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Takeshi Maruo - One of the best experts on this subject based on the ideXlab platform.

  • SEE PROFILE
    2016
    Co-Authors: Noriyuki Ohara, Jin Liu, Mariko Amano, Takeshi Maruo, Regine Sitruk-ware
    Abstract:

    Progesterone Receptor Modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cell

  • Comparative Effects of SPRM Asoprisnil (J867) on Proliferation, Apoptosis, and the Expression of Growth Factors in Cultured Uterine
    2016
    Co-Authors: Leiomyoma Cells, Normal Myometrial Cells, Takeshi Maruo
    Abstract:

    Progesterone plays a pivotal role in controlling uterine leiomyoma growth. The authors review studies they conducted to evaluate the comparative effects of asoprisnil on proliferation, apoptosis, and growth factor expression in cultured leiomyoma and normal myometrial cells. Treatment with asoprisnil decreased the proliferating cell nuclear antigen–positive rate and the number of viable cells and increased the terminal deoxynucleotidyl transferase-mediated 2′-deoxyuridine 5’-triphosphate nick end labeling– positive rate in cultured leiomyoma cells in a dose-dependent manner ( P <.05). Similarly, asoprisnil decreased Bcl-2 expression and increased cleaved caspase-3 and cleaved poly(adenosine 5′-diphosphate-ribose) polymerase in leiomyoma cells but not in normal myometrial cells. Similarly, asoprisnil decreased epider-mal growth factor (EGF), insulin-like growth factor –I (IGF-I), and transforming growth factor (TGF) β mRNA and protein expression, as well as EGF Receptor, IGF-IRα, and TGF RII protein expres-sion in leiomyoma cells but not in cultured normal myometrial cells. These results suggest that asopris-nil selectively inhibits proliferation by downregulating the growth factors and their Receptor expression and induces apoptosis in leiomyoma cells without affecting proliferation and apoptosis in normal myometrial cells. KEY WORDS: Leiomyomata, selective Progesterone Receptor Modulator

  • Cell-type specific actions of Progesterone Receptor Modulators in the regulation of uterine leiomyoma growth.
    Seminars in Reproductive Medicine, 2010
    Co-Authors: Shigeki Yoshida, Noriyuki Ohara, Wei Chen, Koji Nakabayashi, Hiroko Sasaki, Akira Morikawa, Jiayin Wang, Takeshi Maruo
    Abstract:

    Although the traditional concept supports a crucial role of estrogen in promoting leiomyoma growth, unequivocal evidence has emerged indicating that Progesterone also plays a vital role in the regulation of leiomyoma growth. Recent clinical trials have demonstrated the efficacy of asoprisnil, a selective Progesterone Receptor Modulator, and CDB-2914, a novel Progesterone Receptor Modulator, for the treatment of women with symptomatic leiomyomata. These compounds significantly reduced leiomyoma and uterine volume and improved leiomyoma-related symptoms without serious complications. However, the precise mechanism whereby these compounds cause leiomyoma regression remains poorly understood. Our extensive in vitro studies have provided novel evidence for the growth inhibitory effects of asoprisnil and CDB-2914 on cultured leiomyoma cells. Both compounds exhibited antiproliferative, proapoptotic, and antifibrotic actions on cultured leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells. Asoprisnil and/or CDB-2914 modulated the ratio of Progesterone Receptor isoforms (PR-A and PR-B) in cultured leiomyoma cells; decreased the cell viability; suppressed the expression of growth factors, angiogenic factors, and their Receptors in those cells; and induced apoptosis through activating the mitochondrial and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways and eliciting endoplasmic reticulum stress. Furthermore, these compounds suppressed types I and III collagen synthesis by modulating extracellular matrix-remodeling enzymes in cultured leiomyoma cells without affecting those syntheses in cultured normal myometrial cells. These findings indicate that both compounds exert antiproliferative, proapoptotic, and antifibrotic actions on leiomyoma cells in a cell-type specific manner. This supports the notion that asoprisnil and CDB-2914 hold promise for the nonsurgical treatment of uterine leiomyomata.

