Plan B: Literature Review (Part I)

Let's look at another literature review, Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature (Croxatto, et al., 2001), that clearly and distinctly presents the results of LNG studies separate from other EC methods. Though undertaken by proponents of EC, the review does not shy away from suggesting that LNG might have postfertilization effects.

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 process. One of them which is crucial for studying the mode of action of postcoital contraception, is the fact that at variance with the human, coitus always precedes ovulation by 12 h or less. This means that coitus either comes after the ovulatory stimulus has taken place (spontaneous ovulators) or induces the gonadotropin surge immediately thereafter (reflex ovulators), leaving little or no chance for post-coital treatments to interfere with pre-fertilization events. Only a few examples, which illustrate what sex steroids do in these species when used in a manner comparable to that of EC, were arbitrarily selected.

[…]

The effect of levonorgestrel administered in the periovulatory period in non-human primates has not been reported. Since its binding affinity to progesterone receptor (PR) and its progestomimetic activity are several-fold higher than P itself [61], one can expect it will share many of the effects of the natural progestin. The effects of P upon fertility, when administered in the periovulatory phase, have not been reported in the monkey. However, exogenous progesterone antagonizes estrogen-induced gonadotropin release required for ovulation [59,62] and causes asynchronous development of glands and stroma in the endometrium [47,63,64]. Progesterone plays a pivotal role in periovulatory and luteal events through receptor-mediated pathways [65– 68]. Thus, a reduction of P bioavailability by inhibition of its synthesis or by competition with its receptor might interfere with ovulation, fertilization, luteal function, and subsequent endometrial development.

These admissions regarding the downsides of relying on animal studies in these matters are important to bear in mind when reading the remainder of their review, as well as recent papers that I will review in subsequent installments. Some of those who regard Plan B as abortifacient refuse to accept the results of such animal studies. However, endochrinologists have little choice in the matters given the bioethical complications of performing studies on humans. Another paper in this review (Ortiz, et. al, 2004) explains.

For ethical and logistic reasons, it has not been possible to segregate groups of women who take EC after fertilization in order to assess its effect on the establishment of pregnancy. Hence, there is no direct evidence that post-coital treatment with LNG prevents pregnancy by interfering with post-fertilization events. On the other hand, animal experimentation allows the investigator to segregate groups treated before or after critical events, such as ovulation, fertilization and implantation, in order to define the contribution of interference with pre- and post-fertilization events to the contraceptive efficacy of the drug. Although extrapolation of the results to humans has limitations, experiments in animals often shed light on possible mechanisms operating in humans.

Animal experimentation provides an important necessary ethical, if imperfect, means for assessing the methods of action for EC. In fact, some of the authors of the Croxatto, et al., proceded to study the effects of LNG on rats and new-world monkeys.

The following review exerpts represent research that had been completed prior to submission in October, 2000.  

There are few studies designed to look at the mechanism of action of LNG in EC and its exact mode of action remains unknown. Moggia et al. [88] proposed that the post-coital contraceptive effect of LNG is due to changes in the endometrium that prevent implantation. Kesseru et al. [89] provided evidence that single administration of LNG 0.4 mg 3 to 10 h post-coitum: a) decreased the number of sperm recovered from the uterine cavity beginning 3 h after treatment; b) caused pronounced alkalization of the intrauterine fluid beginning at 5 h, which immobilized the sperm, and; c) increased the viscosity of the cervical mucus, beginning at 9 h, which denied further passage of sperm to the uterus. Serege´ly [90] suggested that disturbances in LH pulse frequency following LNG administration were involved. Landgren et al. [21] examined the effects of repeated doses of LNG (0.75 mg) given before (days 2, 4, 6, and 8), during (days 9, 11–13, 15, 16, and 19) or after ovulation (days 16, 18, 20, and 22). Administration in the early follicular phase increased the duration of the follicular phase. Treatment around ovulation resulted in varying effects ranging from anovulation or deficient luteal function in some women to normal ovarian function in others. The administration of LNG during the luteal phase was not followed by changes in cycle length or endometrial morphology. Spona et al. [91] administered single or multiple doses of 0.4 mg LNG before or after the LH peak to 6 subjects. Treatment prior to the LH peak suppressed the gonadotropin surge, reduced the levels of E2 and P, and markedly lowered the cervical mucus score, whereas treatment after the LH peak did not alter these parameters. The effects of these multiple administrations cannot be freely extrapolated to the current EC regimen.

