Window of Implantation (WOI) & IVF

From the talk at COGI, China, Guellin, 2015

 Embryo implantation is mainly dependent on two major factors:

  1. A viable and healthy embryo at the stage of an expanded (hatching) blastocyst.
  2. A receptive endometrium permissive to the attachment of the embryo(s).

The time of endometrial receptiveness is termed window of implantation (WOI).

Synchronization between the two factors is crucial. Physiologically the embryo enters the uterus on day 5 after follicle rupture and 7 days after the LH surge implanting around this time point as hatching blastocyst. In a recent paper Forman and Scott (2014) state the long term knowledge “The uterus is not the physiologically normal environment for day-3 embryos”.

With this knowledge, one has to question why most IVF units worldwide still mostly opt for a day2/3 transfer. It is well documented that transfer on culture day 5 (blastocyst stage) substantially improves pregnancy and implantation rates. At this time point the healthy endometrium opens the WOI. The opening is 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 and is thought to be open for approximately 2 days.

But why do we still have implantation rates far from 100% in IVF cycles even with young patients and top quality blastocysts? One most possible explanation is that the proportion of women with a retarded /faster opening of the WOI or a shortened WOI is higher in IVF patients. Thereby embryo transfer and WOI are not synchronized resulting in implantation failure. Determining the exact time for WOI is crucial to increase implantation rates, however no standardized proven method is evaluable at this time point.

Evidence accumulates that the expression of distinct endometrial factors could predict WOI and the endometrial receptivity, e.g. measured by ERA-array, however application remains to be proven in large clinical trials.  Another reported assay is the analysis of the nuclear channel systems in endometrial cells, however also this approach remains to be further investigated before application in the clinical setting.

Until a proven assay is available, which will essentially increase IVF-results, synchronization between embryo and endometrium can be improved by transfer in cryo-cycles avoiding additional hormonal substitution. Further, slower blastulating embryos can be cultured until blastulation and transferred in a receptive endometrium in a cryo-cycle. This strategy is substantiated by the finding, that fresh transfer of blastocysts on day 6 leads to reduced implantation rates as compared to day 5. However, with vitrification of blastocysts on day 6 and transfer in a cryo-cycle similar implantation rates as with same quality day 5 blastocysts are obtained.   

All these new approaches entering the IVF-clinic at the moment are promising to increase IVF-results. Thereby, still much has to be learned on the complex network of molecules orchestrating the endometrial receptivity as well as on the individuality of the WOI.  

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