  • Translational research with Progesterone Receptor Modulator motivated by the use of levonorgestrel-releasing intrauterine system
    Contraception, 2010
    Co-Authors: Takeshi Maruo, Noriyuki Ohara, Shigeki Yoshida, Wei Chen, Koji Nakabayashi, Hiroko Sasaki, Hideto Yamada
    Abstract:

    The use of levonorgestrel-releasing intrauterine system (LNG-IUS) is effective for management of menorrhagic women with uterine myomas because of reduction in menorrhagia. However, the size of myomas during use of LNG-IUS increased in some but decreased in other instances. This prompted us to characterize the effects of Progesterone (P4) on cultured leiomyoma cell growth. Treatment with P4 resulted in increase in epidermal growth factor (EGF) expression in cultured leiomyoma cells, whereas treatment with E2 augmented EGF-R expression in those cells. This indicates that P4 and E2 act in combination to stimulate myoma growth through induction of EGF/EGF-R expression. Bcl-2 expression in leiomyoma cells was up-regulated by P4. Furthermore, P4 augmented proliferating cell nuclear antigen expression in cultured leiomyoma cells but not in cultured normal myometrial cells. This fact let us to examine the effects of Progesterone Receptor Modulator (PRM) on leiomyoma cell proliferation and apoptosis in comparison with normal myometrial cells. Our studies revealed that CDB-2914 inhibits the proliferation, stimulates apoptosis of cultured leiomyoma cells, and inhibits the expression of angiogenic factors (vascular endothelial growth factor and adrenomedullin) and their Receptors in cultured leimyoma cells, without affecting those in cultured normal myometrial cells. We then evaluated the effects of CDB-2914 on extracellular matrix (ECM) components in cultured leiomyoma cells. CDB-2914 increased ECM metalloproteinase inducer, matrix metalloproteinase (MMP)-1, MMP-8 contents and decreased tissue inhibitors of MMP (TIMP)-1, TIMP-2 contents as well as type I and type III collagen contents in cultured leiomyoma cells, without comparable effects on cultured normal myometrial cells. These findings demonstrate that PRM not only inhibits the proliferation and stimulates apoptosis of cultured leiomyoma cells but also suppresses collagen synthesis in a cell-type specific manner. This is meaningful for understanding the molecular mechanism of the usefulness of PRM in the treatment of uterine fibroids.

  • selective Progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
    Human Reproduction, 2008
    Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    BACKGROUND: A recent clinical trial demonstrated that selective Progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

Kristof Chwalisz - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of the selective Progesterone Receptor Modulator asoprisnil for heavy menstrual bleeding with uterine fibroids pooled analysis of two 12 month placebo controlled randomized trials
    Human Reproduction, 2019
    Co-Authors: Elizabeth A Stewart, Walter Elger, Alistair R.w. Williams, Michael P Diamond, Bruce R Carr, Evan R Myers, Robert A Feldman, C Mattiagoldberg, B Schwefel, Kristof Chwalisz
    Abstract:

    STUDY QUESTION Can asoprisnil, a selective Progesterone Receptor Modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S) This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT’S ENROLMENT 12 September 2002; 6 September 2002.

  • 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 Journal of Clinical Endocrinology & Metabolism, 2008
    Co-Authors: Julia Wilkens, Kristof Chwalisz, Iain T. Cameron, Cong Han, Jane Walker, Susan Ingamells, Alexandra C. Lawrence, Mary Ann Lumsden, Dharani K. Hapangama, Alistair R.w. Williams
    Abstract:

    Introduction: Asoprisnil, a novel orally active selective Progesterone Receptor Modulator, is being studied for the management of symptomatic uterine leiomyomata. The exact mechanism of action is not yet discerned. The primary objectives of this double-blind, randomized, placebo-controlled study included evaluation of the effect of asoprisnil on uterine artery blood flow. Furthermore, we assessed effects of asoprisnil on leiomyoma symptoms. Patients and Methods: Thirty-three premenopausal patients scheduled for hysterectomy due to symptomatic uterine leiomyomata were recruited in four centers and treated with 10 or 25 mg asoprisnil or placebo for 12 wk before surgery. At baseline and before hysterectomy, all patients underwent sonographic assessment to measure impedance to uterine artery blood flow, determined by resistance index and pulsatility index, as well as volumes of largest leiomyoma and uterus. In addition, patients recorded intensity and frequency of menstrual bleeding on a menstrual pictogram. ...

  • selective Progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
    Human Reproduction, 2008
    Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    BACKGROUND: A recent clinical trial demonstrated that selective Progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

  • selective Progesterone Receptor Modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells
    American Journal of Physiology-endocrinology and Metabolism, 2007
    Co-Authors: Noriyuki Ohara, Deborah A Demanno, Kristof Chwalisz, Jin Liu, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399–1412, 2007) has demonstrated that the selective Progesterone Receptor modulat...

