ETHICS & MEDICINE 2000 16.1
The Impact of the Pill
The Impact of the Pill on Implantation Factors -- New Research Findings
For health consumers and health care professionals of an orthodox Judeo-Christian or Islamic tradition, as well as those authentically concerned with the universal 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
The 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 occur. Yet, as we will see, the pill alters the receptive structure of the endometrium, making implantation problematical.
But are concerned groups justified in moving from a position which states that the pill sometimes fails to prevent 'ovum' fertilization, with the result that new human life may begin, to the position of claiming that the pill has an abortifacient capacity? The first position notes that ovulation occurs in women on the pill and fertilization may occur, but claims there is no evidence that implantation is impeded. The alternate view considers that because ovulation has been detected and the lining of the womb is in an undeveloped state, human life is imperiled.
This 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?
This paper will seek to clarify these issues. I will concentrate in some depth on a variety of the implantation factors associated with the micro environment 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 cover the impact of above normal (supraphysiological) levels of estrogen and progesterone on these implantation factors and the role of the pill hormones on the integrity of the endometrium. Particular attention will be given to the impact of the pill on cyclical development of endometrial thickness, and the relation-ship of this uterine feature to the success of implantation of the human embryo. Central to these issues will be a review of the research on 'break-through' ovulation (also known as 'escape-ovulation'), an event which must occur, other-wise all concerns concerning the pill as an abuser of human rights would be shown to be empty.
This paper is of necessity detailed. I hope that the employment of suitable analogies, as well as bracketed discussion of medical terms or concepts, will make it accessible to the scholar and lay reader alike.
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 b (IL-1b)5 platelet-activating factor (PAF),6 7 insulin-like growth factor (IGF),8 leukemia inhibition factor (LIF),9 tumor necrosis factor a (TNF a).10
Many of these chemical factors participate in a process referred to in the medical journals as 'cell-signalling', a process which involves the new human embryo and the cells of the lining of the womb chemically communicating with each other.11 12 13 14 The purpose of this chemical communication is to create an optimally advantageous endometrial environment at the time the human embryo attempts to implant.
Aside from this bio-chemical embryo/uterine-cell communication, successful implantation of the human embryo is dependent also upon a class of molecules known as integrins. Integrins are cell-adhesion molecules found in a 'mirror' fashion on both the human embryo and the lining of the womb.15 16 These integrins bind onto each other, via gluco-proteins (e.g. fibronectin). The success or otherwise of this binding process is intimately linked to the ongoing success or otherwise of the pregnancy.
The reader will note that I am using the orthodox under-standing 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 pregnancy from the time of implantation.
1.2 The Re-Defining of Pregnancy Terminology
Notwithstanding the embryonic, linguistic and time-honoured orthodoxy of 'pregnancy', increasingly frequent attempts have been made to redefine all aspects of pregnancy, but most particularly, when pregnancy begins. The reason for this move is clear; by redefining pregnancy--when it begins, the nature of the embryo etc--the way will be made smooth for the more rapid introduction of RU-486, the morning-after pill, anti-HCG vaccines, anti-implantation factor drugs and other embryocidal drugs. Unwittingly or otherwise, the end result is a semantically based desensitization of the moral conscience of the community.
The 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)
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)
These opinions are starkly at odds with embryology20 and etymology.21
Before examining these features in more detail, and the relational involvement of the pill, it may be of some benefit to propose an analogy to assist in the understanding of the various implantation factors and the role of integrins.
Consider the example of a space shuttle, low on fuel and oxygen, urgently needing to dock with the space station. The mother ship and the shuttle communicate with each other so that the shuttle knows which docking bay to go to. Importantly, the mother ship knows which bay to make ready. Successful communication is imperative. If this electronic communication fails (disrupted embryo-uterine '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 of food 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 embryo/endometrium communication 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.
This then is a brief overview of this review paper. I would like now to analyse these issues in more depth, looking at the specific role and activity of the main implantation factors covered in the research literature. As well, I will expand on the interaction between these factors and the steroidal hormones: estrogen, and its artificial copies (principally ethinylestradiol, ingested via the pill) and pro-gesterone, plus its artificial copies (norethisterone, levonorgestrel, gestodene and desogestrel).
1.3 The Interleukin System
The interleukin (IL) system, composed of IL-la, IL-1b and IL- IL-Ira, is both hormonally regulated and of endometrial origin (Simon, 1996).22 Under normal physiological conditions, progesterone increases the production of IL-la, and IL-lb from the endometrium23 and levels of the IL system reach their maximum during the luteal (post-ovulatory) phase of the menstrual cycle.24
Of the various components of the interleukin system, research suggests that IL-lb plays a key role in the proper orientation of the embryo to the uterine lining, a process known as apposition. Recalling our earlier analogy, apposition could be likened to pre-docking maneuvers responsible for correctly aligning the docking ports of mother ship and shuttle.
Within this framework, the role of IL-lb 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-1b, excessive hormonal levels, known as supra-physiological steroid levels, have been shown to cause a reduction in the levels of IL-lb. 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-lb (as estradiol levels increase, implantation success decreases).28
The 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 vicinity,30 i.e., the endometrium, rather than the more normal, wider area of bodily influence 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
This 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 used). These increased levels are obviously supra (above) physio-logical levels.
As previously outlined by Simon, the disruptive effect on implantation rates caused by high levels of estradiol, or incorrect estradiol/progesterone ratios, means it is biologically plausible to suggest the 'morning-after pill' (MAP) is an abortifacient-empowered medication because of its capacity to interfere with the interleukin system.
Further 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 increased the 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 components36 .
The authors then, in a seemingly contradictory manner, suggest that the 'relatively minor changes in endometrial development does not seem sufficiently effective to prevent pregnancy'.37 This statement would appear to undermine any claim that the MAP acts in part via 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.
In 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 measures of endometrial thickness cannot accurately assess the precise conditions needed for successful implantation this exclusive approach fails to take heed of the implantation factors which are the second, vital characteristic associated with successful implantation.
1.4 PLATELET-ACTIVATING FACTOR (PAF)
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 endometrium.41 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 receptivity.42
PAF is also involved in the cyclical development of the endometrium.43 44 Not surprisingly, the levels of the receptors for PAF vary throughout the menstrual cycle, with the highest endometrial levels detected during the mid-late proliferative 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 with PAF 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
Specifically, these researchers showed that there was, for some pill users, a 50% reduction in endometrial development when compared to that seen in the control (non-pill using) group.49 Therefore, it is reasonable to conclude there is an adverse impact upon the express of PAF receptors. Indeed, given the hormonal influence exerted by estrogen, it would be biologically illogical to conclude no damage to the expression of endometrial PAF receptors.
Article copyrights are held soley by author.