Review articleMechanism of action of emergency contraception
Introduction
Emergency contraception (EC) is defined as the use of any drug or device used after an unprotected intercourse to prevent an unwanted pregnancy. Despite the availability of highly effective methods of contraception, a substantial proportion of pregnancies remains unplanned and results in an induced abortion [1]. More than half of unintended pregnancies — an estimated 45.5 million worldwide — are resolved by induced abortion each year [2]. Many women who experience an unplanned pregnancy have become pregnant as a result of either lack of contraceptive use due to various reasons or contraceptive failure. It has been estimated that millions of unwanted pregnancies could be avoided if effective postcoital EC methods were widely accessible [3]. Although this has been questioned and interventions to make EC available has failed in reducing abortion rates [4], it has also been recognized that the use of EC is still underutilized worldwide. A major barrier to the widespread acceptability and use of EC is concern regarding the mechanisms of action of EC methods. Although a number of available contraceptive methods are effective when used for EC, the knowledge of the mechanism underlying the contraceptive effects remains incomplete [5]. The objective of this review is to give an overview of the effect of EC on female reproductive functions. The focus will be mainly on levonorgestrel (LNG) which is the most widely used EC method worldwide although other alternatives will also be discussed.
Section snippets
EC methods
One of the earliest recommendations on EC use can be found in the first textbook on Obstetrics and Gynecology authored by the gynecologist Soranos of Ephesos (98–138 ad). He stated that, “the woman ought, in the moment during coitus when the man ejaculates his sperm, to hold her breath, draw her body back a little so that the semen cannot penetrate into the os uteri, then immediately get up and sit down with bent knees, and in this position, provoke sneezes. She should then wipe out the vagina
The fertile window
It is only during a limited period during the menstrual cycle that unprotected intercourse may result in a pregnancy [19]. The high-risk fertile phase extends from 5 days before ovulation to the day of ovulation. Fertilization must occur within 12–24 h of ovulation, since after that time the oocyte deteriorates rapidly and fertilization then either fails or gives rise to a defective embryo. In contrast, spermatozoa can survive in the female reproductive tract for 5–6 days after intercourse [20]
Effects on human sperm function
In vitro data indicate that LNG in doses relevant for EC have no direct effect on sperm function [23], [24]. The observations described by Kesserü et al. [25], [26] on LNG effects on cervical and intrauterine mucus are probably of importance when LNG is used as a regular contraceptive but unlikely to be the main mechanism of action of LNG used for EC since sperms can be retrieved from the fallopian tube within minutes after insemination [26], [27]. Furthermore, it was recently reported that
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 administrated at days LH-2 or LH-3, the LH peak was inhibited or delayed and blunted [29], [30] (Fig. 1). The effect on follicular development varied between the 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
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 [40]. Too rapid or too slow tubal transport could also be expected to cause desynchronization between the embryo and the tube and/or the blastocyst and the endometrium. A spatially dependent expression of PRs has been shown in the human fallopian tube [41]. Higher levels of receptors are being
Endometrial receptivity and embryo implantation
A considerable number of factors have been suggested as markers of endometrial receptivity. Treatment with LNG (1.5 mg) on Day LH-2 did not affect endometrial morphology or any studied markers of receptivity during the mid-luteal phase at the expected time of endometrial receptivity and implantation [46].
The dose-dependent endometrial effects of mifepristone administered postovulatory has been investigated in several studies. Once-a-month treatment with a single dose of 200 mg mifepristone on
Corpus luteum function and pregnancy
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. A recent prospective cohort study confirmed that there was no association between the exposure to LNG after failed or mistimed EC use and the risk of major congenital malformation, pregnancy complications or any other adverse pregnancy outcomes [64].
UPA for EC
In a series of clinical trials, the effect of UPA at different follicular diameters and in relation to the LH peak and ovulation was studied [65]. When given prior to the LH rise, UPA inhibited 100% of follicular ruptures. When UPA was administered when the size of the leading follicle was 18 mm, follicular rupture failed to occur within 5–6 days following treatment in 44–59%. Even on the day of the LH peak, UPA could delay ovulation for 24–48 h after administration [65]. Taken together, these
Discussion
Taken together, 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 post-ovulatory events. Consequently, it is ineffective to prevent pregnancy. This is also supported by clinical data on women exposed to unprotected intercourse at the time of ovulation [21]. In a clinical trial
Conclusion
In conclusion, EC with a single dose of 1.5 mg of LNG acts through inhibition or postponing ovulation but does not prevent fertilization or implantation and has no adverse effect on a pregnancy. 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 and thus reduce the number of induced abortions.
Acknowledgment
The studies from the Karolinska Hospital referred to in the article were supported by UNDP/UNFPA/WHO/World Bank Special Programme of Research Development and Research Training in Human Reproduction, World Health Organization, Geneva, Switzerland, and the Swedish Medical Research Council (2003-3869, K2007-54X-14212-06-3), the Karolinska Institute Research Funds and Karolinska Institutet Stockholm City County/Karolinska Institutet (ALF).
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