Review article Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature Horacio B. Croxatto a, *, Luigi Devoto b , Marta Durand c , Enrique Ezcurra d , Fernando Larrea c , Carlos Nagle e , Maria Elena Ortiz a , David Vantman b , Margarita Vega b , Helena von Hertzen d a Instituto Chileno de Medicina Reproductiva, Santiago, Chile b Instituto de Investigaciones Materno Infantil, Hospital San Borja-Arriara ´n, Universidad de Chile, Santiago, Chile c Instituto Nacional de la Nutricio ´n S. Z., Ciudad de Me ´xico, Me ´xico d Human Reproduction Program, World Health Organization, Geneva, Switzerland e Centro de Educacio ´n Me ´dica e Investigaciones Clı ´nicas (CEMIC), Buenos Aires, Argentina Received 16 October 2000; accepted 24 January 2001 1. Introduction This review brings together research efforts done to understand how emergency contraception (EC) methods act to prevent pregnancy and to identify what is known and what are the important gaps that need to be addressed. We expect this review will enroll more scientists in this quest and will stimulate further research to fully elucidate the mode of action. Pursuing more knowledge in this area is needed to attain informed choice. In addition it should contribute to overcome barriers in many settings, facilitate the widespread utilization of preparations for EC, and lead toward further improvements. The mode of action is impor- tant for some users, health providers, policy makers, devel- opers and manufacturers because of sensitive ethical issues. These issues resolve in either 1 of 2 questions. For some, it is whether EC acts before or after fertilization, while for others it is whether it acts before or after implantation. From the biologic perspective, the scenario is far more complex because full understanding of the mode of action implies defining how EC methods act, directly or indirectly, at various levels: the molecular level at which the exoge- nous steroid initiates its action, the signaling level at which regulation of reproduction takes place, the target organs where the signals act to elicit responses and finally the level of the reproductive entities, i.e. the gametes and the devel- oping zygote up to at least the implanting blastocyst stage. This is represented in Table 1. Some of the discrete steps of the reproductive process whose theoretical interference by EC could prevent preg- nancy are: Y follicle maturation Y the ovulatory process Y sperm migration into and through the fallopian tube, including adhesion of spermatozoa to the epithelium needed to acquire and maintain their fertilizing capac- ity Y fertilization Y zygote development in the fallopian tube Y zygote transport through the fallopian tube Y preimplantation development within the uterus Y uterine retentiveness of the free laying morula or blastocyst Y endometrial receptivity Y blastocyst signaling, adhesion and invasiveness Y corpus luteum sufficiency and responsiveness to hCG Figure 1 illustrates the chronology of some of these steps within the normal conceptional cycle of women and the time period within which EC needs to act to interfere with each one of them. 1.1 Historical background The first major trial carried out in women with “modern” contraceptive methods for “emergency purposes” was un- dertaken in Yale in 1963, using diethylstilbestrol 25–50 mg/day or ethinyl estradiol 0.5–2 mg/day for 4 – 6 days following intercourse. No pregnancies occurred among the first 100 cycles reported [1]. It was not until the mid-1970’s that larger studies, conducted in Holland with estrogens alone [2] and in Canada with an estrogen-progestin combi- nation [3], opened the way for a more widespread use of emergency contraception. Attempts to develop a progestin- only post-coital method for regular use, conducted in Peru ´ * Corresponding author. Tel.: +56-2-632-1998; fax: +56-2-633-6204. E-mail address: icmer@terra.cl (H.B. Croxatto). Contraception 63 (2001) 111–121 0010-7824/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0010-7824(00)00184-6