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.

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(1) Somkuti SC, Fritz MA et al. The effects of oral contraceptive pills on markers of endometrial receptivity, op.cit

(2) Johnson GA, Spencer TE, Burghardt RC et al. Progesterone modulation of osteopontin gene expression in the ovine uterus. Biology of Reprod. 2000; 62: 1315-1321

(3) Laird SM, Tuckerman EM, Dalton CF et al. The production of leukemia inhibitory factor by human endometrium: presence in uterine flushings and production by cells in culture. Human Reprod 1997; 12(3): 569-574

(4) Hambartsoumian, op.cit., p.20

(5) Tabibzadeh S. Molecular control of the implantation window. Hum Reprod Update 1998;
4(5): 465-471

(6) Horne, op.cit., p.1301

(7) Meng CX, Anderson KL, Bentin-Ley U et al. Effect of levonorgestrel and mifepristone on endometrial receptivity markers I a three-dimensional human endometrial cell culture model. Fert Steril 2009;91(1):256-264

(8) Nardo LG, Bartoloni G, Mercurio S et al. Expression of avb3 and a4b1 integrins throughout the putative window of implantation in a cohort of healthy fertile women. Acta Obstet Gynecol Scand 2002;81(8):753-8

(9) Nimbkar-Joshi S, Rosario G, Katkam RR et al. Embryo-induced alterations in the molecular phenotype of primate endometrium. J Reprod Immunol. 2009;83:65-71

(10) Kimber SJ, Spanswick C. Blastocyst implantation: the adhesion cascade. Cell & Devel Biol 2000; 11: 77-92

(11) Andreas Herrler, Ulrike Von Rango, Henning M Beier. Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation. Reproductive Biomedicine Online. 2003: 6(2):244-256

(12) Horne AW, White JO, Lalani E-N. The endometrium and embryo implantation. BMJ 2000; 321:1301-1302

(13) Andreas Herrler, Ulrike Von Rango, Henning M Beier, op.cit.

(14) Devoto L, Fuentes A, Palomino A et al. Pharmacokinetics and endometrial tissue levels of levonorgestrel after administration of a single 1.6mg dose by the oral and vaginal route. Fert Steril. 2005;84(1):4650

(15) Bischof P. The Menstrual Cycle. Postgraduate Training Course in Reproductive Health/Chronic Disease. (Viewed February 2010)

(16) Guillebaud, op.cit., p.416

(17) MIMS 2001. Havas MediMedia Leve 2, 1 Chandos Street, St.Leonards, NSW 2065 Australia See levonorgestrel-only birth control monograph

(18) Giudice, op.cit., p.12

(19) Makrigiannakis A, Karamounti M, Petsas G et al. The expression of receptivity markers in the fallopian tube epithelium. Histochem Cell Biol 2009;132:159-167

(20) Blanco O, Tirado I, Munoz-Fernandez R et al. Human decidual stromal cells express HLA-G effects of cytokines and decidualization. 2008;23:(1):144-152

(21) Staun-Ram E, Shalev E. Human trophoblast function during the implantation process. Reprod Bio Endocrin. 2005;3:56 (Viewed February 28,2010.)

(22) Lam K, Chiu P, Chung MK, et al. Glycodelin-A as a modulator of trophoblast invasion. Hum Reprod. 2009;24(9):2093-2103

(23) Goldman S, Shalev E. Difference in progesterone-receptor isoforms ratio between early and late first-trimester human trophoblast is associated with differential cell invasion and matrix metalloproteinase 2 expression. Bio Reprod. 2006;74:13-22

(24) McEwan M, Lins RJ, Munro SK et al.Cytokine regulation during the formation of the fetal-maternal interface: focus on cell-cell adhesion and remodelling of the extra-cellular matrix. 2009; 20:241-249

(25) McEwan, ibid, p.243

(26) Szekeres-Bartho J, Halasz M, Palkovics T. Progesterone in pregnancy; receptor-ligand interaction and signalling pathways. J Reprod Immun. 2009;83:60-64

(27) Ibid, p.60