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Immunology and embryo-endometrial communication at the micro-environmental level

In the last few years newer research has questioned the validity of claimed mechanisms of action of the levonorgestrel (LNG) version of the 'morning-after pill'. Research during the late 80s and early 90s referenced a variety of mechanism of action for LNG, including (but not limited to) an adverse pact on the αvβ3 integrin (1), osteopontin (2), LIF (3) (4) , tumour necrosis factor (TNF)(5), and the mucins. (6)

Research in the last few years has reported that LNG does not adversely affect many of the recognised markers of uterine receptivity. Meng (2009) reported that LNG has no effect on estrogen or progesterone levels, αvβ3 integrin, LIF, IL-1?, VEGF or MUC-1. (7)

Two criticisms of this study can be made.

First, the endometrial samples used by Meng were taken on cycle days 17 to 18 but the maximum expression of this vital integrin is not until day 20-22, during the window of implantation. (8) Thus I would contend that the samples could be too early to make the conclusion that LNF does not adversely impact on this integrin.

Second, the endometrial samples studies by Meng were biopsy samples tested in vitro. What is the point here? It is the fundamental, essential point that implantation is an event that requires the crucial interaction by the human embryo with the mother.

It can be said with unchallenged certainty that the human embryo is a dynamic participant, (9) fully involved in its own survival through a complex, sophisticated process, involving a cascade of interdependent, hormonally controlled "implantation factors" (10) and manipulation of the micro-immune environment of the endometrium as it approaches and prepares to implant. (11)

As Horne (2000) has observed, "The embryo is not passive but is an active orchestrator of its attachment and fate." (12)

A similar statement comes from Heller (2003): "Both partners, the mother as well as the embryo, play equal roles in the embryo-maternal dialogue ... Investigations ... indicate that the embryo participates intensively in this early embryo-maternal signalling." (13) This conclusion is reflective of many opinions I have encountered in preparing this manuscript.

Therefore, studies such as that from Meng, and the conclusions drawn, are, in my opinion, invalid. Without the input from the embryo, researchers are investigating endometrial tissue that is, metaphorically, both deaf and blind. Structural and immunological cross-talk cannot occur.

The following bullet points are a summary of key research papers which highlight how the embryo talks to the endometrium (and vice versa) at both an immune modulating and cell-adhesion level. Underpinning this discourse are the comparative intra-uterine levels of the artificial progestin LNG and natural progesterone. The LNG level within the uterus has been shown to be 64nmol/L (14) compared to a progesterone level of 20nmol/L (15) at the same time of the cycle.

These high intra-uterine levels of LNG reflect the fact that when a woman takes the LNG version of the morning after pill, she is ingesting a post-coital dose equal to taking 40 to 50 standard once-a-daily progesterone-only birth control pills.(16) (17) Supporting this claim are the opinions expressed by researchers who have noted that knowledge acquired about the molecular basis of implantation will be used in two arenas of 'reproductive' health; positively in the treatment of infertility as well as, regretfully, "preventing implantation for contraceptive purposes." (18) My hypothesis is that the "observed pregnancy rate" could be attributed to a disruption to the micro-immune environment of the endometrium at the precise zone of implantation, as well as to the embryo-maternal cell dialogue, by the supra-physiological dose of LNG. It should be noted that the term "observed pregnancy rate" is a scientific term used by researchers to quantify how many pregnancies occurred in a clinical trial that used a post-coital drug or device. The term "expected pregnancy rate" refers to the number of pregnancies that would be expected if no woman in the trial used any drug or device to prevent pregnancy. The "expected pregnancy rate" is calculated using Wilcox's table of probabilities of clinical pregnancy.

• Makrigiannakis (2009) reported that oocytes and pre-implantation embryos have various integrin subunits on their surface. Receptors for these integrins have been found on the surface of the endometrium during the implantation window. Progesterone suppresses the level of a key integrin. (19) As a possible anti-implantation action that is undetectable (recalling the observation by Raymond), LNG could adversely impact on the presence of embryo situated integrins.
• "Among the multiple immune mechanisms that control maternal-fetal tolerance during normal pregnancy human leukocyte antigen (HLA-G) seems to play a key role." HLA-G is supplied by the embryo (from trophoblast cells) and it plays a key role in maternal-fetal tolerance. HLA-G is controlled directly by progesterone but also indirectly via IL-10 and/or INT-γ. (20)
• Staun-Ram (2005) has reported that leukaemia inhibitory factor (LIF) is maximally expressed on the endometrial surface during the implantation window but it is also located on pre-implantation embryos. Again we see this reciprocating involvement of the embryo.(21) The supra-physiological intra-uterine levels of LNG could have a deleterious impact upon the levels expressed by the embryo.
• Lam (2009) has reported that there is "simultaneous expression" of key enzymes and their inhibitors in the human embryo suggesting that a balance between the two regulates implantation. (22) These enzymes, called MMPs, are vital to the dissolving of the endometrial cells at the feto-maternal interface, as part of implantation. But successful implantation depends on the ratio of MMP and its neutralizer. Implantation can fail if this ratio is not physiologically correct. Through a complex path, progesterone controls the levels of some MMPs. (23)
• McEwan (2009) has reported that colony stimulating factor 1 (CSF-1) is expressed by both "the pre-implantation embryo and the maternal endometrium." CSF-1 is required for blastocyst imbedding. (24)
• Interleukin-1 (IL-1) is "intimately involved both in implantation and pre-implamnantion development of the embryo ...it is though that IL-1 may allow the pre-implantation blastocyst to communicate with the uterine endometrium ... enhancing endometrial receptivity, while the blastocyst is still en route to the uterus." (25)
• There are many progesterone targeted genes that are implicated in successful implantation. Briefly these include IHH (an intra-endometrial communicator); Bmp2 (found at the site of implantation); p27 and p53 (involved in trophoblast invasion); Hox-A11(feto-maternal immunological functions). (26) As Szekeres-Bartho has noted: "Progesterone affects the materno-fetal immunological relationship at several levels." (27) It is my hypothesis that the supra-physiological levels of LNG affect the materno-fetal relationship in an adverse manner.

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