In: International Journal of Medical and Biological Frontiers ISSN: 1081-3829

Volume 17, Number 7 © 2011 Nova Science Publishers, Inc.

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POSTOVULATORY EFECTS OF LEVONORGESTREL

USED FOR EMERGENCY CONTRACEPTION.
IS IT ABORTIVE?

Carlos Y Valenzuela*
Programa de Genética Humana, ICBM, Facultad de Medicina, Universidad de Chile Human
Genetics Program, ICBM, Faculty of Medicine, University of Chile, Chile

Abstract
The hypothesis that Levonorgestrel used as emergency contraceptive (LNG EC) has
exclusively pre-ovulatory effects is tested. This hypothesis predicts that the effectiveness
decay of LNG EC used 1, 2, 3, 4, 5 or more days after coitus should agree with absolute
values and decay of the cumulative probability of pregnancy (CPP) after coituses
occurred in days of the fertile windows (FW) around ovulation. This method of testing
pre-ovulatory effects of contraceptives is independent of the type of contraceptive, the
mechanisms of action, the accuracy of fixation of the day of ovulation, the error of
effectiveness estimation and other variables. We choose the curve of CPP for coituses in
the FW, estimated from the symptothermal method and cervical mucus variations that
conferred the maximal advantage to the hypothesis. All the comparisons of expected-
observed values showed that LNG EC has a residual effectiveness not-explained by
preovulatory effects and indicated an evident postovulatory effect that occurs
preferentially in the oviducts delaying the zygote or embryo transit. If this effect is real,
LNG EC must increase the ectopic pregnancy (EP) rate when it fails as anticonceptive.
We demonstrated (in a previous publication) that LNG EC increased the EP rate by 2 to 3
times. LNG used as an intra-uterine device increased the EP rate by more than 30 times.
The increase in the EP rate, when it fails, should be indicated in the pharmacological
properties of the drug. LNG EC cannot be considered either abortive or non-abortive
because abortion is a religiously or ideologically laden conceptualization, and because,
even within these world-visions it could be both abortive and non-abortive depending on
the circumstances among which LNG EC is taken.

Introduction
There is sufficient evidence, in literature, indicating postovulatory actions of
Levonorgestrel for emergence contraception (LNG EC). The evidence comes from two
sources: 1) the increase of the ectopic pregnancy rate when LNG EC fails as
anticonceptive [1]; 2) the smaller decay in effectiveness (DE), when it is used 1, 2, 3, 4

*
Corresponding author: Programa de Genética Humana. Instituto de Ciencias Biomédicas (ICBM), Facultad
de Medicina, Universidad de Chile. Independencia 1027, Casilla 70061, Independencia, Santiago,
CHILE. FAX (56-2) 7373158; Phone (56-2) 9786302.Email: cvalenzu@med.uchile.cl
668 Carlos Y Valenzuela

and 5 days after coitus, than it is expected if LNG EC has only preovulatory effects [2].
Both independent sources of evidences indicate clear postovulatory effects and refute the
hypothesis that LNG EC has exclusive preovulatory effect. These evidences for
postovulatory effects have not been considered sufficient [3] due to the lack of reference
to mechanisms of action of LNG EC, the accuracy of the determination of the day of
ovulation, the errors of assigning the coitus at the fertile windows, the dynamics of sperm
migration and cervical mucus changes, the errors of estimation of the effectiveness of the
drug, and to errors of the curve used to estimate the fertile windows. However, the
analyses of DE when LNG EC is used 1, 2, 3, 4 and 5 days after coitus is not influenced
by the accuracy of the determination of the day of ovulation, provided that a great deal of
women, having coitus at any day of the menstrual cycle, are sampled. This happens
because the windows of the use of LNG EC 1, 2, 3 4 and 5 days after coitus covers the
fertility windows of the menstrual cycle, and the expected effectiveness is calculated
according to the DE due to the obligatory useless action of LNG EC when it was
administered during or after ovulation (under the hypothesis that LNG EC has exclusive
preovulatory effects). Moreover, the analyses on the relative DE of LNG EC used 1, 2, 3,
4 and 5 days after coitus (Table 2 of reference [2]) are independent of the ovulation day,
the mechanisms of action (included sperm migration and cervical mucus changes), errors
of assumptions on the day of coitus at the fertile windows, and bias of estimation of
effectiveness. This occurs because the mechanisms of action, the fixation of the day of
ovulation, and any error of estimation are equal for women that used LNG EC 1, 2, 3, 4
and 5 days after coitus. The objection on the calculation of the probability of conception
based on hCG in urine and not on clinical pregnancies is also irrelevant, provided that a
moderate correlation between hCG in urine and clinical pregnancy yields a similar curve
adjusted to unity (the shape of curves is similar, that is a bell-shaped curve with
maximum near ovulation). However, in this article a different curve for probability of
pregnancies will be used to show that this is not relevant. In the previous article [2], the
relative DE made those objections untenable and it undeniably indicated postovulatory
effects of LNG EC. This conclusion needs a more extensive analysis that is now
presented.

