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health consumers and health care professionals of an orthodox
or Islamic tradition, as well as those authentically concerned with the
respect of unqualified human rights, the asserted capacity of the pill
to act as
an abortifacient, both in its once-a-day and 'morning-after'
permutations, is one
of significant moral weight.
The research on 'break-through' ovulation1,2 leads moralists, philosophers and human rights' advocates to question the use of the title 'contraceptive' to describe the pill. There is tension in this nomenclature. The term 'contraceptive' refers to a drug, device or chemical that prevents the joining of the sperm with the female secondary oocyte (commonly referred to as the ovum).3
problem arises because the female sex cell,
the secondary oocyte, may be present in the reproductive tract at or
near the time
of coitus, hence there exists the possibility that fertilization may
as we will see, the pill alters the receptive structure of the
are concerned groups justified in moving from
a position which states that the pill sometimes fails to prevent 'ovum'
with the result that new human life may begin, to the position of
the pill has an abortifacient capacity? The first position notes that
occurs in women on the pill and fertilization may occur, but claims
there is no
evidence that implantation is impeded. The alternate view considers
ovulation has been detected and the lining of the womb is in an
human life is imperiled.
is a seismic shift in outlook. What merit
is there in this latter claim other than supposition or suspicion? Is
the pill tarnished
with the title of abortifacient on conjecture rather than on fact?
paper will seek to clarify these issues. I
will concentrate in some depth on a variety of the implantation factors
with the microenvironment of the endometrial epithelium. Discussion
will also be
focused on the mechanism(s) of hormonal dialogue between the 5-7 day
old human embryo
(the blastocyst) and the cells which line the endometrium. I will also
impact of above normal (supraphysiological) levels of estrogen and
on these implantation factors and the role of the pill hormones on the
of the endometrium. Particular attention will be given to the impact of
on cyclical development of endometrial thickness, and the relationship
of this uterine
feature to the success of implantation of the human embryo. Central to
will be a review of the research on 'break-through' ovulation (also
known as 'escape-ovulation'),
an event which must occur, otherwise all concerns concerning the pill
as an abuser
of human rights would be shown to be empty.
paper is of necessity detailed. I hope that
the employment of suitable analogies, as well as bracketed discussion
terms or concepts, will make it accessible to the scholar and lay
1.1 EXECUTIVE SUMMARY
The process of implantation of the human embryo into the lining of the womb is a very complex and delicate one.4 Proper attachment and successful implantation is under the guidance and control of a vast array of 'implantation factors' such as interleukin-1 β (IL-1β)5 platelet-activating factor (PAF),6,7 insulin-like growth factor (IGF),8 leukemia inhibition factor (LIF),9 tumor necrosis factor α (TNF α ).10
of these chemical factors participate in a
process referred to in the medical journals as 'cell-signalling', a
involves the new human embryo and the cells of the lining of the womb
communicating with each other.11, 12,13,14
The purpose of this chemical communication is to create an optimally
endometrial environment at the time the human embryo attempts to
from this bio-chemical embryo/uterine-cell
communication, successful implantation of the human embryo is dependent
a class of molecules known as integrins. Integrins are cell-adhesion
in a 'mirror' fashion on both the human embryo and the lining of the
These integrins bind onto each other, via gluco-proteins (e.g.
success or otherwise of this binding process is intimately linked to
success or otherwise of the pregnancy.
reader will note that I am using the orthodox
understanding of the term 'pregnancy'. This definition dates the
beginning of the
pregnancy from the moment of fertilization. I do not use, nor do I
accept the minority
view, influenced as it is by the politics of abortion, that dates a
the time of implantation.
1.2 THE RE-DEFINING OF PREGNANCY
the embryonic, linguistic and time-honoured
orthodoxy of 'pregnancy', increasingly frequent attempts have been made
all aspects of pregnancy, but most particularly, when pregnancy begins.
for this move is clear; by redefining pregnancy -- when it begins, the
the embryo etc -- the way will be made smooth for the more rapid
RU-486, the morning-after pill, anti-HCG vaccines, anti-implantation
and other embryocidal drugs. Unwittingly or otherwise, the end result
is a seman-tically
based desensitization of the moral conscience of the community.
following is an indicative selection of quotes
to illustrate my point.
