Research hones in on EC mechanism of action
The young woman in your examination room has questions about how emergency contraception pills (ECPs) works. How do you explain the method’s mechanism of action?
Recent research from members of the New York City-based Population Council’s International Committee for Contraception Research indicates that levonorgestrel-only ECPs (Plan B, Barr Pharmaceuticals, Pomona, NY) appear to work by interfering with ovulation, thus preventing fertilization of the egg.1,2 The pills do not appear to disrupt post-fertilization events, such as the implantation of a fertilized egg in the uterus, which has been a point of contention among EC opponents.
Further research needs to be done to accrue more indirect evidence to help settle the issue, at least at the technical level, says Horacio Croxatto, MD, a reproductive physiologist at the Chilean Institute for Reproductive Medicine in Santiago, Chile, and co-author of the recent research. This evidence can be obtained when funding for this type of research becomes available, he notes.
Plan B now is available at Canadian pharmacies without a prescription following the April 2005 approval by Canadian regulatory authorities. The drug is distributed in Canada by Montreal-based Paladin Labs. EC proponents continue to await word from the Food and Drug Administration regarding the pending U.S. application for over- the-counter (OTC) status of the drug.
Croxatto and colleagues at the Chilean Institute have studied the effects of levonorgestrel (LNG) on the reproductive cycles of female rats, monkeys, and humans. In one study, performed in female rat subjects, the scientists exposed the rats to very high doses of LNG at various stages of their reproductive cycles.1 LNG appeared to inhibit ovulation completely or partially, depending on the timing of treatment and the dose administered; however, it had no effect on fertilization or implantation.1
Next, the scientists looked at the effects of LNG given to monkeys before ovulation or after intercourse.2 When given before ovulation, LNG was able to inhibit or postpone ovulation but when administered after mating, researchers found that pregnancy rates were identical in cycles treated with LNG or with a placebo. Such findings indicate that the drug did not interfere with any post-fertilization process required for embryo implantation, scientists conclude.2
Ten original research papers focusing on the mechanism of action of LNG have been published from 2001-2004, Croxatto points out.1-10 He offers the following explanation of the published work:
- Five of the studies provide evidence that the drug interferes with ovulation.3-5, 9-10
- Two studies find no alteration in the endometrium that would support the hypothesis that LNG prevents implantation.4,5
- Two studies document, in two animal models, that the drug does not interfere with any of the processes that take place after fertilization, which are necessary for the establishment of pregnancy.1,2
- Two other studies report minimal if any direct effect of LNG upon human spermatozoa in vitro.7,8
- One paper reports effects of LNG on the endometrium in three women who took doses severalfold higher than used for EC6; therefore the findings reported do not apply to the current regimen.
Why then do misconceptions persist that emergency contraception is an abortifacient?
"Some people received the message that this was not a hypothesis, but a proven fact, and for different reasons they have not updated their knowledge on this issue," states Croxatto. "Others have the same concept, but emotionally rooted and are reluctant to accept the contrary, even when they are faced with the evidence."
The political question is not how often ECPs may work after fertilization, but whether they ever work in this way, states James Trussell, PhD, professor of economics and public affairs and director of the Office of Population Research at Princeton (NJ) University.
"Croxotto’s excellent work has shown that Plan B does work in many cases by causing dysfunctional ovulation where the result is a short luteal phase; however, it is possible that even with dysfunctional ovulation that fertilization does occur and not possible to prove that fertilization never occurs," he states.
While the mechanism of action for emergency contraception is not known with certainty, it is believed EC combines delay of ovulation with a local effect on the endometrium and prevention of fertilization, according to a recent commentary by Leon Speroff, MD, professor of obstetrics and gynecology at Oregon Health Sciences University in Portland.11 How much a post-fertilization effect contributes to efficacy is not known, but it is not believed to be the primary mechanism, he notes.
"I would just emphasize that all the evidence that exists has failed to indicate an abortifacient effect; indeed, when pregnancy is established, EC does not work," states Speroff. "We should emphasize, to patients, pharmacists, and colleagues that the evidence is consistent with prevention of implantation."
References
1. Muller AL, Llados CM, Croxatto HB. Postcoital treatment with levonorgestrel does not disrupt post-fertilization events in the rat. Contraception 2003; 67:415-419.
2. Ortiz ME, Ortiz RE, Fuentes MA, et al. Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella. Hum Reprod 2004; 19:1,352-1,356.
3. Hapangama D, Glasier AF, Baird DT. The effects of pre-ovulatory administration of levonorgestrel on the menstrual cycle. Contraception 2001; 63:123-129.
4. Durand M, Cravioto MC, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception 2001; 64:227-234.
5. Marions L, Hultenby K, Lindell I, et al. Emergency contraception with mifepristone and levonorgestrel: Mechanism of action. Obstet Gynecol 2002; 100:65-71.
6. Ugocsai G, Pozsa M, Ugocsai P. Scanning electron microscopic (SEM) changes of the endometrium in women taking high doses of levonorgestrel as emergency postcoital contraception. Contraception 2002; 66:433-437.
7. Yeung WS, Chiu PC, Wang CH, et al. The effects of levonorgestrel on various sperm functions. Contraception 2002; 66:453-477.
8. Bahamondes L, Nascimento JAA, Munuce MJ, et al. The in vitro effect of levonorgestrel on the acrosome reaction of human spermatozoa from fertile men. Contraception 2003; 68:55-59.
9. Marions L, Cekan SZ, Bygdeman M, et al. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception 2004; 69:373-377.
10. Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75 mg dose given on the days preceding ovulation. Contraception 2004; 70:442-450.
11. Speroff L. Pharmacists and emergency contraception. OB/GYN Clin Alert 2005; 21:65-67.
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