Progesterone receptor blockers: historical perspective, mode of function and insights into clinical and scientific applications

 

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Zusammenfassung

Antigestagene (Antiprogestine) sind funktionelle Antagonisten von Progesteron (P4), welche die Vermittlung der biologischen Wirkungen von P4 verhindern, indem sie entweder seine Produktion oder seine Funktionen unterdrücken. Unter Letzteren befinden sich Progesteronrezeptorantagonisten, die die Bindung von P4 an seinen nukleären Rezeptor PGR kompetitiv hemmen. Diese finden sowohl in der Human- als auch in der Veterinärmedizin Anwendung, in der Kleintiermedizin insbesondere zur Nidationsverhütung und zum Trächtigkeitsabbruch. Progesteronrezeptorantagonisten können entsprechend ihrer Wirkungsweise in 2 Klassen eingeteilt werden. Klasse-I-Antagonisten binden an den PGR ohne eine Bindung an Promotoren von Zielgenen zu induzieren (kompetitive Inhibitoren). Antigestagene der Klasse II, einschließlich des in der Veterinärmedizin verwendeten Aglepristons, binden an den PGR, aktivieren dessen Assoziation mit einem Promoter, interferieren jedoch mit den nachgeschalteten Signalkaskaden, z. B. durch Rekrutierung von Transkriptionsrepressoren. Sie wirken dabei als transdominante Repressoren, die negative Auswirkungen auf die Zielgenexpression haben. Wichtig für die experimentellen Wissenschaften ist, dass Antagonisten der Klasse II, als aktive Antagonisten, für ihre Wirkung nicht die Anwesenheit des natürlichen Liganden benötigen. Neben ihrer klinischen Anwendung werden Antigestagene in der Forschung zur Untersuchung P4-abhängiger physiologischer und pathologischer Prozesse eingesetzt. Dieser Artikel gibt einen Überblick über die Geschichte und den aktuellen Einsatz von Progesteronrezeptorblockern in der Veterinärmedizin und Forschung.

Abstract

Antigestagens (antiprogestins) are functional competitors of progesterone (P4) that prevent P4 from mediating its biological functions either by suppressing its production or blocking its function. Among the latter are progesterone antagonists, competitors of P4 binding to its nuclear receptor PGR, which have found application in both human and veterinary medicine, in particular in small animal practice for the prevention of nidation and the interruption of pregnancy. Depending on their mode of action, progesterone receptor antagonists can be divided into 2 classes. Class I antagonists bind to the PGR but fail to induce its binding to promoters of target genes (competitive inhibitors). Class II antigestagens, including aglepristone used in veterinary medicine, bind to the PGR, activate its association with a promoter, but interfere with the downstream signalling cascades, e. g., by recruiting transcriptional repressors. They act thereby as transdominant repressors exerting negative effects on target gene expression. Importantly for experimental sciences, as active antagonists, class II antagonists do not require the presence of the natural ligand for their action. Besides their clinical application, antigestagens are used in research for investigating P4-dependent physiological and pathological processes. Here an overview of the history and the current usage of progesterone receptor antagonists in veterinary medicine and research is presented.

Publication History

Received: 08 October 2020

Accepted: 20 October 2020

Article published online:
04 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
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