The prevention of pregnancy before implantation is contraception and not abortion.17 (Glasier, NEJM, 1997)These opinions are starkly at odds with embryology20 and etymology.21
Predictably, some opponents of abortion allege that emergency contraception is tantamount to abortion . . . even if emergency contraception worked solely by prevention the implantation of a zygote, it would still not be abortifacient... Pregnancy begins with implantation, not fertilization ... fertilization is a necessary but insufficient step toward pregnancy.18 (Grimes, NEJM, 1997)
Emergency contraception works by inhibiting or delaying ovulation or by preventing implantation. Despite some assertions to the contrary, it is not itself a form of abortion.19 (Guillebaud, Lancet 1998)
examining these features in more detail,
and the relational involvement of the pill, it may be of some benefit
an analogy to assist in the understanding of the various implantation
the role of integrins.
the example of a space shuttle, low on
fuel and oxygen, urgently needing to dock with the space station. The
and the shuttle communicate with each other so that the shuttle knows
bay to go to. Importantly, the mother ship knows which bay to make
communication is imperative. If this electronic communication fails
'cell-talk') the shuttle may go to the wrong docking bay, fail to
attach to the
mother ship, drift away, with the result that the crew dies from a lack
and oxygen. Alternatively, the shuttle might go to the right bay but
find that all
the docking apparatus is not in place. Again, the attachment between
the two fails
due to faulty communication and the crew dies. This role of
is fulfilled by implantation factors such as interleukin, TNF, NDF and
PAF. To continue
the analogy, integrins could be thought of as grappling hooks that
'hold' the human
embryo onto the womb whilst the process of implantation is completed.
then is a brief overview of this review paper.
I would like now to analyse these issues in more depth, looking at the
role and activity of the main implantation factors covered in the
As well, I will expand on the interaction between these factors and the
hormones: estrogen, and its artificial copies (principally
via the pill) and progesterone, plus its artificial copies
gestodene and desogestrel).
1.3 THE INTERLEUKIN SYSTEM
The interleukin (IL) system, composed of IL-lα , IL-1β and IL-Ira, is both hormonally regulated and of endometrial origin (Simon, 1996).22 Under normal physiological conditions, progesterone increases the production of IL-lα , and IL-lβ from the endometrium23 and levels of the IL system reach their maximum during the luteal (post-ovulatory) phase of the menstrual cycle.24
the various components of the interleukin system,
research suggests that IL-lβ plays a key role in the proper orientation of the
embryo to the uterine
lining, a process known as apposition. Recalling our earlier analogy,
could be likened to pre-docking maneuvers responsible for correctly
docking ports of mother ship and shuttle.
Within this framework, the role of IL-lβ is thought to be that of a 'signal system' between endometrium and embryo.25'... [S]uccess of embryonic implantation relies on a perfect dialogue between good quality embryos and a receptive endometrium'.26
Huang and co-workers (1997) have also reported that the IL system is 'an important factor in embryo-maternal molecular communication during the implantation process'.27
Whilst normal levels of the ovarian hormones estrogen and progesterone have a beneficial effect on the levels of IL-1β , excessive hormonal levels, known as supra-physiological steroid levels, have been shown to cause a reduction in the levels of IL-lβ . As a result, the rate of implantation drops significantly. Simon and co-workers (J Reprod Immun, 1996) have shown that there is an inverse relationship between estrogen and progesterone levels, and the levels of IL-lβ (as estradiol levels increase, implantation success decreases).28
direct consequence of these findings, as they
relate to the maintenance of pregnancy, are set out by Carlos Simon:
... we have shown prospectively that suprahysiological serum E2 (estradiol) levels during the pre-implantation period are responsible for the impairment of embryonic implantation in patients undergoing I.V.F. It is possible that above normal (supraphysiological) serum E2 levels impair implantation through disrupting regulation of uterine paracrine factors; specifically, the IL-1 system is one possible candidate when considering what is reported in the present study.29
The term 'paracrine' refers to the effect(s) that
are caused by hormones but are localized to cells only in the immediate
i.e., the endometrium, rather than the more normal, wider area of
that characterizes hormones.31
Simon's research indicated that excessive estradiol (an estrogen) levels interfere with implantation as a consequence of disruption to the IL-1 system. I.V.F. research has shown that high levels of estradiol (E2) result in a poor implantation rate of 8.5% whereas reduced E2 levels increased the successful rate of implantation to 29.3%.32
As Simon and co-workers noted, 'High E2 levels, which are known to be interceptive, and altered E2/progesterone ratios, which also are associated with the impairment of endometrial receptivity, are the main factors affecting endometrial receptivity in high responders.'33
The use of the word 'interceptive' is significant. Professor Rahwan, professor of Pharmacology and Toxicology, Ohio State University, defines interception as the 'interference with the implantation (nidation) of an already fertilized ovum, and, from a biological standpoint, must therefore be an early abortifacient approach'.34
research by Simon finds its importance within
the context of the emerging use of the pill in high doses as a
post-coital or 'morning-after'
pill (MAP). The MAP regime comprises the ingestion, within a time-frame
of 12 hours,
of approximately 10 times more estrogen and 10-20 times more
progesterone than a
woman would take via the normal once-a-day pill (depending on the brand
increased levels are obviously supra (above) physiological levels.
