Who picks the embryo? The endometrium!

Among reproductive specialist, the view of pregnancy has been classically “embryo centric”. Consistently, there is a widely held belief that the embryo is somewhat the main factor in deciding if implantation will take place, while the endometrium is often seen as a passive player. Sure, the endometrium needs to be prepared adequately, but it has not been traditionally considered an organ capable of selecting actively which embryo will implant.

A recent review highlights the growing body of research which implicates the endometrium as an active player in embryo adhesion and nidation (Macklon and Brosens, 2014).

Specifically, the authors reflect on the fact that peri-implantation pregnancy loss in humans, unlike in mammals in general or even in other primates, is particularly high. Moreover, it is becoming clear that human embryos possess a high degree of aneuploidy, as several studies on biopsied embryos have shown. One possibility that he authors explore is the fact that aneuploidy, to a certain extent, is not detrimental to the embryo, meaning that certain kind of alteration might confer a selective advantage to the embryo in its relationship with the uterine environment, compared to a “perfect” embryo.

The human endometrium decidualizes in the human species because of signals that are of endocrine nature, rather than signaled by the embryo. In fact, decidualization occurs monthly during the luteal phase regardless of the fact than fertilization had occurred at all. If an embryo is created and it starts producing bHCG, then the pregnancy will be maintained through bHCG signaling to the ovary, which in turn will produce more progesterone and allow for the pregnancy to continue. As a consequence, the decidual cells are programmed to react against embryos which do not produce enough bHCG. This is very important, because from the evolutionary point of view, if a pregnancy is not viable, the sooner it is interrupted, the better.

Opposite to what researcher predicted, it has been shown that the decidua respond very strongly to the presence of an incompetent embryos, changing its gene expression and especially withdrawing the production of IL-1b, HB-EGF, and other factors which are pro-implantatory and necessary for a correct implantation.

On the other hand, the presence on the decidua of a normally developing embryo does not elicit any specific pro-implantatory upregulation, indicating that the endometrium is more able to de-select bad embryos than to select specifically good ones.

These results were gathered from in vitro experiments, and were confirmed in part by in vivo research in mice uteri, where media conditioned by impaired embryos elicited much more gene expression response than media conditioned by viable embryos. Moreover, viable embryos caused smaller but specific changes in the endometrium transcriptome, eliciting the expression of a supportive intrauterine environment.

It is interesting to speculate that while an unviable embryo will trigger a negative selection mechanism in the uterus, a viable one will have uterine support. In order to do this, the viable embryo should not be completely “silent”, metabolically speaking, and a small degree of aneuploidy will in this case be beneficial, because the mosaicism will allow for a more “noisy” embryo to be “heard” by the decidua.

As it is often the case in basic research, more studies will be needed to understand completely the degree of alteration that should be beneficial to an embryo, and to change our long held beliefs. The possibility is, however, very intriguing.

Rita Vassena
Scientific Director, Clinica EUGIN