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Manuela Farris - One of the best experts on this subject based on the ideXlab platform.
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Selective progesterone receptor modulators 1: use during pregnancy.
Expert Opinion on Pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: A large number of synthetic compounds known as selective progesterone receptor modulators can bind to progesterone receptors: the ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. Objectives: Only a dozen or so selective progesterone receptor modulators have been tested to any significant extent: among them are mifepristone (RU 486), asoprisnil (J867), Onapristone (ZK 98 299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Their clinical applications during pregnancy are discussed. Methods: A careful evaluation of existing major review papers and recently published articles was carried out focusing on mifepristone, the most widely studied selective progesterone receptor modulator, which was first used for the voluntary interruption of an early gestation. Other selective progesterone receptor modulators, especially those with partial agonist action, have shown little activity during pregnancy in animal models. Re...
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Selective progesterone receptor modulators 2: use in reproductive medicine.
Expert Opinion on Pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. Objective: There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), Onapristone (ZK 98299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. Results/conclusions: Outside pregnancy, selective progesteron...
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Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry
Expert opinion on pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: A number of synthetic steroids are capable of modulating progesterone receptors with a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. The best known of these are mifepristone (RU 486), asoprisnil (J 867), Onapristone (ZK 98299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Objective: Outside reproduction selective modulators of progesterone receptors have been under investigation for a large variety of indications, for example in oncology as adjuvants in breast, cervical, endometrial, ovarian and prostate cancer, as well as inoperable meningioma and leiomyosarcoma. In addition, they have been used as antiglucocorticoids. It is therefore useful to review the results obtained in these conditions. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone but also on those other selective modulators of proge...
Kristof Chwalisz - One of the best experts on this subject based on the ideXlab platform.
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Expression of MAPkinases (Erk1/2) during decidualization in the rat: regulation by progesterone and nitric oxide.
Molecular human reproduction, 2002Co-Authors: T. Thienel, Kristof Chwalisz, Elke WinterhagerAbstract:The interaction between nitric oxide (NO), progesterone and the MAPkinase signalling pathway involved in decidualization was studied using immunohistochemistry during implantation in the rat. Early pregnant rats were treated with the inhibitor of nitric oxide synthesizing enzyme iNOS, aminoguanidine, either alone or in combination with the low dose antiprogestin, Onapristone. The combined treatment was most effective on days 7 and 9 post coitum leading to a complete loss of embryos. The expression pattern of activated MAPkinases, Erk1/2 and iNOS appeared to be associated with the differentiation process of decidualization. A maximum staining of both enzymes was observed on day 9 post coitum in the mesometrial decidua. In addition, Erk1/2 and iNOS were highly coexpressed around the mesometrial sinusoids. Combined treatment with aminoguanidine and Onapristone for 3 days led to a transient suppression of Erk1/2 and abolished Cox2 expression. Concomitantly, angiogenesis was reduced and dilated sinusoids were missing in the mesometrial decidua. In conclusion, our study suggests that (i) the member of the mitogen-activated protein kinase (MAPK) family, Erk1/2, is activated during implantation and may play an important role during the decidualization process, and (ii) this enzyme may be regulated by both progesterone and NO.
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Endocrine pharmacological characterization of progesterone antagonists and progesterone receptor modulators with respect to PR-agonistic and antagonistic activity.
