inferiority trial and meta-analysis.
      R, SB≤120 h after unprotected intercoursePregnancy rate, %
      Ulipristal acetate (1 × 30 mg)1,1041.8
      Levonorgestrel (1 × 1.5 mg)1,1172.6
      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 et al., 2007
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      R, PC, DB84 dAnovulation rate, % (P value vs. placebo)
      Placebo110
      Ulipristal acetate (2.5 mg daily)119.1 (P=NS)
      Ulipristal acetate (5 mg daily)1181.8 (P<.001)
      Ulipristal acetate (10 mg daily)1080.0 (P<.001)
      General and gynecologic safety data were satisfactory
       Mifepristone
      Emergency contraception
      Jin et al., 2005
      • Jin J.
      • Weisberg E.
      • Fraser I.S.
      Comparison of three single doses of mifepristone as emergency contraception: a randomised controlled trial.
      R, DB≤120 h after unprotected intercoursePregnancy rate, %
      Mifepristone (1 × 10 mg)492.0
      Mifepristone (1 × 50 mg)472.1
      Mifepristone (1 × 600 mg)482.1
      Esteve et al., 2007
      • Esteve J.L.
      • García R.
      • Breto A.
      • Llorente M.
      Emergency contraception in Cuba with 10 mg of mifepristone.
      OLMifepristone (1 × 10 mg)635≤144 h after unprotected intercourse1.1% pregnancy rate

      Acceptable profile of side effects
      Taneepanichskul, 2009
      • Taneepanichskul S.
      Emergency contraception with mifepristone 10 mg in Thai women.
      OLMifepristone (1 × 10 mg)120≤120 h after unprotected intercourse0 pregnancy rate

