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How RU-486 (mifepristone) acts as an abortifacient

Work by Cameron et al (1997) has revealed four attack points of mifepristone. (1)

First, mifepristone administered as a single 200mg or 400mg dose two days after the surge of luteinizing hormone (LH) was found to appreciably reduce the endometrial levels of leukemia inhibitory factor (LIF). The LH surge occurs approximately 36 hours before ovulation and is responsible for stimulating this event.(2) Significantly, the reduction in LIF caused by RU-486 was most evident on the first day of the opening of the window of implantation (6 days after the LH surge).

Second, mifepristone caused the levels of a critical enzyme known as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to be "markedly reduced or absent." In a normal cycle, 15-PGDH acts to retard premature endometrial breakdown i.e., menstrual bleeding. By reducing the levels of this enzyme, RU-486 could indirectly induced menstruation by removing the 'brake' on the too-early onset of this monthly event. Indeed, in one RU-486 treatment-cycle, pre-menstrual break-though bleeding occurred during the time when the embryo would be endeavouring to implant. Obviously a deteriorating, sloughing endometrium is disadvantageous to sustaining a 5-6 day old pregnancy.

Third, RU-486 reduced the levels of glycodelin, produced by the endometrium. Glycodelin is believed to "play an immunosuppressive role in implantation by protecting the embryo from rejection by the maternal immune system."

Fourth, RU-486 retarded the development of a secretory endometrium. The formation of a secretory endometrium is "a prerequisite for implantation." Meng (2009) supports this view, and states that RU-486 renders the endometrium unreceptive within 6 hours of ingestion. This rapid action is due to the stronger binding capacity of RU-486 for the progesterone receptor when compared to progesterone's binding strength. RU-486 binds to the receptor with 2.5 - 5 times greater strength. Progesterone cannot successfully compete. It cannot bind to its own receptor, and therefore cannot perform its normal implantation enhancing actions. (3)

When these four factors are combined with a 100% rate of ovulation in all cycles in this study and a resultant 85% reduction in the expected pregnancy rate it is self-evident that RU-486, as a pre-implantation drug regimen has a potent abortifacient capacity. More recent studies have confirmed the high abortifacient rate of RU-486. A WHO multi-national study (2002) reported that 81% of pregnancies were avoided.(4) Piaggio and co-workers (2003) have reported that "the estimate of pregnancies prevented was 83.4%"(5), and a recent Taiwanese study (2009) of 120 women reported that the pregnancy rate was 0%.(6) Each of these three studies used a single 10mg dose of RU-486.

A fifth attack point has been reported by Bygdeman (1999). When given after ovulation, RU-486 affected the development of the endometrium, including the levels of pro-implantation factors such as leukemia inhibitory factor and integrins. (7)

A sixth mechanism has been proposed by Sanjoy K. Das (2009). Based upon studies in mice and observations using human endometrial stromal cells, it was concluded that RU-486 caused an inhibition of Hoxa-10, resulting in failure in endometrial proliferation required for implantation. Hoxa-10 is an important transcription factor that "can influence a host of uterine genes..." (8)

A seventh mechanism (Meng 2009) is the suppression of the levels of MUC-1, an implantation related molecule normally seen in abundance in the embryo receptive phase of the menstrual cycle. (9)

On final point requires mention: the above mechanisms relate to the post-ovulatory use of RU-486. When administered in the preovulatory phase of a menstrual cycle it acts either via disruption to follicular development or inhibition of ovulation. Jolande G van der Stege (2006) has reported that when 10mg of mifepristone was administered to women prior to the LH surge that triggers ovulation, the LH surge was delayed for 3 days, and "ovulation was postponed for 3 days." Interestingly, one woman in this study who was given mifepristone on the day of the LH surge did ovulate. Ovulation was not delayed. It should be noted that 10mg of mifepristone "is as effective as a dose of 600mg in preventing pregnancy." (10)

Since ovulation was delay for only 3 days, fertilization is still possible because some sperm are viable for 7 days (11) though implantation would be imperiled as a consequence of the seven mechanisms listed above.

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