previously outlined by Simon, the disruptive
effect on implantation rates caused by high levels of estradiol, or
ratios, means it is biologically plausible to suggest the
'morning-after pill' (MAP)
is an abortifacient-empowered medication because of its capacity to
the interleukin system.
supporting this assertion is research by
Swahn et al. (1996), which showed the
administration of the MAP caused a
suppression of the LH surge, decreased the pregnandiol levels and
estrone levels (Fig 1, p. 741).35 These
alterations to the normal menstrual cycle hormonal patterns had an
impact on the
development of the endometrium.
An endometrial biopsy was taken one week after treatment. Although it was difficult to date the biopsy in some women because of the absence of a discernible LH peak, the conclusion was that the endometrium showed significant alterations in endometrial development with a dissociation in maturation of glandular and stromal components 36.
The authors then, in a seemingly contradictory
manner, suggest that the 'relatively minor changes in endometrial
not seem sufficiently effective to prevent pregnancy'.37
This statement would appear to undermine any claim that the MAP acts in
an abortifacient mechanism. Further reading reveals that the
researchers did not
investigate the 'biochemical effects (of the pill) on molecular levels
on the endometrium'.38
That is, the researchers did not investigate the hormonal impact of the
MAP on the
various implantation factors.
my view, this omission negates their attempts
to minimize the abortifacient significance of the 'relatively minor
changes in endometrial
development' caused by the MAP. As will be seen later, relying only on
of endometrial thickness cannot accurately assess the precise
for successful implantation -- this exclusive approach fails to take
heed of the
implantation factors which are the second, vital characteristic
1.4 PLATELET-ACTIVATING FACTOR
Another implantation factor which is associated with successful uterine receptivity of the human embryo is platelet-activating factor (PAF).39 PAF interacts with PAF receptors located on the endometrium. To recall, receptors are bio-chemical binding sites, located on the surface of cells, which are specifically designed to interact exclusively with a specific chemical, in this case PAF. When PAF attaches to the receptor, a message is conveyed to those cells.40
The effect of PAF upon the endometrium is to cause a release of nitrous oxide (NO), leading to vascular dilation and increased vascular permeability of the blood vessels of the endometrium41 The fact that chemical blockage of the PAF binding site (receptor) on the endometrium inhibits implantation supports the view that the PAF receptor has a critical role in uterine receptivity42
is also involved in the cyclical development
of the endometrium.43,44
Not surprisingly, the levels of the receptors for PAF vary throughout
cycle, with the highest endometrial levels detected during the mid-late
phase (i.e., the days preceding ovulation) and the late secretary phase,45
when the endometrium is approaching or at
its state of maximum monthly development. These findings are consistent
having a preparatory role for uterine reception of the human embryo.
As was the case with the interleukin system, control of PAF is under the control of ovarian hormones, estradiol and progesterone.46 As Ahmed has noted: 'PAF production has been shown to be regulated by ovarian hormones...'47
Given the role of ovarian hormones on the activity of PAF and its receptor within the endometrium, it is biologically plausible to suggest that irregular uterine hormone levels, caused by the pill, may have a negative impact on uterine preparedness for implantation. Supporting this view is the work of Rabe and co-workers, who reported a decrease in endometrial thickness in women taking the pill, during the days when implantation would occur.48
these researchers showed that there
was, for some pill users, a 50% reduction in endometrial development
to that seen in the control (non-pill using) group.49
Therefore, it is reasonable to conclude there is an adverse impact upon
of PAF receptors. Indeed, given the hormonal influence exerted by
estrogen, it would
be biologically illogical to conclude no damage to the expression of
1.5 THE EFFECT OF MISSED FILLS
the pill to exhibit the characteristic of an
abortifacient, one biological event is essential: ovulation. The crucial
question is this -- does break-through (or escape) ovulation occur during regular pill ingestion?
