Progesterone receptor modulators in gynaecological practice.

©FSRH J Fam Plann Reprod Health Care 2010: 36(2) Introduction The sex steroid progesterone plays a major role in the regulation of female reproductive activity. Circulating levels of progesterone are maximal in the secretory phase of the menstrual cycle, its main source being the corpus luteum. The effects of progesterone are mediated via the progesterone receptor (PR), which is essential not only for the co-ordination of ovulation, implantation and the maintenance of pregnancy but also for breast development and sexual behaviour. Within the uterus, progesterone predominantly contributes to the regulation of endometrial function. Progesterone is crucial in preparation for implantation by decidualisation, during pregnancy and during the process of menstruation, which occurs when progesterone levels fall in the absence of a conceptus. Since the discovery of natural progesterone in the mid-1930s,1 many synthetic progestogens have been developed and introduced into clinical practice. As contraceptive agents, these compounds have revolutionised fertility control. Progestogens also have an established role in the management of benign gynaecological conditions such as menstrual disturbances and endometriosis, as well as in hormone replacement therapy and assisted reproductive technology. The discovery of the progesterone receptor2,3 enabled the development of synthetic compounds binding to the PR with agonistic but also with antagonistic properties. The first of these to be described in 1981 was mifepristone (RU 486), a PR and glucocorticoid receptor (GR) antagonist.4 Reports soon followed on its effect on menstruation,5 highlighting its potential for cycle regulation and birth control.6 It was established that mifepristone could induce menstruation by interrupting the luteal phase of the menstrual cycle. Its potency to disrupt early pregnancy was then recognised, leading to its clinical application in the termination of pregnancy.7 Various related compounds exerting their effect via the PR have subsequently been developed and are reviewed here.