Antiprogestagenic inhibition of uterine prostaglandin inactivation: a permissive mechanism for uterine stimulation.
The use of antiprogestins as abortifacients is more effective when antiprogestin priming is followed by the administration of a small dose of synthetic prostaglandin. This increased myometrial sensitivity towards PG has not been explained and experiments in the guinea-pig where no myometrial activity is observed after 48 h of antiprogestin administration together with measurements of PG metabolites in uterine vein blood have given rise to the suggestion that prostaglandin synthesis is inhibited by antiprogestins. We have treated groups of 50 day pregnant guinea-pigs with 10 mg RU486 or vehicle alone and examined the ability of homogenised uterine tissues (myometrium/decidua, cervix, chorion and amnion) to metabolize PGE when given a large excess of substrate and sufficient cofactors. In addition we have examined the ability of these homogenates to synthesis PG. Antiprogestin treatment in vivo resulted in a 9-fold reduction in metabolic activity in chorion (P less than 0.02) and a 4-fold reduction in myometrium/decidua (P less than 0.02). Reduction in activity seen in amnion and cervix was not significant. The maximum metabolism was seen in the chorion and minimal metabolism in the amnion. Maximum PG production was seen in the amnion and minimum in the chorion. These results show that the effect of antiprogestin in reducing prostaglandin catabolism would reduce the threshold above which PG production would cause contractions which would in turn stimulate PG production. Thus an explanation is provided of how low doses of exogenous PGs or transient synthesis of endogenous PG within an antiprogestin treated uterus can led to a self sustaining cycle of stimulation which will lead to abortion.
Kelly
R W
RW
Medical Research Council Reproductive Biology Unit, University of Edinburgh Centre for Reproductive Biology, Scotland.
Bukman
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D015735:Mifepristone / Q000494:pharmacology*; D008969:Molecular Sequence Data; D011247:Pregnancy; D011453:Prostaglandins / Q000378:metabolism*; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D011453:Prostaglandins; D015735:Mifepristone