What is the mechanism of action of Plan B?

IcthysPharmD, PharmD candidate

This is a question that has important ethical implications. If levonorgestrel acts by inhibiting implantation, then by many it would be considered to be an abortifacient due to the destruction of a fertilized egg. In this case, the act of dispensing Plan B could be considered morally reprehensible. If on the other hand the mechanism of action was to inhibit ovulation, which would prevent fertilization in the first place, then it would be the morally reprehensible thing to not dispense the medication and thus increase the risk that the mother might seek an actual abortion later on.

What I believe can be shown is that the mechanism of action is by inhibiting ovulation. In order to answer this question I believe we must first take a look at the statistics of pregnancy without any medications applied. We can then use this to deduce what we would expect the efficacy of Plan B to be if its mechanism of action was by inhibiting ovulation only. If this data matches with the actual efficacy of Plan B, then this is evidence for inhibition of ovulation as the exclusive mechanism of Plan B.

We can also look at studies and commentaries done by others on the subject. One important thing to know is if an ovulation does occur despite administration with levonorgestrel, and this leads to fertilization, would implantation then be inhibited as a secondary mechanism?

Statistics of Pregnancy without contraceptives.

In an article from the New England Journal of Medicine, Allen J. Wilcox, et al. discussed the probability of conception.

“Out of 221 healthy women … In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated … Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. … As a preliminary estimate of the chance of conception on individual days, we identified all the cycles in which intercourse occurred on only a single day during the six-day period. On the basis of these 129 cycles (21 percent of the total), the proportion with a detected pregnancy ranged from 0.08 on the first day of the six-day period to 0.36 on the sixth day (the day of ovulation)” (1)

(Figure 1)

Likelihood of ovulation on the same day as Intercourse.

Given that ovulation happens once every 28 days, chances that ovulation will occur over the next days after intercourse. Furthermore, if the mechanism by which Plan B works is only by inhibiting implantation, then pregnancy would only occur if ovulation happened on the same day as intercourse, thus Plan be would be unable to prevent ovulation because it would be administered too late. So we need to know what the likelihood that pregnancy would occur due to an ovulation happening on that same day as intercourse. Given the above that the likelihood of pregnancy is 0.36 for intercourse on the day of conception and that there is a 0.036(3.6%) chance that ovulation would occur on the same day as intercourse, this value should come to 0.013 (1.3%) [From 0.036*0.36). So if Plan B is taken at some time in the next 24 hours of intercourse, it would be expected that it would be ineffective around 1.3% of the time.

Time after intercourse	Chance for ovulation	Pregnancy %
Day of intercourse	0.036 (3.6%)	*0.36 = 1.3%
To 1st day after	0.071 (7.1%)	*0.36 = 2.6%
To 2nd day after	0.107 (10.7%)	*0.36 = 3.9%
To 3rd day after	0.143 (14.3%)
To 4th day after	0.179 (17.9%)
To 5th day after	0.214 (21.4%)
to 6th day after	Past maximum range of sperm survival

Efficacy of Levonorgestrel in comparison to predicted efficacy

Figure 2 below is a table that shows the efficacy of emergency contraception over the course of time after intercourse. When we look at the data for efficacy of Plan B for the 13-24 hour window below, we find that this calculation is near consistent with our prediction of 1.3% rate of failure. Likewise for a 72 hour period we would predict a likelihood of ovulation happening before Plan B and thus result in a pregnancy 3.9% of the time, which is also what we see below. (2)

(Figure 2)

This data is consistent with what we predicted would occur if implantation was the exclusive mechanism of action of Plan B, and this lends evidence to that hypothesis.

Is Implantation inhibited as a secondary mechanism?

If Plan B had an effect on implantation, one would expect to see abnormalities in the endometrium after administration with levonorgestrel. However, in a study by Marta Durand, et al. it was found that

“No significant changes were observed between treated and control specimens in any of the studied parameters. No significant differences among groups were observed. Of particular importance was the finding that the predecidual changes as evaluated by the presence of prominent spiral arteries, which are considered crucial for implantation, were not altered by LNG.” (3)

(Figure 3)

The table above is the data that shows that there is no significant change in the endometrium from those with and without levonorgestrel. This gives evidence to the hypothesis that inhibition of implantation is not a mechanism of levonorgestrel.

Another possible way to answer this question is to look at other species. In a study by M.E. Ortiz, et al. the effect of levonorgestrel, referred to as LNG, is studied before and after ovulation:

“It was shown previously in a rodent model that post‐coital administration of LNG does not affect the rate of embryo implantation, yet pre‐ovulatory administration was able to inhibit ovulation, an effect that was markedly dependent on distance between treatment and ovulation. … In Cebus Apella, …These results show, for the first time in a primate species, that LNG administered as used in EC in women interferes with the ovulatory process when given early in the follicular phase, but when given soon before or after ovulation it has no impact on fertilization and subsequent processes.” (4)

From this we have two examples of other species, rat and monkey, that when levonorgestrel is administered, it does not lead to prevention of implantation. It should be noted that this cannot be directly extrapolated to humans, but I believe it is worthy of noting as evidence to support the hypothesis.

The time course of effectiveness mentioned earlier of levonorgestrel should also be taken into account as evidence that implantation is not a mechanism of Plan B. This was explained in a commentary by Davidoff, Frank MD and Trussell, James PhD.

“If Plan B interferes with implantation, its efficacy should not decrease with short-term delay in use as long as it is taken just before or during implantation. In fact, delay in use causes Plan B to lose its effectiveness progressively in the 72 hours after unprotected intercourse even when use is adjusted for cycle day of unprotected sex. That finding is again consistent with a contraceptive mechanism that is independent of effects on implantation.” (5)

This logic makes sense. Not only that but we also have shown that the mechanism of implantation only may fully explain the efficacy of Plan B. If there was a further secondary mechanism, then Plan B would be expected to be more effective than it is. As such, I believe that this is strong evidence for the hypothesis that the contraceptive effect of levonorgestrel is due to inhibition of implantation, and is not due to affecting any post-fertilization effects

(1) Allen J. Wilcox, M.D., Ph.D., Clarice R. Weinberg, Ph.D., and Donna D. Baird, Ph.D. Timing of Sexual Intercourse in Relation to Ovulation — Effects on the Probability of Conception, Survival of the Pregnancy, and Sex of the Baby. N Engl J Med; 12/7/95, Vol. 333 Issue 23, p1517-1521, 1p

(2) G Piaggioa, , H von Hertzena, DA Grimesa, PFA Van Looka and on behalf of the Task Force on Postovulatory Methods of Fertility. Timing of emergency contraception with levonorgestrel or the Yuzpe regimen. The Lancet; Volume 353, Issue 9154, 27 February 1999, Pages 721

(3) Durand M, delCarmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227–234.

(4) M.E. Ortiz, et al. Post‐coital administration of levonorgestrel does not interfere with post‐fertilization events in the new‐world monkey Cebus paella. Hum. Reprod. (2004) 19 (6): 1352-1356.

(5) Davidoff F, Trussell J. Plan B and the politics of doubt. JAMA. 2006;296:1775-8