      Few side effects
      Wu et al., 2010
      • Wu S.
      • Dong J.
      • Cong J.
      • Wang C.
      • VonHertzen H.
      • Godfrey E.M.
      Gestrinone compared with mifepristone for emergency contraception: a randomized controlled trial.
      R, DB≤72 h after unprotected intercoursePregnancy rate, %
      Mifepristone (1 × 10 mg)4991.8
      Gestrinone (1 × 10 mg)4992.4
      No difference in side effects between arms
      Long-term contraception
      Lakha et al., 2007
      • Lakha F.
      • Ho P.C.
      • Van der Spuy Z.M.
      • Dada K.
      • Elton R.
      • Glasier A.F.
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      R, DB24 wkPregnancy rate, %
      Mifepristone (5 mg daily)730.6
      Levonorgestrel (0.03 mg daily)231.2
      There were no major AEs in either group
      Pei et al., 2007
      • Pei K.
      • Xiao B.
      • Jing X.
      • Lu S.
      • Wei L.
      • Zhao H.
      Weekly contraception with mifepristone.
      R, DB24 wkPregnancy rate, %
      Mifepristone (25 mg weekly)390
      Mifepristone (50 mg weekly)370
      83Side effects were uncommon and mild
      Agarwal et al., 2009
      • Agarwal M.
      • Das V.
      • Agarwal A.
      • Pandey A.
      • Srivastava D.
      Evaluation of mifepristone as a once a month contraceptive pill.
      OL2–12 moPregnancy rate, %
      Mifepristone (200 mg monthly)800.2
      Combined oral contraceptive (COC) daily831.0
      Significantly fewer side effects in the mifepristone vs COC group (P=.001)
       Asoprisnil
      Long-term contraception
      Chwalisz K et al., 2005
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      DB, PC28 dAnovulation rate, % (measured by progesterone levels <3.5 ng/mL during treatment)
      Placebo128.3
      Asoprisnil (5 mg daily)812.5
      Asoprisnil (5 mg twice daily)862.5
      Asoprisnil (10 mg daily)850.0
      Asoprisnil (25 mg daily)837.5
      Asoprisnil (25 mg twice daily)837.5
      Asoprisnil (50 mg daily)887.5
      Asoprisnil was well tolerated
      StudyDesignTreatment and dosenTreatment duration/timingKey results
      Uterine leiomyomata
       Ulipristal acetate
      Levens et al., 2008
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      R, DB, PC3 cycles or 90–102 dChange in leiomyoma volume (%)Amenorrhea during cycle 3 (% women)
      Placebo8+60
      Ulipristal acetate (10 mg daily)8−3687.5
      Ulipristal acetate (20 mg daily)6−21100.0
      Ulipristal acetate was well tolerated
      Nieman et al., 2011
      • Nieman L.K.
      • 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.
      R, DB, PC3 cycles or 90–102 dChange in leiomyoma volume (%)Amenorrhea during treatment (% women)
      Placebo12+70
      Ulipristal acetate (10 mg daily)13−1761.5
      Ulipristal acetate (20 mg daily)13−2492.0
      Ulipristal acetate was well tolerated
       Asoprisnil
      Chwalisz et al., 2007
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      R, DB, PC12 wkMedian change in uterine volume (%)Amenorrhea (% women)
      Placebo31+10
      Asoprisnil (5 mg daily)33−1416
      Asoprisnil (10 mg daily)29−936
      Asoprisnil (25 mg daily)36−1770
      Asoprisnil was well tolerated
      Wilkens et al., 2008
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      R, DB, PC12 wkMedian change in largest leiomyoma volume, %Average number of bleeding days in cycle 3
      Placebo10+4.97.3
      Asoprisnil (10 mg daily)12−0.41.2
      Asoprisnil (25 mg daily)11−25.80.2
      Asoprisnil was well tolerated
       Telapristone acetate
      Wiehle et al., 2008
      • Wiehle R.
      • Goldberg J.
      • Brodniewicz T.
      • Jarus-Dziedzic K.
      • Jabiry-Zieniewicz Z.
      Effects of a new progesterone receptor modulator, CDB-4124, on fibroid size and uterine bleeding.
      R, DB, PC3 moMean 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
      • Eisinger S.H.
      • Bonfiglio T.
      • Fiscella K.
      • Meldrum S.
      • Guzick D.S.
      Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas.
      R, OL1 yChange in mean uterine volume at 1 y, %Amenorrhea at 1 y (% women)
      Mifepristone (5 mg daily)−5275
      Mifepristone (10 mg daily)−5340
      1 patient in the mifepristone 10 mg group showed simple hyperplasia at 1 y
      Fiscella et al., 2006
      • Fiscella K.
      • Eisinger S.H.
      • Meldrum S.
      • Feng C.
      • Fisher S.G.
      • Guzick D.S.
      Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial.
      R, PC26 wkMean change in uterine volume, %Amenorrhea at 26 wk (% women)
      Placebo20+100
      Mifepristone (5 mg daily)22−4741
      No statistically significant differences in adverse events between treatment groups
      Carbonell Esteve et al., 2008
      • Carbonell Esteve J.L.
      • Acosta R.
      • Heredia B.
      • Perez Y.
      • Castaneda M.C.
      • Hernandez A.V.
      Mifepristone for the treatment of uterine leiomyomas: a randomized controlled trial.
      R3 moChange in leiomyoma volume, %Amenorrhea during cycle 3 (% women)
      Mifepristone (5 mg daily)50−5790.0
      Mifepristone (10 mg daily)49−4589.8
      1 patient in the mifepristone 10 mg group showed simple hyperplasia
      Bagaria et al., 2009
      • Bagaria M.
      • Suneja A.
      • Vaid N.B.
      • Guleria K.
      • Mishra K.
      Low-dose mifepristone in treatment of uterine leiomyoma: a randomised double-blind placebo-controlled clinical trial.
      R, DB, PC3 moMedian change in leiomyoma volume, %Amenorrhea during cycle 3 (% women)
      Placebo20+0.50
      Mifepristone (10 mg daily)20−30.284.2
      63.1% of mifepristone-treated patients with endometrial hyperplasia without atypia diagnosis
      Eisinger et al., 2009
      • Eisinger S.H.
      • Fiscella J.
      • Bonfiglio T.
      • Meldrum S.
      • Fiscella K.
      Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
      OL6 moMean change in uterine volume (%) at 6 moAmenorrhea during months 3 and 6, respectively (% women)
      Mifepristone (2.5 mg daily)23−1165 and 32
      Cystic glandular dilation, but no endometrial hyperplasia or atypia
      Engman et al., 2009
      • Engman M.
      • Granberg S.
      • Williams A.R.
      • Meng C.X.
      • Lalitkumar P.G.
      • Gemzell-Danielsson K.
      Mifepristone for treatment of uterine leiomyoma: a prospective randomized placebo controlled trial.
      R, PC3 moMean change in leiomyoma volume, %
      Placebo16+6−12
      Mifepristone (50 mg every other day)14−28−34
      No premalignant changes
      Feng et al., 2010
      • Feng C.
      • Meldrum S.
      • Fiscella K.
      Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone.
      Partially R, PC6 moChange in uterine volume, %Change in health-related quality of life, %
      Placebo19+17.7+40.9
      Mifepristone (2.5 or 5 mg daily)43−17.6+123.4
      Note: AE = adverse event; DB = double-blind; NS = not statistically significant; OL = open label; PC = placebo-controlled; R = randomized; SB = single-blind.

       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 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 studied for this indication (
      • Elger W.
      • Bartley J.
      • Schneider B.
      • Kaufmann G.
      • Schubert G.
      • Chwalisz K.
      Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
      ). A wealth of published data describes the efficacy of mifepristone at doses between 200 mg and 600 mg, followed by a prostaglandin, for the medical termination of pregnancy. These reports include a number of review articles (
      • Schaff E.A.
      Mifepristone: ten years later.
      ,
      • Fiala C.
      • Gemzel-Danielsson K.
      Review of medical abortion using mifepristone in combination with a prostaglandin analogue.
      ,
      • Marions L.
      Mifepristone dose in the regimen with misoprostol for medical abortion.
      ,
      • Schreiber C.
      • Creinin M.
      Mifepristone in abortion care.
      ), 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 (
      • Fiala C.
      • Gemzel-Danielsson K.
      Review of medical abortion using mifepristone in combination with a prostaglandin analogue.
      ).