  • a randomized controlled trial of asoprisnil a novel selective Progesterone Receptor Modulator in women with uterine leiomyomata
    Obstetrical & Gynecological Survey, 2007
    Co-Authors: Kristof Chwalisz, Walter Elger, Lois Larsen, C Mattiagoldberg, Anthony Edmonds, Craig A Winkel
    Abstract:

    The only effective medical treatment of symptomatic uterine leiomyomas has been the gonadotropin-releasing hormone agonist leuprolide acetate depot, which carries a risk of producing hypoestrogenic symptoms. High-dose progestin therapy has been used to control heavy uterine bleeding (HUB) but may cause breakthrough bleeding. Another option is asoprisnil, a selective Progesterone (P) Receptor Modulator that has mixed P agonist and antagonist actions and is highly uterine-selective. In both primate and human studies, it has induced amenorrhea and suppressed endometrial growth. This randomized prospective, double-blind, placebo-control study, carried out at 28 sites in the United States and 1 in Canada, enrolled 129 women 18 to 49 years of age who had at least one leiomyoma measuring 3 cm or more in diameter or multiple small lesions producing a uterine volume exceeding 200 cm 3 . All participants had normal menses and no other significant pelvic pathology. They received either asoprisnil in a daily oral dose of 5, 10, or 25 mg or a placebo for 12 weeks. Uterine bleeding was monitored by daily diaries, and uterine volume was measured sonographically. The 5-, 10-, and 25-mg doses of asoprisnil suppressed uterine bleeding in 28%, 64%, and 83% of patients, respectively. These patients did not have even light bleeding while being treated. No placebo recipient responded. Dose-related rates of amenorrhea, defined as no bleeding or only spotting, were 16%, 36%, and 70%, respectively. Compared with placebo, treatment with 25 mg daily for 4 and 8 weeks was associated with a statistically significant decrease in leiomyoma volume, and by week 12 it was reduced by 36%. The higher doses of asoprisnil significantly reduced bloating and, in patients given 25 mg daily, pelvic pressure also declined significantly by week 12. Hemoglobin concentrations increased significantly more in all treatment groups than in placebo recipients. Treatment had no apparent effect on pelvic pain or dyspareunia. Hypoestrogenic symptoms were minimal. Endometrial thickness was similar in the treatment and placebo groups at the end of the study, and no hyperplasia or other adverse changes were observed. Asoprisnil therapy appeared to inhibit basal gonadotropin concentrations. There were no clinically significant changes in blood chemistry or blood pressure, and no clinically relevant cervical abnormalities were observed. Adverse effects of all types were similarly frequent in the treatment and placebo groups. These findings support the use of asoprisnil to treat complaints related to uterine leiomyomas, notably HUB and bulk-related symptoms, without significantly altering blood estrogen levels at the same time. Treatment with doses as high as 25 mg daily for 12 weeks was well tolerated.

Alistair R.w. Williams - One of the best experts on this subject based on the ideXlab platform.

  • safety and efficacy of the selective Progesterone Receptor Modulator asoprisnil for heavy menstrual bleeding with uterine fibroids pooled analysis of two 12 month placebo controlled randomized trials
    Human Reproduction, 2019
    Co-Authors: Elizabeth A Stewart, Walter Elger, Alistair R.w. Williams, Michael P Diamond, Bruce R Carr, Evan R Myers, Robert A Feldman, C Mattiagoldberg, B Schwefel, Kristof Chwalisz
    Abstract:

    STUDY QUESTION Can asoprisnil, a selective Progesterone Receptor Modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? SUMMARY ANSWER Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. WHAT IS KNOWN ALREADY In a 3-month study, asoprisnil (5, 10 and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dose-dependent manner. STUDY DESIGN, SIZE, DURATION In two Phase 3, double-blind, randomized, placebo-controlled, multicentre studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg or placebo (2:2:1) once daily for up to 12 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N = 907). The primary efficacy endpoint was the percentage of women who met all three predefined criteria at 12 months or the final month for patients who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume and health-related quality of life (HRQL). MAIN RESULTS AND THE ROLE OF CHANCE In all, 90% and 93% of women in the asoprisnil 10-mg and 25-mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P < 0.001). Similar results were observed at month 6 (P < 0.001). The percentage of women who achieved amenorrhea in any specified month ranged from 66-78% in the asoprisnil 10-mg group and 83-93% in the asoprisnil 25-mg group, significantly higher than with placebo (3-12%, P < 0.001). Hemoglobin increased rapidly (by month 2) with asoprisnil treatment and was significantly higher versus placebo throughout treatment. The primary fibroid and uterine volumes were significantly reduced from baseline through month 12 with asoprisnil 10 mg (median changes up to -48% and -28%, respectively) and 25 mg (median changes up to -63% and -39%, respectively) versus placebo (median changes up to +16% and +13%, respectively; all P < 0.001). Dose-dependent, significant improvements in HRQL (Uterine Fibroid Symptom and Quality of Life instrument) were observed with asoprisnil treatment. Asoprisnil was generally well tolerated. Endometrial biopsies indicated dose- and time-dependent decreases in proliferative patterns and increases in quiescent or minimally stimulated endometrium at month 12 of treatment. Although not statistically significantly different at month 6, mean endometrial thickness at month 12 increased by ~2 mm in both asoprisnil groups compared with placebo (P < 0.01). This effect was associated with cystic changes in the endometrium on MRI and ultrasonography, which led to invasive diagnostic and therapeutic procedures in some asoprisnil-treated women. LIMITATIONS, REASONS FOR CAUTION Most study participants were black; few Asian and Hispanic women participated. The study duration may have been insufficient to fully characterize the endometrial effects. WIDER IMPLICATIONS OF THE FINDINGS Daily uninterrupted treatment with asoprisnil was highly effective in controlling menstrual bleeding, improving anemia, reducing fibroid and uterine volume, and increasing HRQL in women with HMB associated with uterine fibroids. However, this treatment led to an increase in endometrial thickness and invasive diagnostic and therapeutic procedures, with potential unknown consequences. STUDY FUNDING/COMPETING INTEREST(S) This trial was funded by AbbVie Inc. (prior sponsors: TAP Pharmaceutical Products Inc., Abbott Laboratories). E.A. Stewart was a site investigator in the Phase 2 study of asoprisnil and consulted for TAP during the design and conduct of these studies while at Harvard Medical School and Brigham and Women's Hospital. She received support from National Institutes of Health grants HD063312, HS023418 and HD074711 and research funding, paid to Mayo Clinic for patient care costs related to an NIH-funded trial from InSightec Ltd. She consulted for AbbVie, Allergan, Bayer HealthCare AG, Gynesonics, and Welltwigs. She received royalties from UpToDate and the Med Learning Group. M.P. Diamond received research funding for the conduct of the studies paid to the institution and consulted for AbbVie. He is a stockholder and board and director member of Advanced Reproductive Care. He has also received funding for study conduct paid to the institution from Bayer and ObsEva. A.R.W. Williams consulted for TAP and Repros Therapeutics Inc. He has current consultancies with PregLem SA, Gedeon Richter, HRA Pharma and Bayer. B.R. Carr consulted for and received research funding from AbbVie. E.R. Myers consulted for AbbVie, Allergan and Bayer. R.A. Feldman received compensation for serving as a principal investigator and participating in the conduct of the trial. W. Elger was co-inventor of several patents related to asoprisnil. C. Mattia-Goldberg is a former employee of AbbVie and may own AbbVie stock or stock options. B.M. Schwefel and K. Chwalisz are employees of AbbVie and may own AbbVie stock or stock options. TRIAL REGISTRATION NUMBER NCT00152269, NCT00160381 (clinicaltrials.gov). TRIAL REGISTRATION DATE 7 September 2005; 8 September 2005. DATE OF FIRST PATIENT’S ENROLMENT 12 September 2002; 6 September 2002.

  • Characterization of Molecular Changes in Endometrium Associated With Chronic Use of Progesterone Receptor Modulators: Ulipristal Acetate Versus Mifepristone
    Reproductive Sciences, 2018
    Co-Authors: Athilakshmi Kannan, Alistair R.w. Williams, Regine Sitruk-ware, Arpita Bhurke, Parameswaran G. Lalitkumar, Kristina Gemzell-danielsson, Robert N. Taylor, Milan K. Bagchi, Indrani C. Bagchi
    Abstract:

    Ulipristal acetate (UPA) is a selective Progesterone Receptor Modulator (PRM), which is used as an emergency contraceptive in women. Recent studies demonstrated the efficacy of an UPA contraceptive vaginal ring (UPA-CVR) as a blocker of ovulation. However, the endometrium of women exposed to UPA over a 6-month period display glandular changes, termed PRM-associated endometrial changes (PAECs). We, therefore, investigated whether UPA-induced PAECs are associated with altered expression of the transcription factor heart- and neural crest derivatives-expressed protein 2 (HAND2) whose downregulation is observed in endometrial epithelial hyperplasia and cancer. Our results showed that while exposure to mifepristone, a well-known PRM, leads to suppression of endometrial HAND2 expression, long-term exposure to UPA-CVR did not cause downregulation of this marker. Further studies, using human primary endometrial stromal cells, confirmed that whereas mifepristone-mediated suppression of HAND2 elevated the levels of its downstream target fibroblast growth factor 18, UPA did not significantly alter the expression of this growth factor. A rationale for the differential regulation of HAND2 by these PRMs was provided by our observation that mifepristone-bound Progesterone Receptors turn over at a faster rate than those bound to UPA. Collectively, these results support the selective effects of different PRMs and indicate that chronic exposure to UPA does not alter the HAND2 pathway whose dysregulation is linked to complex atypical endometrial hyperplasia and cancer. The results from this study involving a limited number of clinical samples should pave the way for a larger study to determine the safety of UPA for long-term use.