Steroids, 2000Co-Authors: Walter Elger, Julia Bartley, Birgitt Schneider, Gunther Kaufmann, Gerd Schubert, Kristof ChwaliszAbstract:Studies were conducted to assess progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) with respect to PR agonistic and antagonistic activities in vivo. These properties are not always adequately reflected in transactivation in vitro models. Studies were performed in pregnant rats, estrogen-primed rabbits (McPhail -Test), and cycling and pregnant guinea pigs. Tested compounds included mifepristone (RU486), Onapristone, J867, J956, J1042, and ZK137316. J-compounds induced sub-maximum endometrial transformation and, paradoxically, inhibited effects of progesterone in rabbits. Mifepristone, Onapristone, and ZK137316 behaved as ‘pure’ antagonists in this species. Inhibition of uterine PGF2α secretion and inhibition of luteolysis in cycling guinea pigs were more sensitive parameters of PR-agonistic and antagonistic properties. ‘Pure’ PAs inhibited uterine PGF2α secretion and luteal regression completely. The PR agonist R5020 reversed both effects which demonstrates a PR mediation. Agonistic PRMs (J-substances and mifepristone) showed no or blunted antiluteolytic effects compared to the ‘pure’ PR antagonist Onapristone. When tested in pregnant guinea pigs for their labor-inducing potential, PR agonistic PRMs had much reduced or abolished abortifacient activity compared to mifepristone (mifepristone > J956 > J867/J912 > J1042). However, in cycling animals, superior antiovulatory and antiproliferative properties of the J-substances were seen. Antiovulatory effects of ‘pure’ and agonistic PRMs are probably due to different mechanisms. The relevance of rodent studies for antiovulatory and uterine antiproliferative effects for the human is still uncertain. The non-abortifacient PRM J1042 induced stromal compaction and inhibition of endometrial proliferation in monkeys, but this effect was not stronger than that of the ‘purer’ PAs. ‘Pure’ PAs are important pharmacological tools analogous to PRKO models to study the role of PR in the menstrual cycle and in pregnancy.
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Synergistic role of nitric oxide and progesterone during the establishment of pregnancy in the rat.
Human reproduction (Oxford England), 1999Co-Authors: Kristof Chwalisz, Elke Winterhager, Thomas Thienel, Robert E. GarfieldAbstract:Successful pregnancy is strictly dependent on the trophoblast-decidual interaction and on an adequate blood supply to the implantation sites. Nitric oxide (NO) has been shown to play an important role during advanced gestation, although its role during early pregnancy is unclear. The aim of the present study in rats was to evaluate whether NO plays a role during the preimplantation [days 1-4 post coitum (p.c.)] and peri-implantation (days 6-8 p.c.) phases of pregnancy. The rats were treated with the non-specific nitric oxide synthase (NOS) inhibitor N G -nitro-L-arginine methyl ester (L-NAME), and the iNOS inhibitor aminoguanidine in the presence and absence of low-dose antiprogestin, Onapristone, and evaluated on days 9 p.c. and 19 p.c., respectively. Before implantation, the treatments alone (L-NAME, aminoguanidine, Onapristone) had little effect on pregnancy outcome. Conversely, aminoguanidine plus Onapristone treatment completely prevented pregnancy, whereas L-NAME plus Onapristone reduced the pregnancy rate to approximately 50%. In addition, both treatments drastically reduced decidualization. Oviductal flushing experiments revealed arrest of embryo development at around the 8-cell stage after aminoguanidine plus Onapristone treatment on days 1-4 p.c. Similarly, treatment during the peri-implantation period with L-NAME, aminoguanidine, and Onapristone each had only marginal effects on pregnancy. However, a combination of L-NAME and Onapristone, and aminoguanidine plus Onapristone prevented pregnancy in 71% and 42% of dams, respectively, as determined on day 19 p.c. These treatments also markedly inhibited the decidualization process. This study demonstrates synergistic effects of NOS inhibitors and an antiprogestin in preventing pregnancy. NOS, particularly the cytokine- and progesterone-inducible iNOS, may represent a new target for novel therapeutic agents capable of promoting or inhibiting pregnancy.