      SPRMs for the treatment of endometriosis

      Endometriosis—the growth of endometrial glands and stroma outside of the uterus (
      • Bedaiwy M.A.
      • Abdel-Aleem M.A.
      • Miketa A.
      • Falcone T.
      Endometriosis: a critical appraisal of the advances and the controversies of a challenging health problem.
      ,
      • Signorile P.G.
      • Baldi A.
      Endometriosis: new concepts in the pathogenesis.
      )—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 (
      • Eskenazi B.
      • Warner M.L.
      Epidemiology of endometriosis.
      ,
      • Crosignani P.
      • Olive D.
      • Bergqvist A.
      • Luciano A.
      Advances in the management of endometriosis: an update for clinicians.
      ). The only definitive, long-term treatment for endometriosis is abdominal hysterectomy with removal of ovaries and all visible endometriosis (
      • Bedaiwy M.A.
      • Abdel-Aleem M.A.
      • Miketa A.
      • Falcone T.
      Endometriosis: a critical appraisal of the advances and the controversies of a challenging health problem.
      ). 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 hormone (GnRH) agonists. However, these two latter therapies suppress estrogen secretion and therefore induce a significant decrease in bone mass in addition to hot flushes and vaginal dryness, which impair the quality of life of those women receiving the treatments (
      • Crosignani P.
      • Olive D.
      • Bergqvist A.
      • Luciano A.
      Advances in the management of endometriosis: an update for clinicians.
      ).

       Rationale

      An ideal medical therapy for endometriosis should be able to ameliorate 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 (
      • 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).
      ,
      • Brenner R.M.
      • Slayden O.D.
      • Nath A.
      • Tsong Y.Y.
      • Sitruk-Ware R.
      Intrauterine administration of CDB-2914 (Ulipristal) suppresses the endometrium of rhesus macaques.
      ,
      • Gopalkrishnan K.
      • Katkam R.R.
      • Sachdeva G.
      • Kholkute S.D.
      • Padwal V.
      • Puri C.P.
      Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies.
      ,
      • Zhang Z.
      • Lundeen S.G.
      • Slayden O.
      • Zhu Y.
      • Cohen J.
      • Berrodin T.J.
      • et al.
      In vitro and in vivo characterization of a novel nonsteroidal, species-specific progesterone receptor modulator, PRA-910.
      ). Similar suppression has been described in human cell lines after treatment with ulipristal acetate or mifepristone (
      • Wu Y.
      • Guo S.W.
      Inhibition of proliferation of endometrial stromal cells by trichostatin A, RU486, CDB-2914, N-acetylcysteine, and ICI 182780.
      ,
      • Moe B.G.
      • Vereide A.B.
      • Orbo A.
      • Sager G.
      High concentrations of progesterone and mifepristone mutually reinforce cell cycle retardation and induction of apoptosis.
      ), and in subjects treated with SPRMs including asoprisnil, lonaprisan, mifepristone, or telapristone acetate (
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Ioffe O.B.
      • Zaino R.J.
      • Mutter G.L.
      Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator.
      ,
      • Wilkens J.
      • Williams A.R.
      • Chwalisz K.
      • Han C.
      • Cameron I.T.
      • Critchley H.O.
      Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN.
      ,
      • Heikinheimo O.
      • Vani S.
      • Carpen O.
      • Tapper A.
      • Harkki P.
      • Rutanen E.M.
      • et al.
      Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study.
      ,
      • Williams A.R.
      • Critchley H.O.
      • Osei J.
      • Ingamells S.
      • Cameron I.T.
      • Han C.
      • et al.
      The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata.
      ,
      • Baird D.T.
      • Brown A.
      • Critchley H.O.
      • Williams A.R.
      • Lin S.
      • Cheng L.
      Effect of long-term treatment with low-dose mifepristone on the endometrium.
      ). Further evidence for the potential of SPRMs in endometriosis comes from the suppression of endometriotic lesions in animal models by mifepristone, onapristone, and ZK136799 (
      • Grow D.R.
      • Williams R.F.
      • Hsiu J.G.
      • Hodgen G.D.
      Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study.
      ,
      • 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.
      ). Moreover, some SPRMs can suppress endometrial prostaglandin production in mammalian model systems (
      • Elger W.
      • Bartley J.
      • Schneider B.
      • Kaufmann G.
      • Schubert G.
      • Chwalisz K.
      Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
      ,
      • 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 antiprogestins in cycling and ovariectomized guinea pigs.
      ,
      • Gemzell-Danielsson K.
      • Hamberg M.
      The effect of antiprogestin (RU 486) and prostaglandin biosynthesis inhibitor (naproxen) on uterine fluid prostaglandin F2 alpha concentrations.
      ), potentially reducing endometrial-associated pain. The relevance of these nonhuman models remains uncertain because SPRMs do not behave similarly in terms of endometrial effects in nonhuman primates and in women (
      • Chwalisz K.
      • Perez M.C.
      • Demanno D.
      • Winkel C.
      • Schubert G.
      • Elger W.
      Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
      ).