Re-analyses and Discussion

In the WHO 1 study [4] the DE from 0-24 hours post coitus (1 day post coitus or 1dpc,
DE = 95%) to 2dpc (85%) was 10% (see Table 2 from reference [2], and Table 2 of this
study that repeat these data but contrast them with another probability curve), while the
expected DE was 17.9%; this disagreement cannot be produced by the preovulatory
action of LNG EC alone. The 7.9% excess of effectiveness should be attributed to
postovulatory effects. The observed DE between 2dpc and 3dpc (2-3dpc DE) was 27%,
and the expected one was 18.9%; a disagreement that could be due to preovulatory
action. However, the fact that the observed 2-3dpc DE was 2.7 times the 1-2dpc DE is in
contradiction with the expected shape of DE under preovulatory action alone (the
expected relationship, under the exclusive preovulatory action of LNG EC, is the inverse,
 Postovulatory Effects of Levonorgestrel Used for Emergency Contraception 669

that is 1-2dpc DE should be 1.5 or more the 2-3dpc DE) . The logic explanation is that, in
groups 1dpc and 2dpc, the effectiveness due to postovulatory effects was extraordinarily
important (in this study). In the WHO 2 [5] the expected DE from 0-72 hours post coitus
to 73->96 hours was 28.2% (lower limit assumed to be 10%); while the observed DE for
2 doses (2D) was 19% and for 1D was 21%; both disagreements indicate postovulatory
effects (the expected DE of 2D should be larger than the 1D DE). This disagreement with
the expected situation indicates that the postovulatory action is more evident with two
doses. In data from Rodrigues et al. (Retal in Table 2) [6] the observed-expected DE were
14.4% - 28.2%, respectively; this is also an incompatible result with exclusive
preovulatory effects. The argument may be summarized, taking only the extremes of the
distribution, as follows: LNG EC used 5 days after the coitus conserves most of its
effectiveness (60-70%) that it has when it is used 1 or 2 days after coitus (80-95%),
independently of the days between the coitus and ovulation, the mechanisms of action of
LNG (included those on sperms and cervical mucus), the errors of estimation of its
effectiveness and any condition that is equal for women that used it 5 or 1-2 days after
coitus. Furthermore, it is possible to calculate the residual effectiveness (RE) which is not
due to the preovulatory effect of LNG EC. To calculate RE, we obtain first the expected
proportion of the DE between both extremes of the distribution: it is, from Table 2,
making (maximal) effectiveness (assuming only preovulatory effects) at 73-96 and >96
hours after coitus equal to 10% = (56.1-10)/56.1 = 82.2%; while the observed DE is
[(87.5-65.0)/ 87.5] = 25.7%. The complement to these proportions is the RE of LNG EC
used between 1 and 2, and over 4 days after coitus: expected RE = 17.8%; observed RE =
74.3%. The observed-expected difference in RE that is 56.5% should be attributed to
postovulatory effects of LNG EC. This result is also independent of the mentioned
restrictions [3]. Thus, there is 56.5% of LNG EC action unexplained by its assumed
exclusive preovulatory action (attention, this is true only if LNG CE is used until 4 or
more days after coitus).
Another probability curve of pregnancies per coitus during a menstrual cycle was
constructed to show that results are independent of the used curve [2, 3]. Analyses and
curves based on the symptothermal method (BBT, basal body temperature) or on the
viscosity of the cervical mucus (Mucus) were chosen [7] (particularly Table 9 of this
reference) to construct a new curve of probability of pregnancy. This is presented in
Table 1. The ovulation was assigned to the day where BBT or Mucus changed. This is
not exactly the ovulation day, because ovulation may occur one or two days before or
after these changes, and these periods vary among samples [7-10]. Even though there are
more precise approximations to the probability of conception after coitus [8-10], the
probability curve of Table 1 is used because it gives the maximal advantage to the
exclusive preovulatory effect of LNG EC. With the cumulative probability curve of Table
1, Table 2 of reference [2] was remade according to the same procedure to calculate the
expected effectiveness with the cumulative probability of pregnancies. It should be
remarked that the effectiveness was assigned to an average of hours of the day intervals,
as for example 12 hours for the interval 0-24 hours, and so on. This must be done because
in the day of ovulation the coitus may be 12 hours before or 12 hours after ovulation;
periods that have different probabilities of pregnancy. LNG EC does not stop ovulation of
670 Carlos Y Valenzuela

big follicles [11]. The final cumulative probability of Table 2 was calculated by the
weighed probabilities of BBT and Mucus of Table 1 using the number of studied cycles
[10]. The interval 5 and more days (>96 hours) is rather open for large values, but it
could have several values close to 96 hours, thus we estimated the expected effectiveness
by assuming 2/3 of the values for 5 days (>96) and 1/3 of the values for 4 days (73-96
hours); this increases the estimate of effectiveness under the hypothesis of exclusive
preovulatory effects of LNG EC.