Wang et al. [92] compared the effects of 0.75 mg LNG given twice, 12 h apart, when the first dose was administered on day LH-2 versus LH+2. The main endpoints were timing and incidence of ovulation and the status of the endometrium at the time of implantation (LH+7). Preovulatory administration had no effect on ovulation, whereas at the level of the endometrium, it caused divergent effects depending on the time of drug intake. Factors believed to be critical for implantation, such as integrins, steroid receptors, or leukemia inhibitory factor, among others, were changed in ways which are likely to alter endometrial receptivity.

The only study that provides a large enough data base to examine the relationship between coitus-treatment interval and outcome shows that LNG as well as the Yuzpe regimen exhibit an inverse relationship between contraceptive efficacy and the length of time from intercourse to treatment. Pregnancy rates increased from 0.5% when treatment was given within the first 12 h period after intercourse to 4.1% when it was given within the fifth 12 h period (61–72 h) [93]. While this fact does not allow for discriminating between possible modes of action, it does lend support to a significant role of pre-fertilization mechanisms in their contraceptive effectiveness, albeit not necessarily the same ones for both methods. Our hypothesis is that…in the case of LNG the earlier it is given, the better the chances it will interfere with sperm migration and function at all levels of the genital tract.

The proposed mechanisms of action can be briefly sumarized as follows.

  • 1974: changes in the endometrium that prevent implantation
  • 1974: hostility to spermatazoa
  • 1975: suppressed gonaotropic surge, reduced levels of E2 and P, thickening of cervical mucus (treatment prior to LH)
  • 1982: interference with LH pulse (and therefore ovulation)
  • 1989: increased follicular phase duration, anovulation, deficient luteal function (depending on time of treatment)
  • 1998: changes to endometrium that could alter receptivity
  • 1999: interference with sperm migration and function (treatment after ovulation)

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 clearcut 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 how pregnancy is prevented whereas abnormal expression of a given molecule in the endometrium lacks that strength until it is shown that its normal expression is essential for pregnancy to occur. [Emphasis mine]

IOW, no egg means no fertilization, i.e., no baby. On the other hand, changes to the endometrium do not inherently indicate any particular method of pregnancy prevention. A change is only relevant in this context if it is demonstrated to interfere with postfertilization events. This is an important point because it weakens the claims of those who believe that any change to the endometrium strongly suggests that LNG intereferes with implantation and is therefore abortifacient. 

It is now well recognized that one of the complexities that researchers have to deal with to find a thorough answer is that the mechanism may differ for the same EC treatment depending upon when it is given relative to time of intercourse and also relative to time of ovulation. A single act of intercourse that takes place up to 5 days before ovulation may result in pregnancy in the human. Therefore, many women who request EC receive the treatment before ovulation and possibly before fertilization if ovulation has occurred. Neither the minimum length of time from coitus to fertilization, when the oocyte is waiting for the sperm, nor the shortest interval from ovulation to fertilization, when the sperm is waiting for the oocyte, have been determined in the human. Therefore, the exact theoretical amplitude of the window for acting before fertilization is undetermined, less so the actual window in real cases.

This problem is highlighted in an interesting 2004 paper by Mikolajczyk and Stanford (yes, that Stanford), which describes problems in common methods for predicting fecundity and presents a new method that seems to be less biased. I'll cover this in some detail in a later installment. 

The contraceptive effectiveness of LNG and the Yuzpe regimen has been shown to depend on the intercourse-treatment interval (the easy one to obtain), whereas there is no data for the ovulation-treatment interval (the difficult one to obtain). Given that in 15–25% of the cycles treated with EC, the expected pregnancy is not prevented, chances are that there is a specific window in the cycle in which treatment is more likely to fail. Attempts to pinpoint the stage of the menstrual cycle at which treatment is given to women requesting EC for subsequent correlation with the contraceptive outcome may shed some light on the mode of action of a particular method. Admittedly, even at a research center, it is difficult to get informed consent for such a study given the anxiety that surrounds every case. Since the intercourse-treatment and ovulation-treatment intervals are inter-related, should information about both become available, complex analyses will be needed to estimate how each one relates to the contraceptive outcome.