Grimes et al. (Obstet Gynecol, 1994) had previously reported that 'suppression of follicular development is incomplete with contemporary low-dose pill'.50
study was characterized by a high rate
of patient compliance, meaning that the women involved in the study
adhered to the
research protocol of daily ingestion of the pill.51
Yet, escape-ovulation was detected even within the context of a
facts argue strongly in favour of escape-ovulation
also occurring within the general populace of women on the pill. This
of women are not necessarily as highly motivated as those participating
in a scientific
study. To adhere to a tedious daily, monthly, yearly regime of pill
supervision is, in the words of one feminist writer a 'bore and a
Because daily pill ingestion is so onerous, patient compliance will be
the necessary ideal. However, does the occasional failure to take the
that 'escape ovulation' will increase in some proportional fashion?
an attempt to determine the frequency of escape-ovulation
under more realistic conditions, researchers have constructed
experiments that required
women in the study to deliberately miss one or more days of the pill. A
of tests, including ultrasound of the ovaries, estradiol (E2),
levels and LH (leutinizing hormone) measurements were used to determine
and co-workers (1992) tested 47 young, healthy
women who missed between 1 and 4 days tablets starting from day 1 of a
'None of the patients experienced normal ovulation' though one, who
missed 3 tablets
at the beginning of the cycle, 'had a follicular rupture', but no LH
surge or progesterone
increases, factors usually associated with normal ovulation53
Note that this study was for only one cycle. Limiting the
study to one cycle was a study weakness, because any follicles which
may have ruptured
during the normal 7 pill free days between cycles would not be detected.
Earlier, Hamilton (1989) had performed a similar study but extended the observations for two consecutive months. Of 30 women in the study, one had a probable ovulation, due to one deliberately omitted tablet on day one of the second cycle.54
More recently, Letterie (1998) published the results of a study employing a new, reduced dosage formulation of the pill. Ten women, divided into 2 groups, used two slightly different formulations comprising a delayed start, limited midcycle use of estrogen and progesterone. Each of the two treatment groups was monitored for 2 consecutive cycles. In total, 30% of cycles exhibited ovulation, all of which occurred in the second cycle.55
It is revealing to look more closely at the data for the two groups. In group one, ovulation occurred in 10% of cycles (1 in 10 cycles). This group took 50mcg ethinyl estradiol/lmg norethinodrone for days 6-10 and 0.7mg norethinodrone for days 11-19. Group two took 50mcg ethinyl estradiol/lmg norethinodrone for days 8-12, and 0.7mg norethinodrone only for days 13-21, 'five ovulation(s) occurred in 10 cycles'.56 This is an ovulation rate of 50%. This study did not investigate implantation; all participants used barrier contraceptives, or abstinence (Private correspondence).57
should be noted that these research findings,
conducted under ideal research conditions, represent the best possible
terms of ovulation suppression by the pill. Yet these results do not
replicate real-life because they do not take into account such common
gastro-intestinal illness or drug interactions. Stomach upset decreases
thus loosening the hold over ovulation otherwise exerted by the pill
drug interactions decrease the amount of active pill hormone available
to act in
a suppressant manner upon the ovaries.58,59 Other researchers and I
are of the view that
these two issues would contribute to an increase in the frequency of
1.6 PILL CONTROL OVER OVARIAN
upon my 20 years experience as a community
pharmacist, I believe the commonly held view is that the pill fully
(anovulation). Yet this view is wrong. The recent work by Rabe et
contradicts this common misunderstanding. Following are some salient
For non-pill users, the rate of follicular cysts was 13.9%.
Some women, notably those on triphasic formulations, had follicles measuring 60mm.
