**7. Conclusion**

There are compelling pre-clinical and clinical evidence to suggest that as well as directly antagonising the effect of progesterone, PRAs also functionally antagonise the effects of estrogen on the endometrium. This coupled with the suppression of ovarian folliculogenesis induces anovulatory amenorrhoea. Evaluation of the PR axis in animal models of endometriosis has suggested that PRAs can suppress the growth of ectopic endometriotic lesions. The mechanism driving this effect is still not clear, but it sufficient to maintain ovarian activity and estradiol levels adequately to protect bone as well as other potential post-menopausal symptoms more commonly encountered with ovarian suppression. In women with endometriosis, the data available from small clinical evaluations, strongly suggest that PRA treatment reduces disease symptoms, whilst maintaining normal levels of bone mineral density. Further clinical evaluation in larger randomised, placebo controlled and blinded studies are warranted, both to underscore the clinical benefit as well as understand the safety of the mechanism compared with existing standard of care therapy (endometrial, cardiovascular and bone safety, in particular). The medicinal chemistry challenge in designing potent, selective and safe PRAs is not inconsiderable, especially given the large number of examples whose clinical development have been curtailed (e.g. onapristone, PF-02413873, asoprisnil). However, the clinical evidence observed so far provides strong confidence that the class could have utility as a chronic treatment for endometriosis as well as a range of other gynaecological indications and malignant conditions.