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Steroid regulation of prostaglandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labor
The Journal of clinical endocrinology and metabolism, 1999Co-Authors: Falguni A. Patel, Kristof Chwalisz, Vicki L. Clifton, John R. G. ChallisAbstract:NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) is the key catabolic enzyme controlling levels of biologically active PGs. PGDH is localized to syncytiotrophoblast in placenta, and to trophoblast cells in chorion. To examine the regulation of PGDH by steroids and to determine any changes with labor, we obtained placenta and chorion from term elective cesarean section or spontaneous delivery and isolated trophoblast cells using a Percoll density gradient. Cells were treated with varying concentrations of cortisol, progesterone, the synthetic progestins R5020, and medroxyprogesterone acetate with or without RU486 or the specific progesterone receptor antagonist, Onapristone, and the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane. The activity of PGDH was assessed by measurement of 13,14-dihydro-15-keto-PGF2alpha. PGDH messenger ribonucleic acid was quantified by in situ hybridization and computerized image analysis. The basal output of 13,14-dihydro-15-keto-PGF2alpha was lower in placenta or chorion collected at spontaneous labor than in that obtained at elective cesarean section. Cortisol had a significant dose-dependent inhibitory effect on PGDH activity in both placental and chorion trophoblast cells and significantly decreased levels of PGDH messenger ribonucleic acid. Responses were similar between tissues from laboring and nonlaboring women. PGDH activity was increased by R5020 and medroxyprogesterone acetate and was inhibited by RU486, Onapristone, and trilostane. We conclude that cortisol inhibits PGDH activity and expression and that progestagens increase PGDH activity in human chorion and placenta.
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Modulation of oestrogenic effects by progesterone antagonists in the rat uterus
Human reproduction update, 1998Co-Authors: Kristof Chwalisz, Klaus Stöckemann, Karl-heinz Fritzemeier, Ulrike FuhrmannAbstract:Antiprogestins can modulate oestrogenic effects in various oestrogen-dependent tissues, dependent on species, tissue, dose and duration of treatment. Enhanced oestrogenic responses to mifepristone and Onapristone occur in vitro and in vivo. However, the antiprogestins mifepristone, Onapristone, and ZK 137 316 can block the ability of oestradiol to increase endometrial growth in non-human primates. Our purposes were firstly, to decide whether mifepristone and Onapristone had direct oestrogenic activity in vitro and in the uterus of spayed and immature rats, and secondly, to discover whether antiprogestins exhibit inhibitory effects on oestrogen action in the uterus in spayed, oestrogen-substituted rats. In transactivation assays, mifepristone induced oestrogenic response, whereas Onapristone had only marginal effects on reporter gene transcription. In immature rats, Onapristone and mifepristone markedly increased uterine weights, and Onapristone, but not mifepristone significantly enhanced endometrial luminal epithelial height, a sensitive oestrogen parameter. Conversely, in spayed and adrenalectomized rats, neither Onapristone nor mifepristone changed uterine weights or endometrial morphology, indicating that their effects in immature rats were indirect. In spayed, oestrogen-substituted rats, antiprogestins did not block oestradiol-stimulated endometrial growth and luminal and glandular epithelium were stimulated more after antiprogestin plus oestrogen, than after oestradiol alone. All compounds induced compaction of the uterine stroma. In spayed rats, Onapristone and some other 13alpha-configured (type 1) antagonists (ZK 135 569, ZK 131 535) reduced oestradiol-stimulated myometrial proliferation and induced an overall uterine weight reduction in animals treated with oestrogen and antiprogestins, in comparison with oestradiol-treated controls. 13beta- configured (type II) antagonists, including mifepristone, lilopristone and ZK 112 993, were not effective. In the uteri of spayed rats, Onapristone was also found to enhance the oestradiol-stimulatory effect on expression of the oestrogen-dependent proto-oncogene, c-fos. In conclusion, antiprogestins do not inhibit, but rather enhance, oestrogen-induced uterine glandular and luminal epithelium in spayed rats, contrary to their effects in primates. The rat model is unsuitable to study endometrial antiproliferative effects of antiprogestins in primate uteri.
Chander P Puri - One of the best experts on this subject based on the ideXlab platform.