Estradiol was present at higher levels (in pill users with enlarged follicles) than in non-pill users (who also had enlarged follicles). The respective levels were 153 pg/ml and 126 pg/ml.63
The estradiol level of 153 pg/ml, seen in pill users with enlarged follicles, is important, as it is close to the 'threshold level 150 to 200pg/ml', which, if persisting for approximately 36 hours, triggers ovulation.64
As a summary of their research, Rabe noted: 'Analysis of the ovarian activity in the current study demonstrated that the total number of developing follicles increased rather than diminished during OC use, without marked differences between OCs'.65
research underscores the pill's precarious
hold over ovulation suppression. It is an event endeavouring to occur.
of a variety of 'lifestyle' factors such as missed doses, drug
interactions or gastro-intestinal
upset, can act to loose the hold exerted by the pill over natural
a footnote to this discussion, the FDA approved,
in late 1998, a low dose estrogen formulation of the pill
1 mg; ethinyl estradiol 20 µg). Similar low-dose estrogen formulations
also now available in Australia.66 The
frequency of escape ovulation can only be expected to increase in this
of reduction hormonal ingestion.
1.7 ENDOMETRIAL THICKNESS AND
the question arises: will a low dose pill,
more inclined than not to permit escape-ovulation, increase the
frequency of implantation
failure due to a under-developed endometrium? The medical literature
there is a critical thickness of the endometrium needed to sustain
of a human embryo.
Issacs (Fert Steril, 1996) reported that an endometrial thickness of at least 10mm or more, around the time of ovulation, 'defined 91% of conception cycles'.67 Spandorfer (Fertil Steril, 1996) noted that 97% of abnormal pregnancies, defined as Fallopian tube lodgment or spontaneous abortion, had endometrial thickness of 8mm or less. 68 Shoham (Fert Steril, 1991) reported that a mid-luteal thickness of 11 mm or more 'was found to be a good prognostic factor for detecting early pregnancy' but no pregnancies were reported in an ovulation induction programme 'when the endometrial thickness was less than or equal to 7 mm'.69
The mid-luteal phase of the menstrual cycle, around day 20, is referred to in the medical literature as the window of expected implantation.70,71
(Journ In Vitro Fert Embryo Transf,
1990) also reported that 'endometrial thickness was significantly
greater in the
group of patients who achieved pregnancy than in the group who did not'.72
Implantation failure was associated with endometrial thickness of
7.5mm, success with endometrial thickness of approximately 8.5-9mm.
study results, which indicate a normative
endometrial thickness of around 8.5mm for successful implantation, are
any claimed interceptive/abortifacient capacity of the pill. Research
Rabe and co-workers (1997) underscore this point.
Rabe reported that study subjects who took the triphasic levonorgestrel/ethinylestradiol formulation had the highest percentage of follicular cysts with a diameter greater than 20mm73 but they failed to develop a median endometrial thickness in excess of 6mm.74 To recall, follicles of this size are 'thought to be associated with increased risk of escape ovulation'.75
The importance of these events is clear; follicles of a suitable size can develop in women taking the pill daily, but endometrial thickness has been shown to be underdeveloped. In the event of follicle rupture and release of an 'ovum', implantation of a human embryo would be greatly hampered. Rabe confirms this very point: '. . . the occurrence of pregnancy would be unlikely because accessory contraceptive mechanisms such as cervical hostility and endometrial suppression are usually in effect'.76
must be pointed out that in this quote Rabe
has falsely defined pregnancy as beginning at implantation. Pregnancy
the fertilization of the female sex cell (ovum) by sperm, the
restoration of the
full complement of 23 pairs of chromosomes and thereby the creation of
a new human
upon these findings, a number of issues present
An endometrial thickness around 8.5mm has been shown to be associated with successful implantation.
Low dose triphasic formulations of the pill, the most popular in Australia, fail to completely stop follicular development, the precursor stage to the release of a female sex cell.
Break-through ovulation is an event straining to occur, even with daily pill ingestion.
If break-through ovulation were to occur, implantation might fail, because of an endometrium that is too thin.
It is important to note that these four
exist independently of the impact of the pill on the various
involved in cell-signaling.
the aforementioned research indicates, the last
few years have seen a remarkable unveiling of the process of
implantation of the
human embryo into the uterine tissue. A large body of evidence now
demonstrates that the process of implantation, rather than being an
dependent on chance, is in fact a multi-factorial, cascading
physiological and hormonal event of spectacular intricacy, complexity,
not, as one might suppose, akin to two pieces of Velcro fortuitously
gripping together. Rather, implantation is, in every sense, as complex,
susceptible to interference, as is the clotting mechanisms of the
PAF, the interleukin system and other factors
mentioned briefly in the introduction, the class of cell adhesion
as integrins also play a critical role in successful implantation of
the human embryo
into the endometrium.