Table 1. Probability distribution of pregnancies per coitus in the days of a fertile

month in relation to the assumed ovulation day according to the symptothermal
(BBT) and cervical mucus (Mucus) methods [10]

Day P Val BBT Mucus

P P Cum P Cum P Cum
Mens 1º -----
-14 to –6 0.020 0.020 0.039 0.039 0.047 0.047
-5 0.042 0.062 0.060 0.099 0.076 0.123
-4 0.089 0.151 0.155 0.253 0.176 0.299
-3 0.042 0.193 0.208 0.461 0.111 0.410
-2 0.189 0.382 0.224 0.685 0.197 0.607
-1 0.179 0.561 0.186 0.872 0.172 0.779
0 (ovul) 0.338 0.899 0.091 0.962 0.131 0.911
+1 0.073 0.972 0.007 0.969 0.065 0.976
+2 0.018 0.990 0.031 1.000 0.019 0.995
+3 to +13 0.010 1.000 0.000 1.000 0.005 1.000
Mens 2º - -
Nº cycles Ref [2] 3175 3265
P = Probability. P Val = Probability from the previous work [2]. Cum = cumulated. Mens = menstruation. Nº
= number.

We observe in Table 2 nothing qualitatively different from the previous analysis

presented in Table 2 of reference [2]. Always the observed effectiveness of LNG EC used
1, 2, 3, 4 and 5 days after coitus was over the expected effectiveness. We have 9
independent comparisons that give, under a statistical sign test, a probability of random
occurrence equal to P = (½)9 = 0.00195. This indicates that the residual observed effect of
LNG EC, as preventing pregnancies, over the maximal possible effect assuming that it
has only preovulatory effect, must be due to postovulatory actions. The analyses on the
decay of effectiveness (DE) also give the same results. While the expected DE by using
LNG EC between 1 to 5 days after coitus was (82.5%-16.7%) 65.8 %, the observed DE
was (as it was mentioned) near 20%. The action of LNG EC does not decay as expected,
assuming it has only preovulatory effects, because it must have postovulatory effects. If
LNG CE continues having 65% of effectiveness when giving it 5 days after coitus, it is
because it has postovulatory effects.
 Postovulatory Effects of Levonorgestrel Used for Emergency Contraception 671

Table 2. Maximal expected and observed effectiveness assuming that LNG EC

acts exclusively as a preovulatory drug

Observed
H-p-Coitus Expected
WHO 1 (2D) WHO-2(2D) WHO-2(1D) Retal
0 - 24 82.5% 95.0% Cumulated Cumulated
25 - 48 64.5% 85.0% 0 to 72 hours 0 to 71 hours
49 - 72 43.5% 58.0% 79% 84% 87.1%
73 - 96 27.6% ---- 73 - >96 horas 72-120 horas
> 96 16.7% ---- 60% 63% 72.7%
H-P-coitus = hours post-coitus when LNG EC was given; D = dose; WHO-1 = reference [4]; WHO-2 =
reference [5]; Retal = reference [7]

Testing Preovulatory Hypothesis with Ectopic Pregnancies

Now, we continue the hypothetic-deductive scientific procedure and take the recently
affirmed hypothesis that LNG EC has postovulatory effects, as a new hypothesis to be
tested by independent biotic processes. If LNG EC has postovulatory effects, it should
acts on oviducts or in uterus preventing pregnancies. LNG EC may alter the uterine
mucosa and biochemical markers of he pregnancy process [12-14], however, it is not sure
that these changes could alter the embryo uterine implantation. LNG EC seems not to
affect some expression of steroid receptors and proliferation of deciduas and chorionic
villi when it is given at the first trimester of pregnancy [15]. It is well known that
progesterone and progestagens protect the implanted embryo, and uterine implantation
occurs 6 to 7 days after fertilization. Thus, the hypothesis that the postovulatory
contraceptive effects of LNG EC are due to an action on the endometrium cannot be
tested with these data. Then, our attention was focused on the oviducts. If LNG EC acts
within the oviducts by delaying the transit of zygotes and embryos it is expected that it
increases the ectopic pregnancy (EP) rate, mostly of tubal pregnancies, when it fails as
anticonceptive. The failure of anti or contraceptive drugs is a natural experiment to test
its action on the transit of zygotes or embryos in the oviduct or uterus, because in this
situation there is a zygote or embryo in the oviduct and LNG EC is acting there. The
action of LNG EC used 5 days after coitus is almost completely restricted to the oviduct.
When LNG EC failed as anticonceptive drug, it increased the rate of EP 2 to 2.5 times
[1]. This effect was observed only with two doses (2D), but not with one. The analyses of
DE in WHO 2 indicated that 2D of LNG EC could produce more marked postovulatory
effects than 1D (see the first analysis and Table 2). If this is true the 2D group should
show more EP than the 1D group. The unique observed ectopic pregnancy belonged to
the 2D group (24 women, rate = 1/24 = 0.0417); no EP was found in the 20 women of the
1D group (rate = 0). The concordance of the evidence given by the DE analyses with this
from EP makes the hypothesis of exclusive preovulatory effect untenable and shows that,
in spite of their true restrictions and errors of estimation, DE has valuable clinical,
biological and epidemiological information. It is important to notice that this increase in
the EP rate when LNG EC fails as anticonceptive has been consistently found in literature
672 Carlos Y Valenzuela