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effects of an antiprogestin Onapristone on the endometrium of bonnet monkeys morphometric and ultrastructural studies
Biology of Reproduction, 2003Co-Authors: Kamala Gopalkrishnan, R.r. Katkam, Geetanjali Sachdeva, S D Kholkute, Varsha Padwal, Chander P PuriAbstract:Our previous studies demonstrated the ability of low doses of antiprogestin ZK 98.299 (Onapristone) to inhibit fertility in bonnet monkeys. In the present study cumulative effects of low doses of ZK 98.299 on the endometrial cytoarchitecture of bonnet monkeys were analyzed. Treatment with either the vehicle (n = 3) or Onapristone at 2.5 mg (n = 4) or 5.0 mg (n = 3) was initiated on Day 5 of the first menstrual cycle and thereafter repeated every third day for four to seven consecutive cycles. The last treatment cycles were anovulatory in two animals treated with 2.5 mg and all animals treated with 5.0 mg. Endometrial biopsies were collected on Day 8 after the midcycle estradiol peak in ovulatory menstrual cycles and on Day 20 in anovulatory menstrual cycles during the last treatment cycle. Ultrathin sections of the fixed endometrium were stained with toluidine blue for morphometric analysis and uranyl acetate and lead citrate for ultrastructural analysis. The ZK 98.299-treated animals showed a dose-dependent endometrial atrophy as evident by a decrease in the height and diameter of the glands and early signs of compaction in the stroma. Ultrastructural analysis also revealed dose-dependent degenerative changes in the subcellular organelles such as the nucleus, mitochondria, endoplasmic reticulum, lysosomes, and Golgi apparatus. This suggests that long-term treatment with low doses of ZK 98.299 leads to the suppression of estrogen-dependent endometrial proliferation. However, this blockade operates independent of estradiol receptor (ER) and progesterone receptor (PR) concentrations as the expressions of these steroid receptors did not show any significant changes even after prolonged treatment. The study demonstrated an antiestrogenic effect of ZK 98.299 on endometrium after prolonged treatment in bonnet monkeys.
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Expression Profiles of Endometrial Leukemia Inhibitory Factor, Transforming Growth Factor β2 (TGFβ2), and TGFβ2 Receptor in Infertile Bonnet Monkeys1
Biology of reproduction, 2001Co-Authors: Geetanjali Sachdeva, R.r. Katkam, Vishakha Patil, Dhananjay D. Manjramkar, Sanjiva D. Kholkute, Chander P PuriAbstract:The expression profiles of leukemia inhibitory factor (LIF), transforming growth factor β2 (TGFβ2), and transforming growth factor β2 receptor (TGFβ2R) were analyzed during the peri-implantation period in regularly menstruating, fertile bonnet monkeys and in animals in which endometrial nonreceptivity was induced by administering an antiprogestin, Onapristone. Based on our previous experiences, a dose of 2.5 or 5 mg of Onapristone was administered s.c. every third day during the menstrual cycle, because these dosages impair endometrial development without upsetting the normal gonadal endocrine profiles. Endometrial biopsy specimens were collected during the proliferative phase (estradiol levels about 200 pg/ml, n = 5) and peri-implantation period (Day 8 after midcycle peak in estradiol levels, n = 5) from normal ovulatory animals and during the peri-implantation period from Onapristone-treated animals (n = 10). The biopsy specimens were processed to determine the expression patterns of LIF, TGFβ2, and TGFβ2R by immunohistochemical and reverse transcription-polymerase chain reaction (RT-PCR) methods. Levels of both protein and mRNA for LIF, TGFβ2, and TGFβ2R (analyzed by immunohistochemistry and RT-PCR, respectively) were greater in the endometrial samples collected during the peri-implantation period compared to samples collected during the proliferative phase in control animals. Treatment with either of the two doses (2.5 or 5 mg) of Onapristone caused a significant (P < 0.05) down-regulation in the expression of LIF in the peri-implantation endometria. The endometrial expressions of TGFβ2 and TGFβ2R mRNAs were reduced significantly in animals treated with 5 mg of Onapristone, but not in those treated with the lower dose. However, immunoreactive TGFβ2 and TGFβ2R proteins were significantly (P < 0.05) down-regulated in the endometrial samples from both the 2.5- and 5-mg-treated groups. The alterations observed in the expression patterns of LIF, TGFβ2, and TGFβ2R were specific, because the expression levels of epidermal growth factor receptor remained unaffected in the endometria from the treated groups. The present study demonstrates derangement in the expression profiles of LIF, TGFβ2, and TGFβ2R during the peri-implantation period in infertile bonnet monkeys. It may be hypothesized that TGFβ2 function is one of the early steps in the regulation of the progesterone-driven cascade of events leading to endometrial receptivity, and that any aberration in this step may adversely affect the subsequent molecular events (i.e., expression of LIF). These data also suggest that potential aberrations in the functional network of locally produced cytokines and growth factors even may occur in an endometrium exposed to the optimal peripheral hormonal levels.
