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Hormonal Regulation in the Treatment of Fibroids
Published in John C. Petrozza, Uterine Fibroids, 2020
Victoria Fitz, Steven L. Young
Asoprisnil was found to have similar effects [38]. There was a dose-dependent decrease in uterine bleeding with suppression of bleeding in 85% of participants for the duration of treatment at the highest dose of 25 mg daily and a 17% reduction in uterine volume [39]. Since asoprisnil has no significant abortifacient properties, it has potential to be a more widely accepted therapy in the United States, but lower efficacy at currently tested routes and doses remains a concern and its clinical development was discontinued in 2009 [37].
Novel treatment modalities
Published in Seema Chopra, Endometriosis, 2020
Another SPRM, asoprisnil significantly reduces nonmenstrual pelvic pain, which is a hallmark of the triad of chronic pelvic pain in women afflicted with endometriosis. Asoprisnil has been investigated for the treatment of endometriosis. In a randomized, placebo-controlled trial, this drug (5, 10, and 25 mg) caused a greater reduction of endometriosis-related dysmenorrhea compared with a placebo [43].
Hormonal regulation of the endometrium and the effects of hormonal therapies
Published in Carlos Simón, Linda C. Giudice, The Endometrial Factor, 2017
Gulcin Sahin Ersoy, Monica Modi, Myles Alderman, Hugh S. Taylor
Mifepristone is also used in the treatment of abnormal menstrual bleeding . Use of mifepristone may cause amenorrhea (139). The amenorrheic state associated with mifepristone use can be a consequence of its antiproliferative effect, although it may also be due to mifepristone's direct effects on endometrial vasculature. In a study conducted on women taking depot MPA, it has been shown that the addition of mifepristone decreased the percent days of breakthrough bleeding from 36% to 15% (152). Asoprisnil is another SPRM, and it has mixed agonist–antagonist activity. Similar to the effects of mifepristone, asoprisnil is used to reduce menstrual bleeding (and to decrease fibroid and uterine volumes) (153,154). Asoprisnil has also been shown to be an effective treatment for endometriosis (147).
Novel pharmacological therapies for the treatment of endometriosis
Published in Expert Review of Clinical Pharmacology, 2022
Laura Buggio, Dhouha Dridi, Giussy Barbara, Camilla E.M. Merli, Giulia Emily Cetera, Paolo Vercellini
SPRMs are compounds that bind the progesterone receptor (PR) and have a mixed agonist-antagonist activity. PRs are expressed through two main isoforms: isoform A (PR-A) and isoform B (PR-B), which entail distinct functions depending on the type of cell expressing them [37]. In particular, mifepristone has a higher binding affinity (100%) for the human PR than progesterone (43%) and its metabolites in endometrial and myometrial samples [38,39]. Mifepristone is able to stimulate PR by inducing dimerization (as A:A, B:B, or A:B); these dimers possess different effects: A:A are functionally silent, A:B can activate transcription, and A:B markedly inhibit transcriptional activation in progesterone responsive cells [39]. Asoprisnil shows a 3-fold higher binding activity to PR than progesterone in the rabbit uterus [39,40]. In an animal model, large doses of asoprisnil have demonstrated a mixed agonist and antagonist effects [39]. Ulipristal acetate (UPA) shows a significant antagonistic and a partial agonistic effect on PR in humans; when UPA binds to PR, it decreases the binding capacity of endogenous progesterone to its receptor and blocks PR-mediated DNA transcription [39,41]. In addition, UPA is aslo able to increase the PR isoform ratio of PR-A to PR-B by reducing the level of PR-B receptor and augmenting PR-A expression [39].
Investigational drugs for the treatment of endometriosis, an update on recent developments
Published in Expert Opinion on Investigational Drugs, 2018
Fabio Barra, Carolina Scala, Valerio Mais, Stefano Guerriero, Simone Ferrero
Asoprisnil, another SPRM with a partial agonist/antagonist progestin activity, is under investigation for the treatment of endometriosis. It is known from studies on primates that this drug causes the suppression of endometrial proliferation and promotes amenorrhea by targeting the endometrium [57]. In an in vivo rat model, asoprisnil did not succeed in reducing of the volume of OEs [59]. In a randomized placebo-controlled trial this drug (5, 10, and 25 mg) demonstrated a higher decrease of dysmenorrhea-related to endometriosis in comparison with placebo [60]. Anyway, the trials on this drug were stopped for the presence of some cases of endometrial hyperplasia [61]. Thus, at the moment very limited evidence is available on the use of asoprisnil for treating endometriosis and better-designed studies are mandatory to investigate its safety and efficacy.
Successes and failures of uterine leiomyoma drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Mohamed Ali, Zunir Tayyeb Chaudhry, Ayman Al-Hendy
Asoprisnil (J867) has been shown to suppress collagen synthesis and induce apoptosis in leiomyomas but spares normal myometrium [40]. It does so by the following mechanisms: decreases expression of antiapoptotic Bcl-2, increases caspase-3 and terminal deoxynucleotidyl transferase-mediated 2ʹ-deox- yuridine 5ʹ-triphosphate nick end labeling (TUNEL) positive cells, and decreases vascular endothelial growth factor (VEGF) and proliferating cell nuclear antigen (PCNA) [11,40,41]. A multicenter, randomized placebo-controlled trial found that at the conclusion of a 12-week regimen, women on asoprisnil experienced effective control of uterine bleeding and reduced fibroid and uterine volumes with minimal hypoestrogenic state symptoms [42]. Unfortunately, it has not been taken further in clinical trials in recent years owing to failing phase 3 clinical trial in 2008, which is attributed to unsafe changes in the endometrial lining of the uterus.