Elsevier

Contraception

Volume 87, Issue 3, March 2013, Pages 300-308
Contraception

Review article
Emergency contraception — mechanisms of action

https://doi.org/10.1016/j.contraception.2012.08.021Get rights and content

Abstract

Concerns regarding the mechanisms of action of emergency contraception (EC) create major barriers to widespread use and could also lead to incorrect use of EC and overestimation of its effectiveness. While the copper intrauterine device (Cu-IUD) is the most effective method available for EC, the hormonal methods are frequently considered to be more convenient and acceptable. Today, the most commonly used method for hormonal EC is levonorgestrel (LNG). More recently, the progesterone receptor modulator ulipristal acetate (UPA) has been shown to be more effective than LNG to prevent an unwanted pregnancy. The main mechanism of action of both LNG and UPA for EC is delaying or inhibiting ovulation. However, UPA appears to have a direct inhibitory effect on follicular rupture which allows it to be effective even when administered shortly before ovulation, a time period when use of LNG is no longer effective.

The main mechanism of action of the Cu-IUD is to prevent fertilization through the effect of Cu ions on sperm function. In addition, if fertilization has already occurred, Cu ions influence the female reproductive tract and prevent endometrial receptivity.

Based on this review of the published literature, it can be concluded that existing methods used today for EC act mainly through inhibition of ovulation or prevention of fertilization. An additional effect on the endometrium as occurs for the Cu-IUD, but not for the hormonal alternatives, seems to increase the efficacy of the method.

Introduction

Emergency contraception (EC) is defined as the use of any drug or device after an unprotected intercourse to prevent an unintended pregnancy [1]. EC offers a second chance to prevent pregnancy when contraception has failed or in the case of unprotected sexual intercourse. If properly used, the widespread use of EC holds the potential to reduce the number of induced abortions. Early methods of hormonal EC were based on existing oral contraceptive preparations, the so-called Yuzpe regimen [2]. Later on, it was shown that levonorgestrel (LNG) alone was more effective than the combined regimen [3]. With LNG, estrogenic side effects could also be reduced or eliminated. Ulipristal acetate (UPA) represents a recent innovation in EC, promising better efficacy than LNG due to a wider time window of action [4]. A single dose of 30 mg UPA has recently been approved in Europe and the United States for EC use up to 120 h of unprotected intercourse. Although less practical and accessible for many women, EC with a copper intrauterine device (Cu-IUD) also offers an immediate long-acting highly effective emergency contraceptive method.

The efficacy of EC pills (ECPs) has been questioned, and interventions to make EC more available have failed in reducing abortion rates [5], [6], [7]. However, it has also been recognized that EC is still underutilized worldwide. Introduction of ECPs in many countries has generated much controversy and litigation. One of the main barriers to the widespread use of EC around the world is the lack of knowledge on the mechanisms of action, especially with regard to the effect on the endometrium, endometrial function and embryo implantation [8]. Therefore, an increased knowledge about the mechanisms of action and safety of EC is essential for the development of new methods as well as for optimizing the use of those already available. This knowledge may also influence individual and cultural acceptability of EC use.

The objective of this review is to give an overview of the mechanisms of action of EC on female reproductive functions. The review is an update of previous reviews [9], [10], [11]. Although other alternatives will be mentioned, the focus in the current article will be mainly on LNG, which is the most widely used EC method worldwide; UPA, the most recent option; and the Cu-IUD, which when used for EC also offers the possibility of long-lasting contraception.

Section snippets

EC methods

Several approaches to EC have been described [12], broadly classified as pills containing synthetic hormones and insertion of a Cu-IUD. Hormonal pills are often referred to as “postcoital pills” or “morning-after pills” in the media and in lay language. Methods used postcoitally have included diethyl stilbestrol, high doses of ethinylestradiol and LNG, danazol and mifepristone [2], [13], [14], [15], [16]. The hormonal methods are usually considered as more convenient than the insertion of a

Effectiveness and timing of EC treatment

Although the Cu-IUD is the most effective method of EC, the administration of oral hormonal pills is usually considered more convenient, with almost no medical contraindications. The absolute efficacy of ECPs remains undetermined and depends on the specific formulation, doses of regimen, time interval between unprotected intercourse and treatment, as well as the risk of conception. The proportion of pregnancies prevented by EC compared with the expected number without treatment has been

Effects on human sperm function

LNG does not influence sperm acrosome reaction [39], [38]. It inhibits spermatozoa–oocyte fusion as well as decreases the curvilinear velocity of spermatozoa only at high concentration, and the contribution of these effects to EC is unlikely to be significant [38].

In vitro data indicate that LNG or mifepristone in doses relevant for EC has no direct effect on sperm function [40], [41], [38]. The observations described by Kesserü et al. [42] on LNG effects on cervical and intrauterine mucus are

Effects on follicular development and ovulation

LNG has been shown to affect follicular development after selection of the dominant follicle but before the rise in luteinizing hormone (LH) has begun. When LNG treatment was administered at days − 2 or − 3 before the LH peak, the LH peak was inhibited or delayed and blunted [53], [52]. The effect on follicular development varied between delayed follicular development and arrested or persistent unruptured follicles. In contrast, treatment given when LH had already started to rise, on day LH − 1 or

Effects on the fallopian tube and fertilization

Fertilization normally occurs in the ampulla of the fallopian tube within 24 h after ovulation. Between day 3 and 4 (approximately on cycle day 18 of an ideal 28-day cycle), the zygote migrates through the fallopian tube until it reaches the uterine cavity at the morula stage [65], [66], [64]. The tubal microenvironment is probably of great importance to ensure normal embryo development, and stage-specific expression of receptors for various growth factors has been found on human embryos [67].

Effect on endometrial receptivity and embryo implantation

Successful implantation is the end result of a complex molecular interaction between the hormone-primed uterus and a mature blastocyst. The estimated rate of implantation in natural cycles is 15% to 30% [80]. Uterine receptivity is defined as “the temporally and spatially unique set of circumstances within the endometrium that allows for successful implantation of the embryo” [81]. The features of uterine receptivity include histological changes in which the endometrium becomes more vascular

Effects on corpus luteum function and pregnancy

A meta-analysis of 12 available prospective studies did not find any statistically significant association between oral contraceptive use in early pregnancy and fetal malformation [107]. An adverse effect of LNG on embryo implantation and pregnancy seems unlikely since gestagens are commonly administered to facilitate implantation following assisted reproduction such as IVF. Postovulatory use of 1.5 mg LNG in women who become pregnant did not cause any changes in the immunoreactivity of various

Discussion

Although the main mechanism of action of both LNG and UPA is preventing follicular rupture and ovulation, the ‘window of effect’ for LNG EC is rather narrow. It begins after selection of the dominant follicle, but ends before LH begins to rise. LNG, if taken at the time when LH has already started to rise, cannot prevent ovulation and has no effect on the endometrium or other postovulatory events [52], [85]. Consequently, it is ineffective to prevent pregnancy. This is also supported by

Conclusion

In conclusion, EC with a single dose of 1.5 mg LNG or 30 mg UPA acts through inhibition of or postponing ovulation but does not prevent fertilization or implantation and has no adverse effect on a pregnancy. The window of action of UPA seems wider than that for LNG since it may, in addition, prevent an ovulation after LH has started to rise. The main mechanism of action of Cu-IUD when used for regular contraception is prevention of fertilization. In addition and in contrast to the hormonal

Acknowledgment

KGD has served on Medical Advisory Boards of HRA-Pharma and Bayer on matters related to emergency contraception.

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