       Clinical Studies

      A small number of clinical studies have demonstrated that SPRMs and PR antagonists have potential for the treatment of endometriosis. Mifepristone at 50 mg daily has been shown to improve pain and cause regression of endometriosis (
      • Kettel L.M.
      • Murphy A.A.
      • Morales A.J.
      • Ulmann A.
      • Baulieu E.E.
      • Yen S.S.
      Treatment of endometriosis with the antiprogesterone mifepristone (RU486).
      ), although a lower dose of 5 mg daily is unable to control the growth of endometriotic lesions (
      • Kettel L.M.
      • Murphy A.A.
      • Morales A.J.
      • Yen S.S.
      Preliminary report on the treatment of endometriosis with low-dose mifepristone (RU 486).
      ). Mifepristone-loaded subcutaneous implants may also be an effective treatment for endometriosis (
      • 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.
      ). Asoprisnil and telapristone acetate have also been reported to relieve pain associated with endometriosis (
      • Chwalisz K.
      • Perez M.C.
      • Demanno D.
      • Winkel C.
      • Schubert G.
      • Elger W.
      Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
      ,
      • Chwalisz K.
      • Mattia-Goldberg C.
      • Elger W.
      • Edmonds A.
      Treatment of endometriosis with the novel selective progesterone receptor modulator (SPRM) asoprisnil.
      ,
      • Spitz I.M.
      Clinical utility of progesterone receptor modulators and their effect on the endometrium.
      ). 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 determined. In the future, intermittent treatment regimens with SPRMs might be appropriate (
      • Spitz I.M.
      Clinical utility of progesterone receptor modulators and their effect on the endometrium.
      ).

      SPRMs for the treatment of dysfunctional uterine bleeding

      Some studies have suggested that SPRMs may be able to control uterine bleeding via a direct effect on endometrial blood vessels (
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ,
      • Chwalisz K.
      • Brenner R.M.
      • Fuhrmann U.U.
      • Hess-Stumpp H.
      • Elger W.
      Antiproliferative effects of progesterone antagonists and progesterone receptor modulators on the endometrium.
      ,
      • Nayak N.R.
      • Slayden O.D.
      • Mah K.
      • Chwalisz K.
      • Brenner R.M.
      Antiprogestin-releasing intrauterine devices: a novel approach to endometrial contraception.
      ), as amenorrhea in patients receiving SPRMs does not appear to depend on inhibition of ovulation in all cases (
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ). The mechanism of the amenorrhea observed after SPRM treatment is still poorly understood (
      • 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 receptor modulator.
      ). Suppression of bleeding 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 matrix composition (
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ). This is a clear difference to the modifications observed after progestin administration (
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ,
      • 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 receptor modulator.
      ,
      • Stephanie R.
      • Labied S.
      • Blacher S.
      • Frankenne F.
      • Munaut C.
      • Fridman V.
      • et al.
      Endometrial vessel maturation in women exposed to levonorgestrel-releasing intrauterine system for a short or prolonged period of time.
      ). Furthermore, intrauterine administration of the SPRM ZK230211 in women scheduled for hysterectomy due to menorrhagia or dysmenorrhea resulted in a reduced number of days with bleeding and spotting compared with intrauterine administration of levonorgestrel (
      • Heikinheimo O.
      • Vani S.
      • Carpen O.
      • Tapper A.
      • Harkki P.
      • Rutanen E.M.
      • et al.
      Intrauterine release of progesterone antagonist ZK230211 is feasible and results in novel endometrial effects: a pilot study.
      ). Finally, women experiencing breakthrough bleeding during progestin treatment show a clear improvement in bleeding pattern following SPRM administration (
      • Gemzell-Danielsson K.
      • van Heusden A.M.
      • Killick S.R.
      • Croxatto H.B.
      • Bouchard P.
      • Cameron S.
      • et al.
      Improving cycle control in progestogen-only contraceptive pill users by intermittent treatment with a new anti-progestogen.
      ,
      • Massai M.R.
      • Pavez M.
      • Fuentealba B.
      • Croxatto H.B.
      • d’Arcangues C.
      Effect of intermittent treatment with mifepristone on bleeding patterns in Norplant implant users.
      ).