  • Selective Progesterone Receptor Modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium.
    Human Reproduction, 2017
    Co-Authors: Lucy Whitaker, Alison D. Murray, Rebecca Matthews, Grace G Shaw, Alistair R.w. Williams, Philippa T. K. Saunders, Hilary O. D. Critchley
    Abstract:

    STUDY QUESTION What is the impact of administration of the selective Progesterone Receptor Modulator (SPRM), ulipristal acetate (UPA) on the endometrium of women with fibroids? SUMMARY ANSWER UPA administration altered expression of sex-steroid Receptors and Progesterone-regulated genes and was associated with low levels of glandular and stromal cell proliferation. WHAT IS KNOWN ALREADY Administration of all SPRM class members results in PAEC (Progesterone Receptor Modulator associated endometrial changes). Data on the impact of the SPRM UPA administration on endometrial sex-steroid Receptor expression, Progesterone (P)-regulated genes and cell proliferation are currently lacking. STUDY DESIGN SIZE, DURATION Observational study with histological and molecular analyses to delineate impact of treatment with UPA on endometrium. Endometrial samples (n = 9) were collected at hysterectomy from women aged 39 to 49 with uterine fibroids treated with UPA (oral 5 mg daily) for 9-12 weeks. Control proliferative (n = 9) and secretory (n = 9) endometrium from women aged 38-52 with fibroids were derived from institutional tissue archives. PARTICIPANTS/MATERIALS, SETTING, METHODS Study setting was a University Research Institute. Endometrial biopsies were collected with institutional ethical approval and written informed consent. Concentrations of mRNAs encoded by steroid Receptors, P-regulated genes and factors in decidualised endometrium were quantified with qRT-PCR. Immunohistochemistry was employed for localization of Progesterone (PR, PRB), androgen (AR), estrogen (ERα) Receptors and expression of FOXO1, HAND2, HOXA10, PTEN homologue. Endometrial glandular and stromal cell proliferation was objectively quantified using Ki67. MAIN RESULTS AND THE ROLE OF CHANCE UPA induced morphological changes in endometrial tissue consistent with PAEC. A striking change in expression patterns of PR and AR was detected compared with either proliferative or secretory phase samples. There were significant changes in pattern of expression of mRNAs encoded by IGFBP-1, FOXO1, IL-15, HAND2, IHH and HOXA10 compared with secretory phase samples consistent with low agonist activity in endometrium. Expression of mRNA encoded by FOXM1, a transcription factor implicated in cell cycle progression, was low in UPA-treated samples. Cell proliferation (Ki67 positive nuclei) was lower in samples from women treated with UPA compared with those in the proliferative phase. LARGE SCALE DATA N/A. LIMITATIONS REASONS FOR CAUTION A small number of well-characterized patients were studied in-depth. The impacts on morphology, molecular and cellular changes with SPRM, UPA administration on symptom control remains to be determined. WIDER IMPLICATIONS OF THE FINDINGS P plays a pivotal role in endometrial function. P-action is mediated through interaction with the PR. These data provide support for onward development of the SPRM class of compounds as effective long-term medical therapy for heavy menstrual bleeding. STUDY FUNDING/COMPETING INTEREST(S) H.O.D.C. received has clinical research support for laboratory consumables and staff from Bayer Pharma Ag and provides consultancy advice (no personal remuneration) for Bayer Pharma Ag, PregLem SA, Gedeon Richter, Vifor Pharma UK Ltd, AbbVie Inc.; A.R.W.W. has received consultancy payments from Bayer, Gedeon Richter, Preglem SA, HRA Pharma; L.H.R.W., A.A.M., R.M., G.S. and P.T.K.S. have no conflicts of interest. Study funded in part from each of: Medical Research Council (G1002033; G1100356/1; MR/N022556/1); National Health Institute for Health Research (12/206/520) and TENOVUS Scotland.

  • a randomized study on pharmacodynamic effects of vaginal rings delivering the Progesterone Receptor Modulator ulipristal acetate research for a novel estrogen free method of contraception
    Contraception, 2014
    Co-Authors: Yongmei Huang, Alistair R.w. Williams, Vivian Brache, Horacio B Croxatto, Narender Kumar, Jeffrey T Jensen, Leila Cochon, Maria Jose Miranda, Heather Sussman, Elena Hoskin
    Abstract:

    Objective To determine whether a 3-month contraceptive vaginal ring (CVR) delivering ulipristal acetate (UPA) can inhibit ovulation in 90% of cycles.