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Endometrial contraception: modulation of molecular determinants of uterine receptivity.
Steroids, 2000Co-Authors: Chander P Puri, R.r. Katkam, Geetanjali Sachdeva, Vishakha Patil, Dhananjay D. Manjramkar, Sanjiva D. KholkuteAbstract:Modulation of endometrial receptivity is a promising approach for fertility regulation since it allows a contraceptive to act specifically at the endometrium. This was corroborated by our previous observations that treatment with low doses of a pure progesterone antagonist (PA, antiprogestin), Onapristone (ZK 98299), in bonnet monkeys inhibited fertility by selectively retarding endometrial development, without affecting the hypophyseal-hypothalamic function. In the present study, further investigations, undertaken to analyze the molecular repertoire of a nonreceptive primate endometrium, determined expression of: steroid hormone receptors, i.e. progesterone receptor (PR) and estrogen receptor (ER); cytokines, i.e. leukemia inhibitory factor (LIF): transforming growth factor beta (TGFbeta) and its receptor (TGFbetaR); and cell adhesion molecules, i.e. integrins (alpha(v)beta(3), alpha(1)beta(1)). These studies were conducted during the different phases of the normal menstrual cycle and following treatment with different doses of Onapristone (2.5 mg, 5 mg, or 10 mg every third day for one cycle) in bonnet monkeys. The molecules were analysed collectively to explore the possibility of a correlation between expression of these markers and endometrial receptivity and to investigate whether there exists a regulatory link between expression of these molecules under in vivo conditions. Three types of expression patterns of endometrial factors were observed during the peri-implantation period following Onapristone treatment: 1) LIF, alpha(v)beta(3), and alpha(1)beta(1) showed significant (P < 0.02) down regulation in glandular epithelium of endometria in animals treated with all three doses of Onapristone as compared to the control group. This was indicative of their critical role in the progesterone-driven cascade leading to implantation. 2) PR, TGFbeta, and TGFbetaR remained unaffected in the endometria from 2.5 mg treated animals and showed down regulation in animals treated with 5 and 10 mg Onapristone as compared to the control group, thereby suggesting that the expression of these markers may not truely reflect endometrial receptivity per se. However, their facilitatory role in preparing the endometrium for implantation can not be ruled out since continued perturbation in the expression of these molecules may affect endometrial growth, remodelling, and differentiation, which in turn may render the endometrium nonreceptive; 3) ER remained unaltered in endometria of animals rendered infertile with 2.5, 5, and 10 mg Onapristone. This observation indirectly suggests that Onapristone-induced endometrial changes are mediated via some specific mechanisms. The present study clearly demonstrates that endometrial non-receptivity induced at low doses of Onapristone is associated with changes in the expression pattern of specific molecular markers. However, no direct correlation was observed between in vivo expression of TGFbeta, LIF, and integrins, thereby lending support to the concept that there exists redundancy or multiple pathways which regulate implantation events.