      SPRMs for the treatment of uterine fibroids

      Uterine leiomyomata arise from the smooth muscle cells of the myometrium (
      • Parker W.H.
      Etiology, symptomatology, and diagnosis of uterine myomas.
      ,
      • Miller C.E.
      Unmet therapeutic needs for uterine myomas.
      ). Despite their benign status, uterine leiomyomata can cause debilitating symptoms, including menorrhagia, abdominal pain, and infertility (
      • Parker W.H.
      Etiology, symptomatology, and diagnosis of uterine myomas.
      ,
      • Miller C.E.
      Unmet therapeutic needs for uterine myomas.
      ,
      • Catherino W.H.
      • Parrott E.
      • Segars J.
      Proceedings from the National Institute of Child Health and Human Development conference on the Uterine Fibroid Research Update Workshop.
      ). There is still much debate regarding the etiology of uterine leiomyomata, with genetics, hormones, and growth factors all thought to play a part (
      • Parker W.H.
      Etiology, symptomatology, and diagnosis of uterine myomas.
      ). It is, however, likely that progesterone and the PR have key roles in their development (
      • 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.
      ,
      • Brandon D.D.
      • Bethea C.L.
      • Strawn E.Y.
      • Novy M.J.
      • Burry K.A.
      • Harrington M.S.
      • et al.
      Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas.
      ,
      • Englund K.
      • Blanck A.
      • Gustavsson I.
      • Lundkvist U.
      • Sjöblom P.
      • Norgren A.
      • et al.
      Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment.
      ,
      • Chen W.
      • Ohara N.
      • Wang J.
      • Xu Q.
      • Liu J.
      • Morikawa A.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ,
      • Shimomura Y.
      • Matsuo H.
      • Samoto T.
      • Maruo T.
      Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma.
      ,
      • 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 apoptosis of human uterine leiomyoma.
      ,
      • Maruo T.
      • Matsuo H.
      • Samoto T.
      • Shimomura Y.
      • Kurachi O.
      • Gao Z.
      • et al.
      Effects of progesterone on uterine leiomyoma growth and apoptosis.
      ,
      • Matsuo H.
      • Maruo T.
      • Samoto T.
      Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone.
      ,
      • Ishikawa H.
      • Ishi K.
      • Serna V.A.
      • Kakazu R.
      • Bulun S.E.
      • Kurita T.
      Progesterone is essential for maintenance and growth of uterine leiomyoma.
      ), and it has been shown that PR–ligand complexes reduce apoptosis and increase proliferation of leiomyoma cells (
      • Catherino W.H.
      • Parrott E.
      • Segars J.
      Proceedings from the National Institute of Child Health and Human Development conference on the Uterine Fibroid Research Update Workshop.
      ). Traditionally, the favored treatment for uterine leiomyoma has been hysterectomy or myomectomy, with more modern, less invasive therapies including uterine artery embolization, high-intensity focused ultrasound, and uterine artery ligation. Available pharmacologic therapies are limited but include GnRH agonists and antagonists, oral contraceptives, and progestins (
      • Miller C.E.
      Unmet therapeutic needs for uterine myomas.
      ,
      • Lumsden M.A.
      Modern management of fibroids.
      ).

       Rationale

      The apparent importance of progesterone for the growth and development of uterine leiomyoma suggests that SPRMs may be an effective treatment. Accordingly, treatment of cultured leiomyoma cells with ulipristal acetate, telapristone acetate, or asoprisnil results in inhibition of proliferation (
      • Chen W.
      • Ohara N.
      • Wang J.
      • Xu Q.
      • Liu J.
      • Morikawa A.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ,
      • Luo X.
      • Yin P.
      • Coon V.J.
      • Cheng Y.H.
      • Wiehle R.D.
      • Bulun S.E.
      The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells.
      ,
      • 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.
      ,
      • Xu Q.
      • Takekida S.
      • Ohara N.
      • Chen W.
      • Sitruk-Ware R.
      • Johansson E.D.
      • et al.
      Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5’-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells.
      ) and induction of the endoplasmic reticulum stress-induced (
      • 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.
      ), intrinsic (
      • Chen W.
      • Ohara N.
      • Wang J.
      • Xu Q.
      • Liu J.
      • Morikawa A.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ,
      • Luo X.
      • Yin P.
      • Coon V.J.
      • Cheng Y.H.
      • Wiehle R.D.
      • Bulun S.E.
      The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells.
      ,
      • Xu Q.
      • Takekida S.
      • Ohara N.
      • Chen W.
      • Sitruk-Ware R.
      • Johansson E.D.
      • et al.
      Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5’-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells.
      ), or extrinsic (
      • Sasaki H.
      • Ohara N.
      • Xu Q.
      • Wang J.
      • DeManno D.A.
      • Chwalisz K.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ) apoptosis pathways. In contrast, these agents have no effect on the proliferation or apoptosis of normal myometrial cells (
      • Chen W.
      • Ohara N.
      • Wang J.
      • Xu Q.
      • Liu J.
      • Morikawa A.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ,
      • Luo X.
      • Yin P.
      • Coon V.J.
      • Cheng Y.H.
      • Wiehle R.D.
      • Bulun S.E.
      The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells.
      ,
      • 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.
      ,
      • Xu Q.
      • Takekida S.
      • Ohara N.
      • Chen W.
      • Sitruk-Ware R.
      • Johansson E.D.
      • et al.
      Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bcl-2 protein expression and up-regulates caspase-3 and poly(adenosine 5’-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells.
      ,
      • Sasaki H.
      • Ohara N.
      • Xu Q.
      • Wang J.
      • DeManno D.A.
      • Chwalisz K.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil activates tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated signaling pathway in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells.
      ). Asoprisnil and ulipristal acetate have also been shown to down-regulate a number of growth factors and their receptors in cultured leiomyoma cells (
      • Wang J.
      • Ohara N.
      • Wang Z.
      • Chen W.
      • Morikawa A.
      • Sasaki H.
      • et al.
      A novel selective progesterone receptor modulator asoprisnil (J867) down-regulates the expression of EGF, IGF-I, TGFβ3 and their receptors in cultured uterine leiomyoma cells.
      ,
      • 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 cultured human uterine leiomyoma cells.
      ). In addition, both asoprisnil and ulipristal acetate can reduce collagen synthesis in cultured leiomyoma cells through up-regulation of the extracellular matrix metalloproteinase inducer (
      • Xu Q.
      • Ohara N.
      • Liu J.
      • Amano M.
      • Sitruk-Ware R.
      • Yoshida S.
      • et al.
      Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells.
      ,
      • Morikawa A.
      • Ohara N.
      • Xu Q.
      • Nakabayashi K.
      • DeManno D.A.
      • Chwalisz K.
      • et al.
      Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.
      ).

