Review articleMechanism of action of hormonal preparations used for emergency contraception: a review of the literature
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 important for some users, health providers, policy makers, developers 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 exogenous 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 developing 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 pregnancy are:
- •
follicle maturation
- •
the ovulatory process
- •
sperm migration into and through the fallopian tube, including adhesion of spermatozoa to the epithelium needed to acquire and maintain their fertilizing capacity
- •
fertilization
- •
zygote development in the fallopian tube
- •
zygote transport through the fallopian tube
- •
preimplantation development within the uterus
- •
uterine retentiveness of the free laying morula or blastocyst
- •
endometrial receptivity
- •
blastocyst signaling, adhesion and invasiveness
- •
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.
The first major trial carried out in women with “modern” contraceptive methods for “emergency purposes” was undertaken 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 combination [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 Perú [4], provided the basis for its application to emergency situations two decades later. In addition, the post-coital insertion of an intrauterine device [5] and the administration of the antiprogestin RU486 [6], have also been used to prevent pregnancy in the context of “emergency situations”.
A comprehensive definition of EC is the following: “specific contraceptive methods that can be used as emergency measures to prevent pregnancy after unprotected intercourse; emergency contraception is used after coitus but before pregnancy has become established; as such, it is considered a back-up method for occasional rather than regular use” [7]. The Consortium for Emergency Contraception [8] has adopted a similar definition: “a number of methods used by women within a few hours or a few days following unprotected intercourse to prevent pregnancy.” Both definitions essentially highlight that EC is to be used within a given period after unprotected intercourse to prevent pregnancy and that it differs from most fertility regulation methods in that it is not intended for regular use.
There are a variety of situations where EC is indicated, among them, condom rupture, unplanned unprotected intercourse (particularly in case of young adults engaging in sexual experiences), incidental misuse of regular contraceptive methods, and sexual assault.
A brief description of the mode of use, efficacy, and most common side effects of the 2 hormonal methods most widely used for EC, the Yuzpe regimen and levonorgestrel, and a promising method under research, mifepristone (RU486), follows.
In recent years this has been the most commonly used method. It consists of 2 doses, given 12 h apart, each providing 100 ug ethinyl estradiol (EE) plus 500 ug levonorgestrel. The pills usually contain 50 ug EE and 250 ug levonorgestrel or 500 ug dl-norgestrel, so that a total of 4 tablets need to be taken. The first dose should be administered within 72 h after unprotected intercourse. Nausea and vomiting are the most common side effects of this method. The effectiveness of the Yuzpe regimen for EC is now well established [3], [9], [10], [11], [12], [13], [14], [15]. A recent meta-analysis found effectiveness rates of 56–89%, with a weighted average of 74% [16]. This does not mean that 26% of users actually get pregnant since of all women who take EC pills, only about 2% get pregnant [8]. It means that it prevents 74% of pregnancies that are to be expected based upon the time of the cycle in which intercourse took place.
Norgestrel or dl-norgestrel is a racemic mixture of d-norgestrel and l-norgestrel. d-Norgestrel, the biologically active enantiomer, is designated as levonorgestrel (LNG). The focus of this section is on LNG used alone for EC.
Hoffman [17] looked for the first time at the efficacy of LNG as an emergency contraceptive. He administered a single dose of 0.6 mg within 12 h of unprotected intercourse and observed a failure rate of 2.9%, not different from the failure rate in a parallel group treated with the Yuzpe regimen.
Ho and Kwan [18] carried out a randomized study to compare the standard Yuzpe regimen with 0.75 mg LNG administered twice, 12 h apart, starting within 48 h after a single unprotected intercourse. Again, the efficacy of LNG was similar to that of the combined estrogen-progestin regimen with failure rates of 2.4% and 2.6%, respectively.
Recently, a randomized, double-blind clinical trial of LNG versus the Yuzpe regimen that enrolled nearly 2,000 women at 21 centers world-wide was reported by the WHO Task Force on Post-Ovulatory Methods for Fertility Regulation [19]. In this study, one tablet containing 0.75 mg LNG plus a placebo tablet were taken no later than 72 h after unprotected intercourse. A second tablet containing the same dose plus a placebo tablet were to be taken 12 h later. The crude pregnancy rate was 1.1% (11/976) in the LNG group compared with 3.2% (31/979) in the Yuzpe group. The proportion of pregnancies prevented, compared with the expected number without treatment, was 85% with LNG and 57% with the Yuzpe regimen. The efficacy of both treatments declined significantly with increasing time since unprotected intercourse. The pregnancy rates were 0.4%, 1.2%, and 2.7% when LNG was given within the first, second or third 24 h period since unprotected coitus.
In all studies, LNG has been associated with a significantly lower incidence of side effects than the Yuzpe regimen [18], [19], [20].