As the description of the molecule suggests, the role of integrins is to bind cells together. Etzioni has suggested that integrin facilitated cell adhesion is 'a process that is essential for anchorage' of cells to each other (Lancet, 1999).79
are a variety of different types of integrins
found within the body -- one that plays an essential role in
implantation is known
as αvβ3. The
now contains many research papers demonstrating the vital role of this
in the process of binding the 5-7 day old human embryo to the
of the womb).
Somkuti and co-workers (Fert Steril, 1996) for example reported that integrins 'might prove useful as markers of normal endometrial receptivity'80 because they have been shown to be absent in women with unexplained infertility and endometriosis.81
Lessey (Am J Reprod Immunol,
1996) reported 'aberrant expression of this integrin is associated with
Hum Reprod, 1997) noted 'the absence of endometrial αvβ3
during the critical period of implantation ... in women with
Others had also commented on the absence or diminution of αvβ3 in
women with recurrent pregnancy loss84
or unexplained infertility.85
Assessing the role of the pill, Somkuti (1996) compared endometrial sampling from women on the pill with samples from non-users and reported integrin expression 'to be altered grossly in OC users'.86
Complementing this work were the observations of Yoshimura (1997):'... a loss of normal αvβ3 expression is associated with primary infertility and milder forms of the disease. These observations suggest that this integrin plays a significant role in the implantation process'.87
Widra and colleagues (1997), at Georgetown
University investigated the role of physiological levels of estrogen
on the endometrial levels of αvβ3.
They reported that estrogen caused a down-regulation in the expression
an important finding in the light of the fact that 'expression of the αvβ3
integrin may, in fact, be necessary
for normal implantation to occur'.89
Castelbaum and co-workers (J Clin Endo Metab, 1997) reported the endometrial expression (presence) of αvβ3 was 'reduced by E2 treatment and further suppressed by E2 plus P...'90
These results indicate a link between the impact of hormones on the expression of integrins, and the role of integrins in implantation. Whilst the inter-relationship between hormones, integrins and implantation is not yet fully understood,91 sufficient evidence exists to conclude that the inter-relationship is significant from the perspective of implantation. This is because implantation occurs only 'on or about day 20 of an idealized 28-day menstrual cycle' 92 and the αvβ3 integrin 'is expressed on endometrial epithelial cells only at the opening of the implantation window, on postovulatory day 6'.93
1.9 INSULIN-LIKE GROWTH FACTOR
IGF system is an important growth factor, playing
a key role in the monthly development of the endometrium and in the
process of implantation.94
There are two subsets, IGF-1 and IGF-11. The first is believed to
mitotic action of estradiol [E2] in the endometrium, whilst IGF-11
in mid-late secretory endometrium, may be a mediator of progesterone
Aside from this hormonal aspect, the most abundant expression of IGF-11
is in the
columns of the invading trophoblast in the anchoring villi.
From this it can be seen that IGF has a promotional effect upon the process of implantation. But IGF is in turn regulated. 'The biological actions of IGFs are modulated by a family of binding proteins (IGFBPs). The demonstration of IGF and IGFBP transcripts [copying facilities] in pre-implantation embryos indicates that the influence of IGFs and IGFBPs in fetal development begins even prior to implantation'.96
Thus far, it can be seen that these factors have a key role to play in both the preparation for and process of implantation. As Han et al. have noted: 'Presumably, IGF-11 and IGFBPs are used for cell to cell communications between fetal trophoblasts and maternal decidual cells at the feto-maternal interface for placental development and/or function'.97
Against this background, the role of the hormones in the pill, particularly their influence over implantation, is important. A number of researchers have shown that the pill causes an increase in IGFBP-1 levels and a decrease in plasma concentrations of IGF-1.98,99 More specifically, during the pill free-week 'IGFBP-1 was significantly lower on the medication-free day than on day 14 of the cycle ... The short absence of exogenous estrogen and progestin during the medication-free week also affected IGF-1 levels, which were significantly increased'.100
The superabundance of IGFBP induced by the pill has, from an implantation perspective, significance. Giudice has reported that: 'IGFBP's bind IGF's with high affinity and, for the most part, inhibit IGF bioavailability to their receptors for action in their target organs'.101 Thus, the supraphysiological levels of IGFBP, induced by the pill, may be detrimental to the process of implantation via an inhibitor action on the levels of IGF. Giudice highlights this point: 'IGFBP-1 has been shown to inhibit trophoblast invasion into decidualised endometrial stromal cultures, suggesting that this IGFBP-1 is a maternal "restraint" on trophoblast invasion'.102