  • Selective Progesterone Receptor Modulators.
    Current Opinion in Obstetrics and Gynecology, 2014
    Co-Authors: Lucy Whitaker, Alistair R.w. Williams, Hilary O. D. Critchley
    Abstract:

    PURPOSE OF REVIEW: Review of recent data from clinical trials and descriptions of endometrial morphology with administration of selective Progesterone Receptor Modulators (SPRMs). RECENT FINDINGS: Recent reports concerning administration of SPRMs specifically the efficacy of ulipristal acetate in reducing fibroid size and rapid control of menstrual blood loss have renewed clinical interest in this class of compound. Histological data from studies with SPRMs report that this class of drugs is associated with Progesterone Receptor Modulator-associated endometrial changes. Data on mechanisms of action are lacking. The antagonistic Progesterone effect of SPRMs has shown promising results in animal studies with endometriosis. Sex steroid Receptor effects of PRMs outside the reproductive tract raise the potential for use in neurology and oncology and although there are several randomized trials in these areas there are limited small studies published to date. SUMMARY: The SPRM ulipristal acetate is an effective treatment for preoperative treatment of fibroids and a reliable emergency contraceptive. This class of compounds holds the potential for long-term effective medical management of fibroids and may have utility in the management of other sex steroid-dependent conditions.

Noriyuki Ohara - One of the best experts on this subject based on the ideXlab platform.

  • SEE PROFILE
    2016
    Co-Authors: Noriyuki Ohara, Jin Liu, Mariko Amano, Takeshi Maruo, Regine Sitruk-ware
    Abstract:

    Progesterone Receptor Modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cell

  • Cell-type specific actions of Progesterone Receptor Modulators in the regulation of uterine leiomyoma growth.
    Seminars in Reproductive Medicine, 2010
    Co-Authors: Shigeki Yoshida, Noriyuki Ohara, Wei Chen, Koji Nakabayashi, Hiroko Sasaki, Akira Morikawa, Jiayin Wang, Takeshi Maruo
    Abstract:

    Although the traditional concept supports a crucial role of estrogen in promoting leiomyoma growth, unequivocal evidence has emerged indicating that Progesterone also plays a vital role in the regulation of leiomyoma growth. Recent clinical trials have demonstrated the efficacy of asoprisnil, a selective Progesterone Receptor Modulator, and CDB-2914, a novel Progesterone Receptor Modulator, for the treatment of women with symptomatic leiomyomata. These compounds significantly reduced leiomyoma and uterine volume and improved leiomyoma-related symptoms without serious complications. However, the precise mechanism whereby these compounds cause leiomyoma regression remains poorly understood. Our extensive in vitro studies have provided novel evidence for the growth inhibitory effects of asoprisnil and CDB-2914 on cultured leiomyoma cells. Both compounds exhibited antiproliferative, proapoptotic, and antifibrotic actions on cultured leiomyoma cells in the absence of comparable effects on cultured normal myometrial cells. Asoprisnil and/or CDB-2914 modulated the ratio of Progesterone Receptor isoforms (PR-A and PR-B) in cultured leiomyoma cells; decreased the cell viability; suppressed the expression of growth factors, angiogenic factors, and their Receptors in those cells; and induced apoptosis through activating the mitochondrial and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathways and eliciting endoplasmic reticulum stress. Furthermore, these compounds suppressed types I and III collagen synthesis by modulating extracellular matrix-remodeling enzymes in cultured leiomyoma cells without affecting those syntheses in cultured normal myometrial cells. These findings indicate that both compounds exert antiproliferative, proapoptotic, and antifibrotic actions on leiomyoma cells in a cell-type specific manner. This supports the notion that asoprisnil and CDB-2914 hold promise for the nonsurgical treatment of uterine leiomyomata.

  • Translational research with Progesterone Receptor Modulator motivated by the use of levonorgestrel-releasing intrauterine system
    Contraception, 2010
    Co-Authors: Takeshi Maruo, Noriyuki Ohara, Shigeki Yoshida, Wei Chen, Koji Nakabayashi, Hiroko Sasaki, Hideto Yamada
    Abstract:

    The use of levonorgestrel-releasing intrauterine system (LNG-IUS) is effective for management of menorrhagic women with uterine myomas because of reduction in menorrhagia. However, the size of myomas during use of LNG-IUS increased in some but decreased in other instances. This prompted us to characterize the effects of Progesterone (P4) on cultured leiomyoma cell growth. Treatment with P4 resulted in increase in epidermal growth factor (EGF) expression in cultured leiomyoma cells, whereas treatment with E2 augmented EGF-R expression in those cells. This indicates that P4 and E2 act in combination to stimulate myoma growth through induction of EGF/EGF-R expression. Bcl-2 expression in leiomyoma cells was up-regulated by P4. Furthermore, P4 augmented proliferating cell nuclear antigen expression in cultured leiomyoma cells but not in cultured normal myometrial cells. This fact let us to examine the effects of Progesterone Receptor Modulator (PRM) on leiomyoma cell proliferation and apoptosis in comparison with normal myometrial cells. Our studies revealed that CDB-2914 inhibits the proliferation, stimulates apoptosis of cultured leiomyoma cells, and inhibits the expression of angiogenic factors (vascular endothelial growth factor and adrenomedullin) and their Receptors in cultured leimyoma cells, without affecting those in cultured normal myometrial cells. We then evaluated the effects of CDB-2914 on extracellular matrix (ECM) components in cultured leiomyoma cells. CDB-2914 increased ECM metalloproteinase inducer, matrix metalloproteinase (MMP)-1, MMP-8 contents and decreased tissue inhibitors of MMP (TIMP)-1, TIMP-2 contents as well as type I and type III collagen contents in cultured leiomyoma cells, without comparable effects on cultured normal myometrial cells. These findings demonstrate that PRM not only inhibits the proliferation and stimulates apoptosis of cultured leiomyoma cells but also suppresses collagen synthesis in a cell-type specific manner. This is meaningful for understanding the molecular mechanism of the usefulness of PRM in the treatment of uterine fibroids.

  • selective Progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
    Human Reproduction, 2008
    Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    BACKGROUND: A recent clinical trial demonstrated that selective Progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

  • Progesterone Receptor Modulator cdb 2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells
    Molecular Human Reproduction, 2008
    Co-Authors: Noriyuki Ohara, Jin Liu, Mariko Amano, Regine Sitrukware, Shigeki Yoshida, Takeshi Maruo
    Abstract:

    Effects of Progesterone Receptor Modulator CDB-2914 on the expression of the extracellular matrix (ECM) components were examined in cultured human uterine leiomyoma and myometrial cells. ECM metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagen levels were assessed by Western blot analysis, MMP activity assay and real-time RT – PCR. RNA interference (RNAi) of EMMPRIN was performed using small interfering mRNA. In cultured leiomyoma cells, CDB-2914 treatment at concentrations greater than or equal to 10 28 M significantly increased EMMPRIN, MMP-1 and MMP-8 protein contents and MMP-1, MMP-2, MMP-3 and MMP-9 mRNA levels, and activity of MMP-1, MMP-2, MMP-3 and MMP-9 in the medium. TIMP-1 and TIMP-2 were significantly decreased at mRNA and protein levels by CDB-2914 treatment at concentrations � 10 27 M in these cells. CDB-2914 treatment decreased types I and III collagen protein contents. However, CDB-2914 treatment did not affect the ECM component expression in cultured myometrial cells. RNAi of EMMPRIN abrogated CDB-2914-mediated both induction of MMPs and reduction of TIMPs and collagens in cultured leiomyoma cells. These results suggest that CDB-2914 modulates the expression of EMMPRIN, MMPs, TIMPs and collagens in cultured leiomyoma cells without comparable effects on myometrial cells.

Deborah A Demanno - One of the best experts on this subject based on the ideXlab platform.

  • selective Progesterone Receptor Modulator asoprisnil down regulates collagen synthesis in cultured human uterine leiomyoma cells through up regulating extracellular matrix metalloproteinase inducer
    Human Reproduction, 2008
    Co-Authors: Akira Morikawa, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    BACKGROUND: A recent clinical trial demonstrated that selective Progesterone Receptor Modulator asoprisnil is effective in reducing uterine leiomyoma volume. We investigated the effects of asoprisnil in vitro on the expression of the extracellular matrix (ECM)-remodeling enzymes and collagens in cultured leiomyoma and matching normal myometrial cells. METHODS: The expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs) and collagens were assessed by western blot analysis. RESULTS: Untreated cultured leiomyoma cells had significantly lower EMMPRIN ( P< 0.05), MMP-1 ( P< 0.05) and membrane type 1-MMP (MT1-MMP) ( P< 0.01) protein contents, but significantly higher TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.05) and type III ( P< 0.01) collagen protein contents compared with untreated cultured myometrial cells. Treatment with asoprisnil at concentrations � 10 27 M for 48 h significantly ( P< 0.05) increased EMMPRIN, MMP-1 and MT1-MMP protein contents, and decreased TIMP-1 ( P< 0.05), TIMP-2 ( P< 0.01), type I ( P< 0.01) and type III ( P< 0.05 at 10 27 M; P< 0.01 at 10 26 M) collagen protein contents in cultured leiomyoma cells compared with control cultures. However, asoprisnil treatment did not affect the protein contents of ECM-remodeling enzymes and collagens in cultured myometrial cells. CONCLUSIONS: These results suggest that asoprisnil may reduce collagen deposit in the ECM of cultured leiomyoma cells through decreasing collagen synthesis and enhancing the expression of EMMPRIN, MMPs and TIMPs without comparable effects on cultured myometrial cells.