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Onapristone zk 98 299 a potential antiprogestin for endometrial contraception
American Journal of Obstetrics and Gynecology, 1995Co-Authors: R.r. Katkam, Kristof Chwalisz, Kamla Gopalkrishnan, Eckard Schillinger, Chander P PuriAbstract:Abstract OBJECTIVES: The effects of the antiprogestin Onapristone (ZK 98.299) on fertility; menstrual cycle length; duration of menses; serum estradiol, progesterone, and cortisol concentrations; and endometrial morphologic features were studied in adult bonnet monkeys. STUDY DESIGN: Five animals were treated subcutaneously with the vehicle and another nine with either 2.5 ( n = 4) or 5 mg of Onapristone per animal ( n = 5). Treatment was initiated on day 5 of the first treatment cycle, and thereafter Onapristone was administered every third day for four to seven consecutive cycles. The females were placed with adult males during the periovulatory period, which was assessed by frequent analysis of serum estradiol concentrations. In the final treatment cycle an endometrial biopsy was performed on day 8 after a midcycle estradiol peak in the ovulatory cycle, or around day 20 if the cycle was anovulatory. Blood samples for estradiol, progesterone, and cortisol measurement were collected every third day, except for the periovulatory period when sampling was more frequent. RESULTS: Each of the five animals treated with the vehicle became pregnant: one in the first, three in the second, and one in the third mated cycle, whereas only one of nine treated with Onapristone became pregnant. Four animals treated with 2.5 mg of Onapristone for 17 cycles and another four treated with a 5 mg dose for 21 cycles did not conceive. In eight animals that did not conceive the first three treatment cycles of six were ovulatory, and in the remaining two animals two cycles of each were ovulatory. During treatment the mean menstrual cycle length was not altered significantly; however, in one it was shortened and in another two it was prolonged. Similarly, the mean duration of menses was not significantly affected, but in some cycles it was reduced. Moreover, there was only slight bleeding in some treatment cycles. Ovulation occurred in 30 of 45 treatment cycles, including the final treatment cycle during which the biopsy was taken, as indicated by serum estradiol and progesterone concentrations. In some of the ovulatory cycles prolonged treatment suppressed luteal activity; however, in the ovulatory cycles the duration of follicular and luteal phases was not significantly affected. In the anovulatory cycles there was a delayed increase in serum estradiol concentrations, suggesting a partial inhibition of folliculogenesis. In treated animals endometrial growth and development was retarded and rendered out of phase. In animals treated with the higher (5 mg) Onapristone dose the endometrial glands had partially regressed, the secretory activity was blocked,and stromal compaction was evident. The treatment had no significant effect on serum cortisol levels. CONCLUSIONS: This study demonstrates that low-dose Onapristone treatment throughout the menstrual cycle prevents pregnancy without disturbing the menstrual cycle and ovulation in the majority of cycles. However, anovulation and luteal insufficiency occurred in some animals during prolonged treatment. The contraceptive effect in the ovulatory cycles seems primarily related to the retardation of endometrial development resulting in the inhibition of endometrial receptivity. It appears likely that a dose or treatment regimen of Onapristone that will inhibit endometrial receptivity and prevent implantation without affecting the menstrual cycle even on prolonged treatment could be identified.
Giuseppe Benagiano - One of the best experts on this subject based on the ideXlab platform.
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Selective progesterone receptor modulators 1: use during pregnancy.
Expert Opinion on Pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: A large number of synthetic compounds known as selective progesterone receptor modulators can bind to progesterone receptors: the ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. Objectives: Only a dozen or so selective progesterone receptor modulators have been tested to any significant extent: among them are mifepristone (RU 486), asoprisnil (J867), Onapristone (ZK 98 299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Their clinical applications during pregnancy are discussed. Methods: A careful evaluation of existing major review papers and recently published articles was carried out focusing on mifepristone, the most widely studied selective progesterone receptor modulator, which was first used for the voluntary interruption of an early gestation. Other selective progesterone receptor modulators, especially those with partial agonist action, have shown little activity during pregnancy in animal models. Re...
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Selective progesterone receptor modulators 2: use in reproductive medicine.
Expert Opinion on Pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: Synthetic compounds can bind to progesterone receptors and these progesterone receptor ligands exhibit a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. These substances have been classified as antiprogestins or as selective progesterone receptor modulators. Objective: There are several hundred selective progesterone receptor modulators available, although only a dozen or so have been evaluated to any significant extent. The best-known selective progesterone receptor modulators are mifepristone (RU 486), asoprisnil (J 867), Onapristone (ZK 98299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone, but also on those other selective progesterone receptor modulators for which data are available. Results/conclusions: Outside pregnancy, selective progesteron...