Aside from the indirect anti-implantation effect of excessive levels of IGFBP upon IGF, IGFBP also has a direct, anti-attachment effect upon the human embryo. 'IGFBP-1 specifically binds to first trimester trophoblast and that it binds to the 'α5β1 integrin in trophoblast. Furthermore, it inhibits trophoblast attachment to fibronectin; another RGB ligand found in the placental bed.'103
In summary, the pill causes an increase in IGFBP levels, leading to a decrease in IGF levels. This may have a negative impact upon implantation. IGFBP also may have a direct effect at the level of trophoblast/endometrial integrin binding. More research is required to understand fully the roles of IGF and IGFBP. This represents a new, emerging field of research into the multitudinous factors involved in the process of implantation. Whilst the above research indicates that the pill facilitates anti-implantation endometrial environment, confirming evidence is yet to be found. Hence there exists a reasonable suspicion only, a point made by key researchers in the field.104
discussion has had as its focus the multifactorial
nature of embryo implantation. On occasion, this discussion has
analysis of the relevant factors influencing the success of this event.
it is not possible to speak of these events, centred as they are on the
of human life, without a certain measure of complexity and detail. To
who have struggled with this material I apologize.
paper does not presume to be the final word
on this complex and evolving branch of medical knowledge. New research
monthly to illuminate further and sometimes confuse this emerging
Nevertheless, I hope I have briefed the reader on issues related to the
of all humans -- the right to stay alive. Some may seek to discount the
abortifacient capacity of the pill. For three reasons, this would be a
precarious position to adopt.
First, I am of the view that the preceding evidence strongly argues the case in favour of the pill possessing an interceptive/abortifacient capacity. At the very least, the evidence is repetitive and circumstantial. Indeed, how more clear and straightforward could the issue be than the following statement from Eric Widra and colleagues? 'Demonstration of complimentary integrin expression on preimplantation embryos has further buttressed the argument that these molecules are important for the initiation of pregnancy'.105
even researchers view as the new arena
of 'contraceptive' research the interrelated system of implantation
Simon and colleagues (Fertil Sterility, 1998),
after discussing the interdependent
relationship between the interleukin-1 system, the αvβ3 integrin
and implantation, conclude by stating that the interleukin-1 system
would be a promising
new area of research apropos the development of new 'contraceptives'.106
Given this sentiment, I am of the view that anti-interleukin chemicals
will be the
RU-486 of the next decade.
Third, and most tellingly, the abortifacient capacity of the pill is recognized by those who support abortion. Consider the following, taking from the Guttmacher Report. 'The best scientific evidence suggests that ECP's [emergency contraceptive pill] most often work by suppressing ovulation. But depending on the timing of intercourse in relation to a woman's hormonal cycle, they -- as is the case with all hormonal contraceptive methods -- also may prevent pregnancy either by preventing fertilization or by preventing implantation of a fertilized egg in the uterus' (my emphasis).107
more be said?
B.Pharm MPS MACPP, is a pharmacist in Baulkham Hills, Australia.
M.P.S., is the Director of the Drug Information Service of Western
Sydney. He lectures
to graduate pharmacists at the University of Sydney. He is a Director
of API (Australian
Pharmaceutical Industries) Health Care/Pharmacist Advice group. He is
editor and member of the MicroMedex International Editorial Board. He
the pharmaceutical press. He has worked as a community pharmacist for
15 years. During this time he has developped a strong interest in
and in the correct administration of drugs. He published "A
Consumer Guide to the Pill and Other Drugs" (2nd
edition, 1997, ALL, USA, ISBN 1-890712-25-6).
1. Van der Vange
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This article has been originally published in Ethics & Medicine, 2000, vol. 16, n°1, pp. 15-22, 0226-688X. Ethics and Medicine is published in USA, in UK and The Netherlands by The Center for Bioethics and Human Dignity, Illinois, USA; The Centre for Bioethics and Public Policy, London, UK; The Prof. GA Lindeboom Instit, Ede, Netherlands. This publication is made at the initiative of TDD with the authorisation of the author. T.D.D., BP167, 92805 PUTEAUX CEDEX, France