       Clinical Studies

      A number of clinical trials have investigated the efficacy and safety of SPRMs as a treatment for uterine leiomyoma. Trials before 2005 have been reviewed previously elsewhere (
      • Chabbert-Buffet N.
      • Meduri G.
      • Bouchard P.
      • Spitz I.M.
      Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications.
      ,
      • Chwalisz K.
      • Perez M.C.
      • Demanno D.
      • Winkel C.
      • Schubert G.
      • Elger W.
      Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis.
      ,
      • Spitz I.M.
      Clinical utility of progesterone receptor modulators and their effect on the endometrium.
      ), and key trials from 2005 onward are summarized in Table 2. Studies have demonstrated that mifepristone, ulipristal acetate, asoprisnil, and telapristone acetate are all effective at reducing leiomyoma and uterine volume. Leiomyoma volumes are reduced by 17% to 57% and uterine volume by 9% to 53% during treatment with SPRMs, compared with general increases in volume in patients receiving placebo (see Table 2). In contrast to GnRH agonist therapy, these SPRMS are also able to suppress bleeding rapidly in women with uterine leiomyomata, without suppressing estrogen secretion, with the majority of women experiencing 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 (
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      ,
      • Nieman L.K.
      • 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.
      ,
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ,
      • Fiscella K.
      • Eisinger S.H.
      • Meldrum S.
      • Feng C.
      • Fisher S.G.
      • Guzick D.S.
      Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial.
      ,
      • Eisinger S.H.
      • Fiscella J.
      • Bonfiglio T.
      • Meldrum S.
      • Fiscella K.
      Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
      ,
      • Feng C.
      • Meldrum S.
      • Fiscella K.
      Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone.
      ).

      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 progestins able to stimulate proliferation of breast cancer cells and enhance their invasiveness (
      • Gellersen B.
      • Fernandes M.S.
      • Brosens J.J.
      Non-genomic progesterone actions in female reproduction.
      ,
      • Ismail P.M.
      • Amato P.
      • Soyal S.M.
      • DeMayo F.J.
      • Conneely O.M.
      • O’Malley B.W.
      • et al.
      Progesterone involvement in breast development and tumorigenesis—as revealed by progesterone receptor “knockout” and “knockin” mouse models.
      ). Importantly, treatment of Brca1/p53 –/– deficient mice with mifepristone prevents mammary tumorigenesis (
      • Poole A.J.
      • Li Y.
      • Kim Y.
      • Lin S.C.
      • Lee W.H.
      • Lee E.Y.
      Prevention of Brca1-mediated mammary tumorigenesis in mice by a progesterone antagonist.
      ). The potential role that SPRMs may play in preventing or treating breast cancer has been reviewed previously elsewhere (
      • Benagiano G.
      • Bastianelli C.
      • Farris M.
      Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry.
      ) and lies outside the scope of this article. However, it is also important 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 antiproliferative effect in a number of systems. Exposure of mammary glands from progesterone-primed virgin mice to ZK114043 led to a reduction in epithelial cell proliferation and differentiation of alveolar cells (
      • Li M.
      • Spitzer E.
      • Zschiesche W.
      • Binas B.
      • Parczyk K.
      • Grosse R.
      Antiprogestins inhibit growth and stimulate differentiation in the normal mammary gland.
      ). In primates, too, treatment with asoprisnil or mifepristone results in antiproliferative effects in breast tissue (
      • 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).
      ,
      • Engman M.
      • Skoog L.
      • Söderqvist G.
      • Gemzell-Danielsson K.
      The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology.
      ), and the antiproliferative effects of mifepristone have been described in the normal human breast (
      • Engman M.
      • Skoog L.
      • Söderqvist G.
      • Gemzell-Danielsson K.
      The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology.
      ). These data suggest that treatment with SPRMs may lower the risk for breast cancer, although 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 (