According to Mikolajczyk and Stanford, the estimated failure rate of 15-25% is based on flawed estimations of fecundity and may be well below the mark. If so, the "residual" pregnancy-preventing capacity that so many insist must be accounted for by postfertilization effects may be illusory.

Most mechanistic studies have attempted to assess to what extent ovulation inhibition is involved. However, none has used ultrasound to confirm follicular rupture and to pinpoint at what stage of follicular development treatment was given. It is clear that EC appears to prevent ovulation in many cases but not so clear what the conditions are in terms of timing of treatment relative to the stage of follicular development. The criteria used to time treatment lacks this precision in practically all studies reviewed. Because ultrasound has not been used, the occurrence of ovulatory dysfunctions, such as luteinized unruptured follicle, has not been determined.

Later studies on new-world monkeys (Ortiz, et al., 2004), surgically sterilized women (Durand, et al., 2001),  and women made sterile by tubal ligation or nonhormonal IUDs (Müller, et al., 2003) employed ultrasound to observe follicular development.

Both logistic and ethical constraints prevent designing and performing experiments that can directly address what in fact happens to the crucial biologic entities – sperm, oocyte, zygote or preimplantation embryo – in the genital tract of women who receive EC in comparison to those who receive placebo. The fate of spermatozoa and of the oocyte can be studied without risking the occurrence of conception if either one is absent from the genital tract. It is easy to avoid the presence of sperm for this purpose, without altering the biologic environment. In order to suppress the presence of the oocyte, one could inhibit ovulation using a GnRH-antagonist and give appropriate sex steroid replacement therapy to provide a “normal environment for sperm”. The effect of EC treatment on sperm could then be studied at centers where retrieval of spermatozoa from the site of fertilization is feasible. In fact, with the exception of Kesseru et al. [89], no other study has focused on the effects of EC upon spermatozoa.

A later literature review (Gemzell-Danielsson and Marions, 2004), which will be discussed in another installment, refers to studies that observed the effects of LNG on sperm migration and function. 

Alterations in embryo transport through the fallopian tube or uterus following EC, are also difficult to explore. Delayed transport or retention in the tube cannot be excluded a priori, although no increased incidence of tubal pregnancy has hitherto been reported with the current methods.

Reports, or lack thereof, of increased rates of tubal pregnancy will not be discussed in my review. However, if any of my readers have compelling evidence in this matter, they are encouraged to share them in comments. Tubal pregnancy (a dangerous condition that requires abortion) certainly qualifies as an anti-implantation effect; I have only omitted discussion on this topic due to time constraints as a busy grad student who has his own research to worry about.

Accelerated transport through the tube appears unlikely since neither estradiol nor progesterone given in high doses right after ovulation have this effect in women [102]. Expulsion of the egg from the uterus could result from myometrial effects of wide steroid oscillations.

The first statement means that high doses of estradiol (which is present in the Yuzpe regimen) or progesterone (which is present in both Yuzpe and Plan B) have not induced accelerated transport of a zygote from a fallopian tube. Timing of zygote transport to the uterus is important in the implantation process. Accelerated transport might result in a zygote encountering an inhospitable environment for implantation and therefore be aborted.

The second statement is very confusing. As a nonexpert I found it difficult to parse and am open to correction of the assessment that follows. As I understand it, means that by flooding the body with LNG, some uterine or endometrial effect may be triggered that would evict the egg somehow. That is, a woman using LNG might still ovulate, but that egg might never have a chance to fertilize and any observed changes to the endometrium that might impede implantation in other situations actually contributed to evicting the egg.  

Several studies have focused attention on alterations of the endocrine profile during the luteal phase. Luteal insufficiency, caused by EC, cannot be claimed to contribute to pregnancy prevention until it is shown to persist through a hCG challenge test.

Under normal circumstances, following the release of the egg from the ovary, the follicle that held the egg collapses on itself. What remains is called the corpus luteum (Latin for "yellow body"). It remains in the interior ovarian wall and secretes progesterone for 12 to 16 days. At this time in the cycle progesterone is important for preventing the release of additional eggs and causing the thickening of the uterine lining (endometrium). If the latter does not occur, an embyro might not be able to implant.

