November 29, 2012 — Summary of "Emergency Contraception -- Mechanisms of Action," Gemzell-Danielsson/Berger, Contraception, Oct. 31, 2012.
Emergency contraception is defined as the use of any drug or device after unprotected sex to prevent an unintended pregnancy, according to Kristina Gemzell-Danielsson and Cecilia Berger of the Karolinska University Hospital's Division of Obstetrics and Gynecology. In the article, they review the effects of various types of EC on female reproductive functions. They argue that misunderstanding about EC's mechanisms of action contributes to its underutilization and that improved knowledge could spur development of new methods, optimize use of current ones and influence acceptability of EC use.
EC methods can be broadly classified as emergency contraceptive pills (ECPs) containing synthetic hormones or the insertion of a copper intrauterine device (Cu-IUD). Hormonal pills -- often referred to as "morning-after pills" by the media -- used for EC have included diethyl stilbestrol, high doses of ethinylestradiol and levonorgestrel (LNG), danazol and mifepristone. In addition, the EC ulipristal acetate (UPA) -- sold in the U.S. under the brand name "ella" -- was approved by FDA in June 2010.
While hormonal pills are typically considered more convenient than the insertion of a Cu-IUD, the latter method is the most effective. The Cu-IUD is underutilized, in part because contraceptive providers infrequently recommend it and women generally are not aware of it, according to the authors.
Effectiveness, Timing of EC Treatment
The Cu-IUD is highly effective up to five days after intercourse. The effectiveness of ECPs depends on the specific drug regimen, dosage, time interval between sex and treatment, and the risk of conception. The percentage of pregnancies prevented by ECPs compared with the expected number of pregnancies without treatment can range from 57% to more than 95%.
In a meta-analysis of data on 3,445 women from randomized controlled trials, the risk of pregnancy among women treated with UPA within 72 hours of unprotected sex was almost half of that for women receiving LNG. If taken within 24 hours of unprotected sex, UPA reduced the risk of pregnancy by almost two-thirds more than LNG.
Effects on Human Sperm Function
Research has shown that the doses of LNG used in EC are not high enough to affect sperm function. By contrast, Cu-IUD insertion releases copper ions that cause an inflammatory response that increases the levels of certain fluids that are toxic to sperm.
Effects on Follicular Development, Ovulation
LNG has been shown to inhibit or delay the rise in luteinizing hormone (LH) that normally occurs before ovulation, if the drug is administered two or three days before the LH peak. Treatment administered after LH has started to rise does not inhibit ovulation.
Studies suggest "that UPA may have a direct inhibitory effect on follicular rupture," the authors write. Thus, UPA is an effective option when LH has already started to rise and LNG is no longer effective.
Effects on the Fallopian Tube, Fertilization
Fertilization typically takes place in the fallopian tubes within 24 hours after ovulation. The fertilized egg then travels through the fallopian tube between days three and four to reach the uterine cavity. A number of factors, including expression of progesterone and estrogen receptors, have been shown to affect transport of the zygote through the fallopian tube.
In vivo, treatment with LNG two days after the LH peak did not affect progesterone and estrogen receptors. LNG also does not affect embryo viability or increase the risk of ectopic pregnancy.
If fertilization occurs after insertion of a Cu-IUD, the method lowers the chance that the embryo will survive to reach the uterus, suggesting that the method's major postfertilzation effect is destruction of the early embryo in the fallopian tube, according to the authors. They note that because the main mechanism of action for the Cu-IUD is to prevent fertilization, "[i]f any embryos are formed in the presence of an IUD, it happens at a much lower rate than in non-IUD users."
Effects on Endometrial Receptivity, Embryo Implantation
Treatment with LNG or UPA in the levels used in ECPs does not interfere with endometrial receptivity or prevent embryo implantation. Copper in doses similar to those in the Cu-IUD has been shown to stimulate the uterine wall, which could contribute to its contraceptive effect. In addition, continuous use of a Cu-IUD produces an inflammatory reaction that affects the fluids in the genital tract and prevents the formation of embryos.
If a blastocyst does reach the uterus, copper can alter molecules in the endometrial lining to inhibit implantation. Research has found that in this case, the Cu-IUD likely prevents, rather than interrupts, embryo implantation.
Effects on Corpus Luteum Function, Pregnancy
A recent cohort study also found that that there was no link between exposure to LNG after failed or mistimed EC use and negative pregnancy outcomes. To date, only a very small number of pregnancies have been exposed to UPA, and the effects are being studied. If conception occurs when a Cu-IUD is inserted, the device should be removed as soon as possible. There is no increased risk of adverse effects if the removal occurs without inducing contractions or miscarriage.
Discussion and Conclusion
In summary, the main mechanism of action for both LNG and UPA is preventing follicle rupture and ovulation, according to the authors. However, they note that LNG has a fairly narrow "window of effect" and cannot prevent ovulation if LH has already started to rise, indicating that "there is still a need to develop more effective EC methods."
In contrast to LNG, UPA has been shown to have a direct inhibitory effect on follicular rupture, which is why it is effective when administered shortly before ovulation.
The primary mechanism of action for the Cu-IUD is to prevent fertilization through the effect of copper ions on sperm viability and function. The method also can affect the oocyte and endometrium to help prevent pregnancy if intercourse occurs after ovulation, which likely contributes to its high efficacy.
Knowledge about the mechanisms of action of EC is important to ensure correct use. The authors note that insertion of an Cu-IUD offers the advantages of effective EC at any time during the menstrual cycle as well as continued long-term contraception.
A single dose of 30 milligrams of UPA is recommended as soon as possible after unprotected sex and no later than five days. If UPA is not available, LNG offers an alternative treatment that is easily accessible and has minimal side effects.
"Taken together, there is still a need to develop more effective EC methods," the authors write, adding, "To ensure the highest efficacy and to cover the entire window of fertility, the ideal agents for EC also need to target the endometrium and should be possible to use on demand pre- and postcoitally."
The authors conclude, "Increased knowledge of the mechanism of action could hopefully increase the acceptability and, thus, availability of EC to offer women a chance to prevent an unwanted pregnancy."