Following single oral administration of 0.75 mg, LNG serum concentration reach a maximum (5–10 ng/mL) approximately at 2 h and decline rapidly during the first 24 h with considerable inter- and intra-individual variation [21], [22], [23] The scientific literature examined does not allow for assertion that the current dose being used is optimal or that the second tablet contributes significantly to the contraceptive effectiveness of this method.
Mifepristone is an 11-dimethyl-amino-phenyl derivative of norethindrone with high affinity for progesterone receptors and less so for glucocorticoid receptors. At low doses suitable for EC, it exhibits antiprogestin but no antiglucocorticoid action. The pharmacokinetics following single oral administration are characterized by rapid absorption, peak serum concentrations in the micromolar range and a long half-life of 25 to 30 h [24].
Glasier et al. [6], [12] and Webb et al. [13], compared the efficacy and side effects of a single dose of 600 mg of mifepristone with those of the Yuzpe regimen. None of the nearly 600 women who received mifepristone became pregnant, whereas, nine pregnancies were observed among those given the Yuzpe regimen. Significantly more women who were treated with mifepristone had a delay in the onset of menstruation but other than that, this treatment was associated with minimal side effects.
A recent multicenter study, which included 1,717 women seeking EC, showed that reducing the mifepristone dose from 600 to 50, and even to 10 mg, did not decrease its efficacy (pregnancy rates 1.3%, 1.1%, and 1.2%, respectively); overall, 84 to 86% of expected pregnancies were prevented. Lower doses were associated with less disturbance of the menstrual cycle and lower incidence of unpleasant side effects; overall, 12–17% of the subjects reported nausea, headache or dizziness [25].
In summary, the results of these clinical studies, indicate that mifepristone is a highly effective EC agent, and its only apparent disadvantage from the user perspective is that the next menstrual period comes after the expected date in nearly half of the cases.
Section snippets
Effects of post-coital administration of steroids upon fertility in non-primate animal models
Numerous studies have shown that pregnancy can be prevented in a variety of mammalian species by post-coital administration of sex steroid hormones, their synthetic agonistic and antagonistic analogs as well as non-steroidal drugs that share in part their pharmacologic properties. The species that comprise this group, which are most commonly used in the laboratory, e.g., rabbit, rat, mouse, hamster, and guinea pig, differ from the human and other primates in many aspects of their reproductive
Studies in non-human primates
Hormonal compounds currently used for EC have not been tested, as such, in non-human primates, therefore, this review focuses on the effects of estrogens, progestins or the antiprogestin mifepristone, administered in the periovulatory period to macaques and the New World monkey Cebus apella.
The Yuzpe regimen
Rowlands et al. [80], gave the combination EE-dl-norgestrel to 14 women requesting EC up to 120 h after unprotected intercourse. LH, pregnanediol glucuronide, hCG, and creatinine were monitored in daily urine samples. Normal parameters were observed in 4 subjects, suppression or deferral of the LH peak in 3, and shortening or insufficiency of the luteal function in the remaining 7. In no case was hCG detected. The timing of treatment within the cycle was not reported
Effects of the Yuzpe regimen administered before the LH surge
Swahn et al. [81]
Cogitation
Numerous attempts to determine the involvement of selected steps of the reproductive process in the mechanism by which EC prevents pregnancy have been done. In spite of that, a wide gap of information persists that hinders a clear-cut answer to the question.
With few exceptions, the fact that an entity or a process is altered by the treatment does not necessarily mean that it explains how pregnancy is prevented in real life situations. In this respect, ovulation inhibition can explain by itself
Acknowledgements
This review was supported by the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction
References (102)
Interception. Postcoital estrogens in 3,016 women
Contraception
(1976)- et al.
Postcoital contraception with dl-norgestrel
Contraception
(1973) - et al.
Postcoital contraception with mifepristone
Lancet
(1991) - et al.
A multicenter clinical investigation employing ethinyl estradiol combined with dl-norgestrel as a postcoital contraceptive agent
Fertil Steril
(1982) - et al.
Updated estimates of the effectiveness of the Yuzpe regimen of emergency contraception
Contraception
(1999) - et al.
The effect of levonorgestrel administered in large doses at different stages of the cycle on ovarian function and endometrial morphology
Contraception
(1989) - et al.
A multicenter clinical study on two types of levonorgestrel tablets administered for postcoital contraception
Int J Gynecol Obstet
(1991) - et al.
Pharmacokinetics and metabolism of RU486
J Steroid Biochem
(1987) - et al.
Biological microscopic and scanning electron microscopic investigation of the effects of postinor d-norgestrel in rabbits
Contraception
(1984) - et al.
Interceptionthe use of postovulatory estrogens to prevent implantation
Am J Obstet Gynecol
(1973)