The implantation window

The endometrium is tissue which covers the uterine wall At the start of each menstrual cycle, it thickens and becomes richly vascularised in order to accept an embryo. This period of several days is commonly called the ‘implantation window’ (Psychoyos, 1973). This window extends from 5 to 9 days after ovulation (it takes place during the secretory phase of the menstrual cycle). During this period, the endometrium provides maximum receptivity to implantation.

This period is characterised by transformations of cells in the endometrium which induce structural change. In parallel, some immune cells leave the endometrium, while others arrive (Natural Killer uterine cells (uNK), regulatory T cells, etc.). The uNK cells (which are not spontaneous “killers”) will play an essential role in the implantation of the embryo and construction of the placenta, permitting the establishment of new immunological equilibrium.

Implantation

Embryo implantation is defined in three large stages:

  • Apposition
  • Adhesion of the embryo to the maternal wall
  • Deep invasion of the placental cells

embryo implantation

Phenomenon in the stage required on the endometrial slope

  • transitory inflammatory destabilisation
  • followed by establishment of a tolerogenic cytokine environment

The uterus spontaneously becomes anti-adhesive. That is why a change in immunological balance in the endometrium takes place, to permit adhesion of the embryo to the endometrium, then a deep invasion of the placental cells. From an immunological point of view, the embryo is different from its mother. It is therefore necessary for the immunological mechanisms to be put in place so that the embryo is not rejected, and that it is supported and supplied in order to develop.

If there is an implantation failure or, in some cases, unexplained miscarriages, dysregulation of the uNK cells can cause failure through various mechanisms:

Implantation failure:  due to cytotoxicity and excessive apoptosis

Immune under-activation:

  • Lack of mobilisation of the immune cells
  • Immaturity of the immune cells (normal or increased number): low IL-15 or IL18
  • Insufficient endometrial vascularisation
  • Insufficient adhesion responsiveness
  • If there is a lack of mobilisation and/or cell immaturity, the minimum desirable reaction for implantation will not take place.
  • On the contrary, if the uNK cells are too active they will, on the one hand, provoke self-destruction of the endometrium and, on the other hand, reject the embryo which is found to be foreign.

Implantation failure: an adhesion fault

Excess of immune activation:

  • Hyper-activation of uNK cells, which can destroy the embryo and trigger a generalised apoptosis process in the endometrium (IL-18/TWEAK, IL-15/Fn-14)
  • the embryo is destroyed because it is recognised as not-self