  • selective Progesterone Receptor Modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells
    American Journal of Physiology-endocrinology and Metabolism, 2007
    Co-Authors: Noriyuki Ohara, Deborah A Demanno, Kristof Chwalisz, Jin Liu, Shigeki Yoshida, Koji Nakabayashi, Takeshi Maruo
    Abstract:

    A recent clinical trial (Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. Fertil Steril 87: 1399–1412, 2007) has demonstrated that the selective Progesterone Receptor modulat...

  • 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 myometri
    The Journal of Clinical Endocrinology and Metabolism, 2007
    Co-Authors: Hiroko Sasaki, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Shigeki Yoshida, Jiayin Wang, Takeshi Maruo
    Abstract:

    Context: We previously demonstrated that asoprisnil, a selective Progesterone Receptor Modulator, induces apoptosis of cultured uterine leiomyoma cells. This study was conducted to evaluate whether asoprisnil activates TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptotic pathway in cultured uterine leiomyoma and matching myometrial cells. Objective and Methods: After subculture in phenol red-free DMEM supplemented with 10% fetal bovine serum for 120 h, cultured cells were stepped down to serum-free conditions for 24 h in the absence or presence of graded concentrations of asoprisnil. The levels of TRAIL signaling molecules and cellular inhibitors of apoptosis protein were assessed by Western blot analysis. Results: TRAIL contents in untreated cultured leiomyoma cells were significantly (P < 0.01) lower compared with those in untreated cultured myometrial cells. There was no difference in death Receptor (DR)4 and DR5 contents between the two types of cells. Asoprisnil treatment significantly (P...

  • 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
    Human Reproduction, 2006
    Co-Authors: Jiayin Wang, Deborah A Demanno, Kristof Chwalisz, Noriyuki Ohara, Takeshi Maruo, Wei Chen, Hiroko Sasaki, Akira Morikawa, Zhuo Wang
    Abstract:

    BACKGROUND This study was conducted to evaluate the effects of a novel selective Progesterone Receptor Modulator (SPRM) asoprisnil on the expression of growth factors and their Receptors and on growth factor-induced proliferation of cultured uterine leiomyoma and matching myometrial cells. METHODS The expression of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I) and transforming growth factor (TGFbeta3) was assessed by immunocytochemistry and semi-quantitative RT-PCR. The expression of phosphorylated EGF Receptor (p-EGFR), IGF-I Receptor alpha subunit (IGF-IRalpha) and phosphorylated TGFbeta Receptor type II (p-TGFbeta RII) was assessed by Western blot analysis. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. RESULTS Treatment with 10(-7) M asoprisnil decreased EGF, IGF-I and TGFbeta3 mRNA and protein expression as well as p-EGFR, IGF-IRalpha and p-TGFbeta RII protein expression in leiomyoma cells cultured for 72 h. EGF (100 ng/ml), IGF-I (100 ng/ml) and TGFbeta3 (10 ng/ml) increased the number of viable leiomyoma cells cultured for 72 h, whereas the concomitant treatment with 10(-7) M asoprisnil antagonized the growth factor-induced increase in leiomyoma cell proliferation. In cultured myometrial cells, however, asoprisnil affected neither the growth factor and their Receptor expression nor the cell proliferation. CONCLUSION Asoprisnil inhibits the expression of EGF, IGF-I, TGFbeta3 and their Receptors in cultured leiomyoma cells without affecting their expressions in myometrial cells.

  • selective Progesterone Receptor Modulator development and use in the treatment of leiomyomata and endometriosis
    Endocrine Reviews, 2005
    Co-Authors: Kristof Chwalisz, Deborah A Demanno, Gerd Schubert, Craig A Winkel, Maria Pérez, Walter Elger
    Abstract:

    Selective Progesterone Receptor Modulators (SPRMs) represent a new class of Progesterone Receptor ligands. SPRMs exert clinically relevant tissue-selective Progesterone agonist, antagonist, or mixed agonist/antagonist effects on various Progesterone target tissues in vivo. Asoprisnil (J867) is the first SPRM to reach an advanced stage of clinical development for the treatment of symptomatic uterine fibroids and endometriosis. Asoprisnil belongs to the class of 11β-benzaldoxime-substituted estratrienes that exhibit partial Progesterone agonist/antagonist effects with high Progesterone Receptor specificity in animals and humans. Asoprisnil has no antiglucocorticoid activity in humans at therapeutic doses. It exhibits endometrial antiproliferative effects on the endometrium and breast in primates. Unlike Progesterone antagonists, asoprisnil does not induce labor in relevant models of pregnancy and parturition. It induces amenorrhea primarily by targeting the endometrium. In human subjects with uterine fibroi...