Progesterone Receptor Modulators (PMRS) and Progesterone Antagonists (PAS)

Since the discovery of mifepristone (RU 486), other antiprogestins have been synthesized   as   onapristone(ZK   98.299)  and   lilopristone(ZK   98.734)  which compete with progesterone at the receptor level. These compounds are grouped in the large family of progesterone receptors ligands that include pure progesterone antagonists(PAs) and   progesterone   receptor   modulators   (PMRs)(1).

Selective progesterone   receptor   modulators (SPRMs)  have   mixed   agonist-antagonist properties.  Antiprogestins can modulate estrogenic effects in various estrogen-dependent tissues. Their complex modulatory effects depend on species, tissues, type of compound, dose and duration of treatment (2).

A high dose of mifepristone, 200mg administered immediately following ovulation,is highly effective in preventing implantation; however, this antiprogestin is generally used to terminate pregnancy of less than 9 weeks duration. The contraceptive potential of the antiprogestins has been evaluated in clinical and experimental studies.

Some of these formulations have partial agonist activity which is mediated primarily through the N-domain of the B-isoform of progesterone receptors (PR), although the mechanism has not yet been defined (3). Both,  PMRs as well as PAs have proven antiproliferative effects on endometrium due to interaction with its mitotic activity, in a   dose-dependent   manner(2). These   effects   are   endometrium-specific, since the estrogenic effects in the oviduct and vagina are not inhibited by PAs. 

Administration of antiprogestins such as mifepristone and onapristone,during the follicular phase of the menstrual cycle, postpones the estrogen rise and the luteinising hormone surge and delays endometrial maturation(4).  Studies in animal model reported that anovulation and luteal insufficiency may occur during prolonged treatment(5).

As long as treatment is continued, follicular development is delayed or arrested and ovulation inhibited. Because of anovulation, there may be an unopposed estrogen effect on the endometrium, although this risk may be mitigated by noncompetitive anti-estrogenic activity exhibited by both PAs and PRMs.(6). Interestingly, the treatment with these products is not associated with hypo-estrogenism and bone loss (1).

It is assumed that this inhibitory effect of antiprogestins on ovulation is mediated by a blocking effect of progesterone on the pituitary level.  Intermittent administration of mifepristone, together with periodic administration of a gestagen, both inhibit ovulation and induce regular withdrawal bleeding. 

Low weekly 2,5 mg to 5 mg and daily doses 0,5mg of mifepristone which do not inhibit ovulation, retard endometrium maturation indicating its strong sensitivity to these compounds (6,7).

In contrast,when mifepristone is administered every month, at the end of the cycle, either alone or together   with   prostaglandins, it   is   not   very   effective   in   preventing pregnancy(6). Some PRMs have potential use in women with dysfunctional uterine bleeding because of their antiproliferative effects(4). Chronic,  low dose PAs treatment may provide a new option for women who wish to suppress their menstrual periods inducing reversible amenorrhoea (8).  In humans,  chronic administration of high doses of antiprogestins has,  on rare occasions,  been associated with endometrial hyperplasia, presumably a consequence of unopposed estrogen activity. This does not occur with low-doses(9).

Intrauterine devices (IUDs) that release progestins are highly effective contraceptives, but they induce breakthrough bleeding that some women find unacceptable. Because progesterone antagonists (APs) are known to suppress the endometrium, induce amenorrhea and inhibit   fertility,  AP-releasing   IUDs   (AP-IUDs) has   been   experimented   in macaques. 

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