Emergency Contraception's mode of action clarified.

Emergency contraceptive pills, a hormonal treatment that can prevent pregnancy if taken within 72 hours of unprotected intercourse, have been the subject of heated debate. At issue is the method's mechanism of action: does it prevent the meeting of egg and sperm, or does it prevent a fertilized egg from implanting in the uterus? Recent research by members of the Population Council's International Committee for Contraception Research (ICCR) and other scientists shows that the most popular method of emergency contraception appears to work by interfering with ovulation, thus preventing fertilization, and not by disrupting events that occur after fertilization.

The most common and effective form of emergency contraception contains levonorgestrel, a progestin. It is sold in the United States and Canada under the name Plan B[R]. Reproductive physiologist Horacio B. Croxatto of the Chilean Institute for Reproductive Medicine in Santiago, Chile, and his colleagues studied the effects of levonorgestrel on the reproductive cycle of female rats, monkeys, and humans. Croxatto and one of his study partners, biomedical researcher Vivian Brache of PROFAMILIA in Santo Domingo, Dominican Republic, are members of the ICCR.

Emergency Contraception in Animal Studies

Croxatto and his colleagues exposed female rats to very high doses of levonorgestrel at various stages in their reproductive cycle, either before or after ovulation or before or after mating. "When a woman uses emergency contraception," Croxatto explained, "she does not know whether she is taking the pills before or after ovulation or before or after fertilization." The researchers found that levonorgestrel inhibited ovulation totally or partially, depending on the timing of treatment and the dose administered. However, the drug had no effect on fertilization or implantation when it was administered shortly before or after mating or before implantation.

Next, Croxatto and his colleagues studied the effects of levonorgestrel given to Cebus monkeys either before ovulation or postcoitally. The reproductive cycle of each animal was monitored by ultrasound examination of the ovaries, vaginal smears, and measurements of blood hormone levels, in order to time the administration of levonorgestrel. The researchers found that, when given before ovulation, levonorgestrel was able to inhibit or postpone ovulation. Alternatively, when it was given after mating--at a time when fertilization was believed to have occurred (on the basis of previous monitoring)--the pregnancy rates observed were identical in cycles treated with levonorgestrel or with a placebo. This indicates that levonorgestrel did not interfere with any postfertilization process required for embryo implantation.

Emergency Contraception in Women

Women may become pregnant when they have intercourse in the five days before ovulation. This is because sperm can live in the female reproductive system for up to five days. An egg, however, is usually viable for only six to 12 hours after it is released. Croxatto, Brache, and their colleagues studied the effects of levonorgestrel administered during this fertile preovulatory period of women's menstrual cycle.

Twenty-nine women in Santiago and 29 women in Santo Domingo were enrolled in the study. All of the women were protected from pregnancy by tubal ligation or a nonhormonal intrauterine device. The study was randomized, double-blind, and placebo-controlled: the gold standard for clinical trials. Women were treated with either placebo, a full dose of Plan B emergency contraception, or a half dose of the drug. They were followed over several cycles and, by the end of the study, each woman had received all three of these treatments, separated by resting cycles. The women were randomly assigned to receive the treatments at specific times during the fertile preovulatory period, according to the diameter of the leading ovarian follicle, as determined by ultrasound. The leading ovarian follicle is the structure that ruptures to release the mature egg.

In 82 percent of Plan B-treated cycles, follicles failed to rupture within the five-day period following treatment (the maximum time span sperm would survive in the female reproductive tract), or there was some significant ovulatory dysfunction. These conditions occurred in only 41 percent of placebo cycles. The rate of ovulatory dysfunction observed with Plan B treatment is identical with the estimated efficacy rate of Plan B emergency contraception. Blood tests indicated that Plan B affects ovulation by suppressing the surge of luteinizing hormone (LH) that normally acts as a trigger for the ovulatory process.

"There is no doubt that fertilization would not have taken place in those women should they have had intercourse prior to treatment," says Croxatto. "We conclude that the effects exerted by Plan B, when it is taken before the onset of the LH surge, may fully explain the pregnancies averted by emergency contraception. Failure to affect the LH surge, because treatment was begun too late in the fertile preovulatory period, explains the 20 percent failure rate of this method."

Resource

1. HB Croxatto, V Brache, M Pavez, L Cochon, ML Forcelledo, R Alvarez, A Massai, A Faundes, and AM Salvatierra, "Pituitary--ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation," Contraception 70.6 (2004):442-450.

2. MR Ortiz, RE Ortiz, MA Fuentes, VH Parraguez, and HB Croxatto, "Post-coital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella," Human Reproduction 19 (2004):1352-1356.

3. AL Muller, CM Llados, and HB Croxatto, "Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat," Contraception 67.5(2003):415-419.

This article was originally published in Population Briefs, May 2005, Vol. 11, No. 2

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