Mechanism of Action

(Published March 2011)

Emergency contraception pills (ECPs) may theoretically prevent pregnancy through several mechanisms. The most likely mechanism of action is the inhibition or delay of ovulation.

Several clinical studies have shown that combined ECPs containing the estrogen ethinyl estradiol and the progestin levonorgestrel can inhibit or delay ovulation.^1-4 Although early studies indicated that alterations in the endometrium after treatment with the regimen might impair receptivity to implantation of a fertilized egg, more recent studies have found no such effects on the endometrium.^5,6 Additional possible mechanisms include interference with corpus luteum function; thickening of the cervical mucus resulting in trapping of sperm; alterations in the tubal transport of sperm, egg, or embryo; and direct inhibition of fertilization.^7-10 No clinical data exist regarding the last three possibilities.

Treatment with levonorgestrel-only ECPs as soon as possible after unprotected sex has been shown to impair the ovulatory process and luteal function. Levonorgestrel-only ECPs can inhibit ovulation but do not always do so even when given before ovulation.^11-16 Inhibiting ovulation may be the only mechanism of action for levonorgestrel-only ECPs. Recent studies have found no effect on the endometrium.^16-18 In one study, levonorgestrel 1.5 mg had no effect on the quality of cervical mucus or on the penetration of spermatozoa in the uterine cavity.¹⁷

Animal studies demonstrated that levonorgestrel administered in doses that inhibited ovulation had no postfertilization effect that impaired fertility.^10,19,20 Whether these results can be extrapolated to humans is unknown. Based on those animal studies and their own studies in women, Novikova et al.²¹ argued that most, if not all, of the contraceptive effect of both combined and progestin-only ECPs can be explained by inhibited or dysfunctional ovulation. This question of postfertilization effect may never be answered unequivocally because no test exists for fertilization; however, the best available evidence indicates that levonorgestrel does not interfere with any postfertilization events.²²

When levonorgestrel EC is taken too close to ovulation, it is ineffective. In contrast, when ulipristal acetate (UPA) is taken at the same time, it can delay ovulation. By the time the leading follicle reaches 15-17 mm, follicular rupture is prevented within 5 days no more often after levonorgestrel administration than after placebo administration.¹⁵ In contrast, when taken when the leading follicle reaches 18-20 mm (and ovulation should occur within 48 hours) and the probability of conception exceeds 30%, UPA prevents follicular rupture within 5 days of administration in 59% of cycles, compared with 0% in placebo cycles.²² Follicular rupture failed to occur within 5 days after treatment with UPA in all women treated before onset of the LH surge, in 79% of women treated after the onset of the LH surge but before the LH peak, and in 8% of women treated after the LH peak. Another study found that ulipristal acetate altered the endometrium, but whether this change would inhibit implantation is unknown.²³

As medical authorities such as the National Institutes of Health,²⁴ the American College of Obstetricians and Gynecologists²⁵ and the US FDA define pregnancy as beginning with implantation, ECPs do not interrupt an established pregnancy, they are not abortifacients.²²

References:

1. Swahn ML, Westlund P, Johannisson E, et al. Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle. Acta Obstet Gynecol Scand. 1996;75:738–44.
2. Ling WY, Robichaud A, Zayid I, et al. Mode of action of DL-norgestrel and ethinyl estradiol combination in postcoital contraception. Fertil Steril. 1979;32:297–302.
3. Rowlands S, Kubba AA, Guillebaud J, et al. A possible mechanism of action of danazol and an ethinyl estradiol/norgestrel combination used as postcoital contraceptive agents. Contraception. 1986;33:539–45.
4. Croxatto HB, Fuentalba B, Brache V, et al. Effects of the Yuzpe regimen, given during the follicular phase, on ovarian function. Contraception. 2002;65:121–8.
5. Taskin O, Brown RW, Young DC, et al. High doses of oral contraceptives do not alter endometrial alpha 1 and alpha v beta 3 integrins in the late implantation window. Fertil Steril. 1994;61:850–5.
6. Raymond EG, Lovely LP, Chen-Mok M, et al. Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity. Hum Reprod. 2000;15:2351–5.
7. Glasier A. Emergency postcoital contraception. N Engl J Med. 1997;337:1058–64.
8. Ling WY, Wrixon W, Acorn T, et al. Mode of action of dl-norgestrel and ethinyl estradiol combination in postcoital contraception. III. Effect of preovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis. Fertil Steril. 1983;40:631–6.
9. Croxatto HB, Devoto L, Durand M, et al. Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception. 2001;63:111–21.
10. Croxatto HB, Ortiz ME, Müller AL. Mechanisms of action of emergency contraception. Steroids. 2003;68:1095–8.
11. Hapangama D, Glasier AF, Baird DT. The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle. Contraception. 2001;63:123–9.
12. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception. 2001;64:227–34.
13. Marions L, Hultenby K, Lindell I, et al. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynecol. 2002;100:65–71.
14. Marions L, Cekan SZ, Bygdeman M, et al. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception. 2004;69:373–7.
15. 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;70:442–50.
16. Okewole IA, Arowojolu AO, Odusoga OL, et al. Effect of single administration of levonorgestrel on the menstrual cycle. Contraception. 2007;75:372–7.
17. do Nascimento JA, Seppala M, Perdigao A, et al. In vivo assessment of the human sperm acrosome reaction and the expression of glycodelin-A in human endometrium after levonorgestrel emergency contraceptive pill administration. Hum Reprod. 2007;22:2190–5.
18. Palomino WA, Kohen P, Devoto L. A single midcycle dose of levonorgestrel similar to emergency contraceptive does not alter the expression of the L-selectin ligand or molecular markers of endometrial receptivity [published online ahead of print November 10, 2009]. Fertil Steril.
19. Müller AL, Llados CM, Croxatto HB. Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat. Contraception. 2003;67:415–9.
20. Ortiz ME, Ortiz RE, Fuentes MA, et al. Postcoital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella. Hum Reprod. 2004;19:1352–6.
21. Novikova N, Weisberg E, Stanczyk FZ, et al. Effectiveness of levonorgestrel emergency contraception given before or after ovulation: a pilot study. Contraception. 2007;75:112–8.
22. Davidoff F, Trussell J. Plan B and the politics of doubt. JAMA. 2006;296:1775–8.
23. Stratton P, Levens ED, Hartog B, Piquion J, Wei Q, Merino M, Nieman LK. Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914. Fertil Steril. 2010;93:2035-41.
24. OPRR reports: protection of human subjects. Code of Federal Regulations 45CFR 46, March 8, 1983.
25. American College of Obstetricians and Gynecologists. Obstetric-gynecologic terminology. Philadelphia: F.A. Davis; 1972.
26. International Consortium for Emergency Contraception, International Federation of Gynecology & Obstetrics. Statement on mechanism of action: how do levonorgestrel-only emergency contraceptive pills (LNG ECPs) prevent pregnancy? Accessed at www.cecinfo.org/publications/policy.htm, May 1, 2010.