The impact of LNG when administered at different points in the menstrual cycle

It is important to note that levonorgestrel has a different reproductive impact depending on the time of the cycle it is ingested.

In a key study by Okewole (Contraception, 2007) it was reported that when LNG was given 3 days prior to ovulation, there was a significant delay in the FSH (follicle stimulating hormone) and LH (luteinizing hormone) peaks by about 96-120 hours, and the cycle was extended by approximately 13 days.(1) Ovulation was blunted. By comparison, when LNG is administered 24 hours before expected ovulation, "the FSH and LH peak were insignificantly delayed by just 24 hours..."

And further: "This (study) shows that LNG administration at late follicular phase (just prior to ovulation) did not interfere with estradiol-mediated mid-cycle gonadotrophin surge and probably ovulation but did alter progesterone production by the corpus luteum. It suggests that LNG might cause premature degeneration of the corpus luteum." (2)

As a consequence: "... it is possible that LNG in emergency contraception, as all progestins, has a direct effect on the endometrium." (My clarifications)

These conclusions are unambiguous: When LNG is given just prior to ovulation, ovulation is delayed but not always stopped, the function of the CL is altered, and there is likely a direct effect on the endometrium.

Further proof of this last point is provided in this study - one woman had vaginal bleeding that commenced seven days after taking LNG and continued until the end of that cycle. Obviously such an event precludes implantation.

But this is not the end of the evidence in support of the argument that LNG can act as an abortifacient if ovulation occurs. Data from papers by von Hertzen (Lancet, 2002) and Creinin (2006) show, in my view, evidence of an abortifacient action.

Consider the following: In tablet 2, page 1807 of the von Hertzen paper, the observed and expected pregnancy numbers are provided for women who took either RU-486, or LNG as a single or two dose regime. From this table, 1356 women took the two dose LNG regimen. The expected pregnancy rate without LNG use was 106 pregnancies, but with LNG use only 24 pregnancies occurred - a prevention rate of 77%.

But this is not my main point: rather, I wish to highlight a ratio between the number of women in the study and the expected pregnancy rate. From the above data, it was expected that 1356 women should yield 106 pregnancies (based upon the Wilcox tables of conception probability). (3) Hence the ratio is 1356 women = 106 expected pregnancies, or, for every 12 women having intercourse, one pregnancy is expected (1356 divided by 106, and round down to avoid over exaggeration). Or, more simply, 12 women = 1 pregnancy.

Now I shall apply this ratio to data from the paper by Creinin, which also employed the two dose LNG method. (4) Table 4 reported that 377 took LNG between one and 4 days after the expected day of ovulation. Based upon the 12 women = 1 pregnancy ratio derived above (and based on Wilcox), the 377 women would be expected to yield 31 pregnancies (377 divided by 12), but the study reported that only 7 pregnancies were detected.

Even more telling is the data for the smaller subset of 81 women who took LNG 2-3 days after expected ovulation. For 81 women, it is expected that there would be approximately 6 pregnancies (81 divided by 12). But table 4 reported that for this sub-group of women, there were no reported pregnancies.

How were all six pregnancies prevented?

It is argued by some that LNG can affect sperm mobility or have a detrimental impact upon its fertilizing capacity, though recent research has demonstrated that, under the influence of uterine contractions, rapid transport of sperm-sized spheres to the Fallopian tube can take only one minute.(5) The MAP is not taken within 1 minute of intercourse.

More significant is research by Brito and co-workers (2005) who showed that when human sperm was subjected to "three concentrations of levonorgestrel (LNG) comparable to the levels found in serum following ingestion of LNG as emergency contraception ... there is no influence in the fertilizing capacity of spermatozoa." (6) Hence this purported post-ovulatory mechanism is, in my view, non-existent.

Thus I return to the earlier question. If the Wilcox tables of probability of conception predict that 6 detected pregnancies should occur if 81 women have one act of intercourse, yet none occurred, and LNG does not affect sperm fertility, and LNG was administered after the expected day of ovulation, but endometrial damage is evident post-LNG in the form of premature vaginal bleeding (due to endometrial degeneration), it must be evident that the only remaining mechanism of action that can account for zero detected pregnancies is an anti-implantation action. There would appear to be no other scientifically rational explanation.

Yet some may counter this argument with the proposal that the likelihood of conception is nonexistent in the days after ovulation due to the short life of the oocyte. Two rejoinders can be offered:

First, Wilcox and co-workers (Contraception, 2001) reported that for days 13, 14, 15, 16, 17 and 18 of a regular cycle, the probability of a clinical pregnancy from a single act of intercourse was 0.093, 0.085, 0.073, 0.059, 0.047 and 0.036. (Table 1, p.213)(7) Therefore, conception is possible.

Second, in the Creinin paper cited, five pregnancies occurred in women who took LNG four or more days after the expected day of ovulation. This result validates the previous conclusion.

Both these citations authentic the claim that fertility many days after expected ovulation is a scientific fact.

One final point must also be made: can the MAP be given at any time during the cycle such that there is no potential for conception and hence a possible LNF-induced abortion? According to the probability of conception tables developed by Wilcox, the answer is 'no'. On days one and two of the menstrual cycle the probability of ovulation is close to zero, that is, less than 1% but it is not zero.

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(1) Okewole IA, Ayodele O . Arowojolu, Okanlawon L et al. Effect of single administration of levonorgestrel on the menstrual cycle. Contraception. 2007;75:372-377

(2) When the oocyte ruptures from a follicle, the remaining structure is called the corpus luteum (CL). The role of the CL is to produce progesterone so as to maintain the endometrium in a receptive state and support the embryo and the pregnancy for the first 8 weeks. Thereafter, the placenta takes over the progesterone producing role.

(3) Wilcox AJ, Weinberg CR, Baird DD. Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy and sex of the baby. NEJM 1995; 333(23): 517-521

(4) Creinin MD, Schlaff W, Archer DF et al. Progesterone receptor modulator for emergency contraception: A Randomized Controlled Trial. Am J Obstet Gynaec 2006;108:1089-1097

(5) Kunz G, Beil D, Deininger H, Wildt L, Leyendecker G. The dynamics of rapid sperm transport through the female genital tract: evidience from vaginal sonograph of uterine peristalsis and hyperosalpingoscintography. Hum Reprod 1996; 11(3): 627-632

(6) Brito KS, Bahamondes L, Nascimento JA et al. The in vitro effect of emergency contraceptiondoses of levonorgestrel on the acrosome reaction of human spermatozoa. Contraception. 2005;72(3):225-8

(7) Wilcox Aj, Dunson DB, Weinberg CR et al. Likelihood of conception with a single act of intercourse: providing benchmark rates for assessment of post-coital contraceptives. Contraception. 2001;63:211-215