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Selective progesterone receptor modulators 3: use in oncology, endocrinology and psychiatry
Expert opinion on pharmacotherapy, 2008Co-Authors: Giuseppe Benagiano, Carlo Bastianelli, Manuela FarrisAbstract:Background: A number of synthetic steroids are capable of modulating progesterone receptors with a spectrum of activities ranging from pure antagonism to a mixture of agonism and antagonism. The best known of these are mifepristone (RU 486), asoprisnil (J 867), Onapristone (ZK 98299), ulipristal (CDB 2914), Proellex™ (CDB 4124), ORG 33628 and ORG 31710. Objective: Outside reproduction selective modulators of progesterone receptors have been under investigation for a large variety of indications, for example in oncology as adjuvants in breast, cervical, endometrial, ovarian and prostate cancer, as well as inoperable meningioma and leiomyosarcoma. In addition, they have been used as antiglucocorticoids. It is therefore useful to review the results obtained in these conditions. Methods: A careful evaluation of existing major review papers and of recently published articles was carried out for the indications under review, focusing not only on mifepristone but also on those other selective modulators of proge...
Carsten Möller - One of the best experts on this subject based on the ideXlab platform.
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In vitro characterization of ZK 230211--A type III progesterone receptor antagonist with enhanced antiproliferative properties.
The Journal of steroid biochemistry and molecular biology, 2010Co-Authors: Wiebke Afhüppe, Ulrike Fuhrmann, Johanna M Beekman, Christiane Otto, Daniel Korr, Jens Hoffmann, Carsten MöllerAbstract:The progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from contraception to potential treatment of progesterone-dependent diseases like uterine leiomyomas. Based on in vitro characteristics such as DNA binding activity and partial agonistic transcriptional behavior in the presence of protein kinase A activators (cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist ZK 230211 in comparison to the classical antagonists Onapristone and mifepristone. We focused on PR actions in genomic signaling pathways, including DNA binding activity, nuclear localization and association with the nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of c-Src kinase signaling and cyclin D1 gene promoter activity. ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to mifepristone and Onapristone. When liganded to the progesterone receptor, ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in CV-1 cells. Furthermore, ZK 230211 displays less agonistic properties with regard to the association of PR isoform B and the cytoplasmic c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular estradiol-induced S phase entry. In summary, our studies demonstrate ZK 230211 to be a type III progesterone receptor antagonist which is characterized by very strong DNA binding activity and strong antiproliferative effects in the cancer cell lines HeLa and T47D.
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In vitro characterization of ZK 230211—A type III progesterone receptor antagonist with enhanced antiproliferative properties
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Wiebke Afhüppe, Johanna M Beekman, Christiane Otto, Daniel Korr, Jens Hoffmann, Ulrike Dr. Fuhrmann, Carsten MöllerAbstract:The progesterone receptor (PR) is a key regulator of female reproductive functions. Compounds with progesterone inhibiting effects (PR antagonists) have found numerous utilities in female reproductive health, ranging from contraception to potential treatment of progesterone-dependent diseases like uterine leiomyomas. Based on in vitro characteristics such as DNA binding activity and partial agonistic transcriptional behavior in the presence of protein kinase A activators (cyclic-AMP), three types of PR modulators with antagonistic properties have been defined. In this study, we analyzed the in vitro characteristics of the PR antagonist ZK 230211 in comparison to the classical antagonists Onapristone and mifepristone. We focused on PR actions in genomic signaling pathways, including DNA binding activity, nuclear localization and association with the nuclear receptor corepressor (NCoR) as well as actions in non-genomic signaling, such as the activation of c-Src kinase signaling and cyclin D1 gene promoter activity. ZK 230211 represents a type of PR antagonist with increased inhibitory properties in comparison to mifepristone and Onapristone. When liganded to the progesterone receptor, ZK 230211 induces a strong and persistent binding to its target response element (PRE) and increases NCoR recruitment in CV-1 cells. Furthermore, ZK 230211 displays less agonistic properties with regard to the association of PR isoform B and the cytoplasmic c-Src kinase in HeLa cells. It represses T47D cell cycle progression, in particular estradiol-induced S phase entry. In summary, our studies demonstrate ZK 230211 to be a type III progesterone receptor antagonist which is characterized by very strong DNA binding activity and strong antiproliferative effects in the cancer cell lines HeLa and T47D.