[1]. If this is true, higher concentrations of LNG in uterus or oviduct should increase
more times the rate of EP. LNG as an intrauterine system increased more than 30 times
the rate of EP, after its contraceptive failure [1, 16]. The most probable explanation for
the mentioned increase of EP is that an important action of LNG is to delay the transit of
zygotes or embryos in the oviduct; this action explains also the large residual
effectiveness when LNG EC is used as late as 5 days after coitus. Laboratories that
produce LNG should indicate that when the drug fails as anticonceptive, it could increase
the rate of ectopic pregnancy.

Abortion and LNG EC

Is LNG EC abortive? This question cannot be solved scientifically as we solved its
postovulatory effects because abortion implies an ideologically or religiously laden
conceptualization. It depends on the belief of the time or stage at which humans begin to
be humans. For biologists, multicellular organisms originated from a zygote are
individuals of the species from the zygote stage; any other definition is incompatible with
most of main biological notions and theories (cell, inheritance and evolutionary theories)
[17]. However, this exclusive scientific approach is not accepted for most philosophers,
theologians, sociologists end cultural anthropologists. They say that humans are not only
matter-energy processes and the community relationships, spiritual reality and other non
necessarily matter-energy determined realities should be taken into account to define
humans properly. The word abortion is also a polysemic word. Etymologically abortion
comes from ancient Indo-European roots (a-bort) = (non-birth). This is very different to
the clinical definition ―interruption of pregnancy with fetus (or embryo) non-viable ex
uterus‖. The definition of pregnancy also differs. For some clinical purposes pregnancy
begins at the moment of implantation (uterine or ectopic); for other ideological positions
pregnancy begins at the moment when there is a zygote or embryo in the maternal
organism. It seems that nobody accepts pregnancy as the existence of a zygote or embryo
anywhere. However, for those who accept that humans begin at the zygote stage an
abortion is the interruption of life conditions (non-birth) at any moment or circumstance;
to eliminate a Petri-dish with a human zygote or embryo should be an abortion, because
for them abortion does not need pregnancy.
There are scientific and technical considerations that make improper the assignment
to LNG EC as an abortive or non-abortive drug (this occurs with any chemical, physical
or biotic agent). Let us put into the most extreme ideological frame that assigns mankind
to human zygotes and abortion as non-birth. Now, let us ask: what is the probability that
LNG EC, given at any moment of the menstrual cycle after an intercourse, stop the
development of the zygote or embryo (be abortive)? Most of the cycle is unfertile; the
probability of pregnancy for coitus at any day of the cycle is near 3% (using an
approximation with data of Table 1 and from references [2, 8]). In 97% of times LNG EC
will be useless. Among these 30 in one thousand possible pregnancies 20% will die for
genetic and environmental causes (mutation, chromosome anomalies, genetic diseases,
mal-implantation, hormonal insufficiencies, and so on; this is the rate of spontaneous
 Postovulatory Effects of Levonorgestrel Used for Emergency Contraception 673

abortion). Among the 24 remaining possible pregnancies, and if we accept data form both
WHO studies, LNG EC will be useful in 80% of the cases, that is 19 cases (5 cases will
be a healthy newborn around 9 months after), most (80%) of the anticonceptional action
of the drug will be preovulatory (15 cases) and only 4 cases could be an arrest of
development in the oviduct. Thus LNG EC will be abortive (in this ideological frame)
only in 4 per thousand of cases, it will be non-abortive in 15 per thousand of cases and
mostly useless in 981 per thousand of cases. In these circumstances, smoking, alcohol,
drug abuse, emotional stress and other noxious agents that occur during pregnancy could
be more abortive than LNG EC. In this context, for any agent we should rather say: it is
abortive in X%, non abortive in Y% and useless in (100-X-Y) %.
Moreover, the moral validity of a behavior depends in a great amount on the intention
of the person who realizes it. But, who can judge intentions?

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