Reproductive Medicine - Implantation window

Summary of the talk by Nicolas Zech at COGI 2015


As stated by Forman and Scott in 2014: “The uterus is not the physiologically normal environment for day-3 embryos, and embryos with reproductive potential routinely develop into blastocysts in high-quality IVF laboratories”.

The window of implantation (WOI) is the moment when the endometrium becomes permissive to attachment of blastocysts. The rest of the menstrual cycle normally poses an efficient barrier to implantation.

But when does it effectively open and when does it close? The opening seems to be initiated primarily with the rise in progesterone after follicle rupture (day 0/1) or with the beginning of administration of progesterone in an IVF-cycle, which is usually started on the day of oocyte pick-up (day 0, HCG application+2) or on day 1. But when is it truly open and receptive for implantation and at which stage does it close? This is still a black-box.

Seeing that even pronuclear stage embryos (day 1 after follicle retrieval, thus somehow reflecting day 1 after the beginning of progesterone rise) transferred to the endometrium on day 1 can establish pregnancies, the observed results could pretend that this supposedly non-receptive endometrium is already receptive for such stages of embryos. And seeing that transfer of embryos on day 6/7 after oocyte pick-up have already very low implantation potential seems to reflect the start of the closing of the WOI.

Physiologically the embryo arrives on day 5 after follicle rupture (day 0, LH-surge+2) in the endometrium and starts to implant around this day. New data on molecular signatures of the WOI such as with the endometrial receptivity array (ERA) as well as a recent report on nucleolar channel systems (NCSs; 1-micron–sized membranous organelles that develop transiently in the nuclei of secretory-phase endometrial epithelial cells and are sensitive to progesterone) seem to further strengthen the notion that the WOI is open for a very short time and probably around day 5/6 after the beginning of the rise in progesterone.

Still much has to be learned also on the individuality and of other factors besides progesterone which could lead to the opening/ closing of the WOI.  At the time being, the menstrual cycle can be categorized into 4 distinct phases: proliferative, pre-receptive, receptive, and post-receptive. Now the era has to start to individually understand exactly when these phases start and end.

I like to make comparisons with nature: we are all flowers, some of us might represent swamp flowers needing a lot of water and not much sun, others might be cactuses needing a lot of sun and only very few water. We might have the same skin color but the one gets sun burn fast, others need a couple of sun baths to get brown, still others get a nice skin color very fast. In the northern hemisphere a farmer is seeding crops usually around March/ April (reflecting day 5/6) and not in November; similar to the opening and closing of the WOI with the right amount of progesterone at the right time for the individual patient to name but a few.

Maybe in the future we have to freeze a blastocyst on day 5 and transfer it individually on day 3 or day 7 to have the highest chance for this embryo to implant when the endometrium is ready for it? Or we have to administer progesterone earlier/later for the individual patient or with different application routs. And probably: those embryos which show implantation after transfer of embryos on day 1/2/3/4 just survived in a “non-physiological” environment and then implanted. Still much to learn!

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