      Safety of treatment of uterine fibroids with asoprisnil. http://clinicaltrials gov/ct2/show/NCT00156208 2010.

      ,

      Abbott CM-G. Study of asoprisnil in the treatment of uterine fibroid. Available at: http://clinicaltrials.gov/ct2/show/NCT00156156. Last accessed September 14, 2011.

      ,
      • Eisinger S.H.
      • Meldrum S.
      • Fiscella K.
      • le Roux H.D.
      • Guzick D.S.
      Low-dose mifepristone for uterine leiomyomata.
      ). These unusual changes are characterized by dilated, weakly secretory endometrial glands with few mitotic figures, and stromal effects ranging from compaction to nonuniform edema (
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Eisinger S.H.
      • Bonfiglio T.
      • Fiscella K.
      • Meldrum S.
      • Guzick D.S.
      Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas.
      ,
      • Eisinger S.H.
      • Fiscella J.
      • Bonfiglio T.
      • Meldrum S.
      • Fiscella K.
      Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata.
      ). 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 (
      • Horne F.M.
      • Blithe D.L.
      Progesterone receptor modulators and the endometrium: changes and consequences.
      ). It is clear that modifications to the diagnostic criteria are required to describe these unusual changes, which have been termed progesterone receptor modulator-associated endometrial changes (PAECs) (
      • Mutter G.L.
      • Bergeron C.
      • Deligdisch L.
      • Ferenczy A.
      • Glant M.
      • Merino M.
      • et al.
      The spectrum of endometrial pathology induced by progesterone receptor modulators.
      ). Short-term studies of asoprisnil, ulipristal acetate, and telapristone acetate have confirmed the absence of endometrial hyperplasia in all subjects when pathologic review encompasses the spectrum of PAECs (
      • Wilkens J.
      • Chwalisz K.
      • Han C.
      • Walker J.
      • Cameron I.T.
      • Ingamells S.
      • et al.
      Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy.
      ,
      • Ioffe O.B.
      • Zaino R.J.
      • Mutter G.L.
      Endometrial changes from short-term therapy with CDB-4124, a selective progesterone receptor modulator.
      ,
      • Wilkens J.
      • Williams A.R.
      • Chwalisz K.
      • Han C.
      • Cameron I.T.
      • Critchley H.O.
      Effect of asoprisnil on uterine proliferation markers and endometrial expression of the tumour suppressor gene, PTEN.
      ,
      • Williams A.
      • Bergeron C.
      • Chabbert-Buffet N.
      • Ferenczy A.
      Progesterone receptor modulator-associated endometrial changes (PAEC): a pilot histological, dose-escalation study of ulipristal acetate.
      ). 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 telapristone acetate (50 mg), which led to suspension of the phase 3 trials of this drug in patients with uterine fibroids (

      Repros Therapeutics. Repros Therapeutics Inc. provides clarification on increased liver enzymes at highest dose in Proellex clinical program. July 23, 2009. News Blaze.com. Available at: http://newsblaze.com/story/2009072303060800003.bw/topstory.html. Accessed August 20, 2011.

      ,

      BioMedReports.com/ Repros Therapeutics Inc. suspends dosing of Proellex and provides update on financial status. BioMedRports, August 3, 2009. Available at: http://biomedreports.com/200908033992/repros-therapeutics-inc-suspends-dosing-of-proellexr-and-provides-update-on-financial-status.html. Accessed August 20, 2011.

      ). Clinical trials with this drug have restarted employing lower doses (

      Repros Therapeutics. Determination of the lowest, safe and effective dose of the anti-progestin, Proellex, in healthy women. Last updated June 28, 2011. Available at: http://clinicaltrials.gov/ct2/show/NCT01187043. Accessed August 20, 2011.

