Effects of the progesterone antagonists onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis in intact rats*
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The progesterone antagonists onapristone and ZK 136 799 inhibited the growth of surgically induced endometriosis foci in rats, with ZK 136 799 demonstrating greater efficacy.
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Abstract
The effects of the progesterone antagonists (antiprogestins) onapristone (ZK 98 299) and ZK 136 799 on surgically induced endometriosis were studied in intact female rats. Endometriosis was induced by transplanting homologous endometrium to the parietal peritoneum of the abdominal wall (location A) and to the mesentery of the small intestine (location B). The animals were treated daily for 4 weeks at doses of 0.4 and 2.0 mg onapristone or ZK 136 799. The growth of the endometriosis-like foci was measured with a calliper during both pre- and post-treatment laparotomy. Both antiprogestins exerted inhibitory effects on the growth of the endometriosis-like foci in terms of complete remission. A 40 and 50% remission of endometriosis was observed at each location after the administration of 2.0 mg onapristone, whereas 50 and 63% (location A) and 50 and 75% (location B) remissions were found after the administration of 0.4 and 2.0 mg of ZK 136 799 respectively. ZK 136 799 was also more potent than onapristone in growth inhibition (85 versus 48% for location B) in animals with persistent endometriosis. Growth inhibition of the endometriosis-like foci was confirmed by histology and immunohistochemical staining of the proliferating cell nuclear antigen. The antiprogestins caused a reduction in glandular and luminal epithelial cells in the ectopic endometrium. Both antiprogestins tended to cause a decrease in uterine weight. Unlike the inhibitory effects in the ectopic endometrium, both onapristone and ZK 136 799 exhibited some stimulatory effects on the epithelial cells within the eutopic endometrium. Serum 17 beta-oestradiol concentrations did not vary significantly among the different treatment groups. No antiglucocorticoid effect of the antiprogestins was observed at either dose. This study indicates that the antiprogestins onapristone and ZK 136 799 exhibit antiproliferative effects in the ectopic but not the eutopic endometrium via mechanisms which remain to be established. The better efficacy of ZK 136 799 is more likely caused by its higher antiprogestagenic activity than its partial androgenic activity. These findings may be a further indication of the future potential of antiprogestins such as onapristone and ZK 136 799 in the treatment of endometriosis.
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Cited by (21)
- Progesterone receptor ligands for the treatment of endometriosis: the mechanisms behind therapeutic success and failure 2020
- Traitement médical de l’endométriose : prise en charge de la douleur et de l’évolution des lésions par traitement hormonal et perspectives thérapeutiques 2017
- Innovations in classical hormonal targets for endometriosis 2015
- Emerging treatment of endometriosis 2015
- Novel agents for the medical treatment of endometriosis 2014
- Antiprogestins in gynecological diseases 2014
- Intérêt actuel des selective progesterone receptor modulators (SPRM) dans l’endométriose 2013
- Progesterone Resistance and Targeting the Progesterone Receptors: A Therapeutic Approach to Endometriosis 2012
- The immninent dawn of SPRMs in obstetrics and gynecology 2012
- Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety 2011
- Treatment strategies for endometriosis 2008
- Expression und Regulation von Enzymen des Östrogenmetabolismus in humanen Endometriumläsionen kultiviert in der Nacktmaus 2007
- Role of oxidative stress in endometriosis 2006
- Future Perspectives in the Medical Treatment of Endometriosis 2005
- Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications 2005
- Novel targets for the treatment of endometriosis 2004
- Human endometriotic xenografts in immunodeficient RAG-2/γ(c)KO mice 2004
- Immunomodulators and aromatase inhibitors: are they the next generation of treatment for endometriosis? 2003
- Immunomodulators and aromatase inhibitors: are they the next generation of treatment for endometriosis? 2003
- Medical Management of Endometriosis: Novel Targets and Approaches towards the Development of Future Treatment Regimes 2003
- Using Rats as a Research Model for the Study of Endometriosis 2002
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