If I understand the argument being made correctly, observations of luteal insufficiency in studies may simply indicate lack of an embryo. Since hCG (human chorionic gonadotropin) is secreted by an embryo and helps to maintain the corpus luteum, if a bolus of hCG were administered after ovulation and progesterone levels did not rise, then one could conclude that EC had impaired the corpus luteum to the point of making the endometrium inhospitable to implantation. A positive response to the test, however, would indicate that corpus luteum function is not impaired. Such a hCG challenge test would be difficult to perform, however, due to complicated timing issues and bioethical complications regarding performing tests in the possible presence of an embryo. 

The most difficult parameter to assess with certainty is endometrial receptivity. Endometrial markers of receptivity have been established so far with certainty only in rodents. Even if endometrial receptivity is shown to be altered by EC, other steps that precede implantation may also be altered enough to interrupt the process at an earlier stage.

IOW, even if the endometrium were rendered entirely hostile to implantation, it would not matter if fertilization had already been prevented via anovulation, impeded sperm migration and/or function, or other means. That is, the endometrial changes may be part of the effect rather than the cause. Remember, correlation doesn't require causation.

Well, that's the state of LNG activity research as of late 2000. As it stands at this point, it seems that LNG acts primarily via prefertilization effects. However, there is insufficient evidence to rule out the possibility that it acts after fertilization in some cases. Especially troubling are changes to the endometrium that might affect receptivity. In the next installment, I'll cover the paper On the mechanisms of action of short-term levonorgestrel administration in emergency contraception (Durand, et al., 2001), which reports a study of the effects of LNG on the pituitary-ovarian axis, corpus luteum function, and endometrium.

Comments 4

  1. Rob wrote:

    Incredible. You’ve done an excellent job, better than I think I could have done.

    Thank you. I look forward to more.

    Posted 17 Sep 2006 at 11:47 pm
  2. Xavier wrote:

    What a knotty problem. Thanks for trying to look into.

    Posted 18 Sep 2006 at 3:39 am
  3. Funky Dung wrote:

    To those viewing this post on September 19:

    For the duration of the day, all of the posts on this blog will appear to have been written by a pirate. Everything will go back to normal at the end of the day.

    Posted 19 Sep 2006 at 12:06 am
  4. Lightwave wrote:

    An excellent detail oriented review of the available research. This should be a particularly useful resource for all those on the internet who would like to understand the meaning and appropriate application of these studies.

    Might I suggest meta tags, etc. that would help folks looking for the layman’s read on these studies to find this?

    Posted 06 Oct 2006 at 2:08 pm

Trackbacks & Pingbacks 4

  1. From just another day of Catholic pondering on 19 Sep 2006 at 9:53 am

    (something he knows as well as we do is not true); then it doesn’t matter if abortion is legal. He even quotes the USCCB! SFO Mom writes “Morning/Mourning,” reflections on a morning spent praying outside an abortion mill. Ales Rarus posts”Plan B: Literature Review (Part I).” In order to satisfy my own curiosity and my critics,I’ve reviewed recent scientific literature related to the question ofwhether or or not Plan B is abortifacient. This post is the first of several planned installments.

  2. From Lux Venit on 16 Sep 2006 at 4:43 am

    it, he takes a look past the Moslem controversy to discover the crux of The Pope’s message, to The West: The need for a philosophical revolution which reconciles faith with reason. Ales Rarus, in order to satisfy his own curiosity and his critics, has investigated the recent scientific literature regarding Plan B. Is it abortifacient? This is the first of a series of posts. First we go downstairs to warm up with a walk around the track and a quick stretch. We’ll discuss our goals and how to stay focused. Patricia at

  3. From Plan B: Literature Review (Part II) @ Ales Rarus on 23 Oct 2006 at 11:15 am

    […] The first post in this series can be found here. […]

  4. From Ross Douthat (September 07, 2007) - The Morning After (Culture Wars) on 07 Sep 2007 at 4:35 pm

    […] For the curious, here are a pair of studies that suggest that Plan B does not, in fact, have an abortifacient affect. And you can find a more in-depth look at the subject from a pro-life blogger here. […]

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