      ). The development of another SPRM, onapristone, was also halted due to liver toxicity (
      • Klijn J.G.
      • Setyono-Han B.
      • Foekens J.A.
      Progesterone antagonists and progesterone receptor modulators in the treatment of breast cancer.
      ). For other SPRMs, only mild and transient elevation of transaminases has been reported (
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      ,
      • Nieman L.K.
      • 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.
      ,
      • Carbonell Esteve J.L.
      • Acosta R.
      • Heredia B.
      • Perez Y.
      • Castaneda M.C.
      • Hernandez A.V.
      Mifepristone for the treatment of uterine leiomyomas: a randomized controlled trial.
      ,
      • Engman M.
      • Granberg S.
      • Williams A.R.
      • Meng C.X.
      • Lalitkumar P.G.
      • Gemzell-Danielsson K.
      Mifepristone for treatment of uterine leiomyoma: a prospective randomized placebo controlled trial.
      ). 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 (

      Repros Therapeutics. Repros requests lift of clinical hold on Proellex. April 05, 2010. Available at: http://www.businesswire.com/news/home/20100405005089/en/Repros-Requests-Lift-Clinical-Hold-Proellex. Accessed August 20, 2011.

      ).

       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 generally small, asymptomatic, and resolve without treatment (
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      ,
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Stratton P.
      • Levens E.D.
      • Hartog B.
      • Piquion J.
      • Wei Q.
      • Merino M.
      • et al.
      Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914.
      ,
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Lakha F.
      • Ho P.C.
      • Van der Spuy Z.M.
      • Dada K.
      • Elton R.
      • Glasier A.F.
      • et al.
      A novel estrogen-free oral contraceptive pill for women: multicentre, double-blind, randomized controlled trial of mifepristone and progestogen-only pill (levonorgestrel).
      ,
      • Cameron S.T.
      • Thong K.J.
      • Baird D.T.
      Effect of daily low dose mifepristone on the ovarian cycle and on dynamics of follicle growth.
      ).

       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 (
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      ,
      • Nieman L.K.
      • 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.
      ). Another study of ulipristal acetate (
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      ) and studies of mifepristone and asoprisnil (
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Engman M.
      • Granberg S.
      • Williams A.R.
      • Meng C.X.
      • Lalitkumar P.G.
      • Gemzell-Danielsson K.
      Mifepristone for treatment of uterine leiomyoma: a prospective randomized placebo controlled trial.
      ) 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 (
      • Baird D.T.
      • Thong K.J.
      • Hall C.
      • Cameron S.T.
      Failure of oestrogen induced luteinizing hormone surge in women treated with mifepristone (RU 486) every day for 30 days.
      ,
      • 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 endometrium in normal women: a prospective, randomized, placebo-controlled trial.
      ,
      • Chwalisz K.
      • Elger W.
      • Stickler T.
      • Mattia-Goldberg C.
      • Larsen L.
      The effects of 1-month administration of asoprisnil (J867), a selective progesterone receptor modulator, in healthy premenopausal women.
      ,
      • Croxatto H.B.
      • Salvatierra A.M.
      • Croxatto H.D.
      • Fuentealba B.
      Effects of continuous treatment with low dose mifepristone throughout one menstrual cycle.
      ,
      • Liu J.H.
      • Garzo G.
      • Morris S.
      • Stuenkel C.
      • Ulmann A.
      • Yen S.S.
      Disruption of follicular maturation and delay of ovulation after administration of the antiprogesterone RU486.
      ,
      • 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).
      ,
      • Stratton P.
      • Levens E.D.
      • Hartog B.
      • Piquion J.
      • Wei Q.
      • Merino M.
      • et al.
      Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914.
      ,
      • Chwalisz K.
      • Larsen L.
      • Mattia-Goldberg C.
      • Edmonds A.
      • Elger W.
      • Winkel C.A.
      A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.
      ,
      • Levens E.D.
      • Potlog-Nahari C.
      • Armstrong A.Y.
      • Wesley R.
      • Premkumar A.
      • Blithe D.L.
      • et al.
      CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.
      ) and thus maintain bone mineral density (
      • Grow D.R.
      • Williams R.F.
      • Hsiu J.G.
      • Hodgen G.D.
      Antiprogestin and/or gonadotropin-releasing hormone agonist for endometriosis treatment and bone maintenance: a 1-year primate study.
      ,
      • Kettel L.M.
      • Murphy A.A.
      • Morales A.J.
      • Ulmann A.
      • Baulieu E.E.
      • Yen S.S.
      Treatment of endometriosis with the antiprogesterone mifepristone (RU486).
      ).

      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 nonphysiologic endometrial changes, suppressing bleeding, and reducing the size of uterine leiomyoma. Nonetheless, differences are also apparent, 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 development 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 improve surgical outcomes. Currently, GnRH agonists are often used in this capacity and have been shown to improve preoperative and postoperative hemoglobin levels and hematocrit, reduce the proportion of hysterectomies with difficult surgery, reduce the invasiveness of the surgical technique used, and reduce the duration of hospital stay (
      • Lethaby A.
      • Vollenhoven B.
      • Sowter M.
      Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids.
      ,
      • Lethaby A.
      • Vollenhoven B.
      • Sowter M.
      Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review.
      ). 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 demonstrate 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 (
      • Spitz I.M.
      Clinical utility of progesterone receptor modulators and their effect on the endometrium.
      ).

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