An embryo must implant into the endometrium after it is transferred to the uterus. This window of implantation is a short amount of time where the endometrium needs to be receptive to the embryo. Conventionally, it was believed the window of implantation spanned 4 to 5 days, but recent molecular studies have narrowed this down to 30 – 36 hours.
We know that the embryo accounts for a significant proportion of implantation failures. However, a receptive endometrium is also essential to implantation. One may think that the endometrium is either receptive to an embryo or not. However, research has shown that chemical signals are exchanged between the two and this complex cross-talk leads us to the concept of endometrial selectivity.
Theoretically, a functioning endometrium has to be selective in which embryos it implants. An embryo that is healthy, with a normal number of chromosomes (euploid) should be implanted, but an unhealthy embryo that is never destined to become a healthy baby should be rejected. A healthy endometrium should act as natures quality control system.
When things go wrong, it could be that the endometrium hasn’t functioned properly. For example, healthy embryos repeatedly not implanted may a cause of unexplained infertility or recurrent implantation failure. Conversely, accepting poor quality embryos that should never have been implanted may explain some biochemical pregnancies and miscarriages.
All this theory sounds interesting, but what do we do from a practical point of view? Ideally, we would like to test a marker that can inform us whether the endometrium is adequate or not. Based on this we would know when to perform the embryo transfer.
Endometrial receptivity is a hot topic for researchers. Over recent years the number of research studies published has increased exponentially. A recent summary of all these studies was published in Human Reproduction Update.
Ultrasound is the most popular test used to measure a variety of markers of endometrial receptivity.
Almost all women who have walked into a fertility clinic will have had a measurement of endometrial thickness. A transvaginal ultrasound measures the white stripe in the centre of the uterus from one surface to the other. But is this measurement useful?
The endometrial thickness changes during the menstrual cycle and during IVF treatment. The best time to measure is on the day of HCG trigger injection or the day or embryo transfer.
Looking at studies we can see that thicker endometrium is better for every cut-off with the largest difference for thin cut-offs of 6, 7 or 8 mm, and less significant for higher cut-offs.
This means that a pregnancy is less likely with an endometrial thickness of less than 6mm compared to those who have a thickness higher than 6 mm. However, the same goes for 7 mm, 8mm and so on until 17mm. The more the better for every cut-off.
This association with pregnancy outcome is very exciting, but when looking at how accurate it is at predicting the outcome of an embryo transfer it is disappointing. The accuracy of endometrial thickness overall is 57%, just slightly more than tossing a coin.
After endometrial thickness, the pattern of the endometrium is the most popular marker. This relates to the triple line appearance of the endometrium on ultrasound which is generally thought of as a positive finding. Unfortunately, research shows us there is no association between endometrial pattern and pregnancy in IVF.
Complex molecular tests
The theory behind these modern tests is that embryo development may be out of sync with endometrial development.
A variety of tests have been developed to look at the endometrium in a trial cycle and use the results to guide future embyro transfer. These tests assume that each cycle is identical to another which we know isn’t the case from other basic research studies.
The ERA test is the most established of these tests and was first published in a research journal in 2011. A randomised-controlled trial included 458 women who were randomised to personalised ET or standard treatment. Both groups had similar outcomes, but the cumulative pregnancy rate was higher in the ERA group.
The published paper was controversial and drew much criticism from the scientific community. The researchers presented their data to positively reflect the ERA test despite no difference overall. The cumulative pregnancy rate wasn’t something they initially planned to look at and reporting it is considered bad science. The study was funded by the company marketing the ERA test which also raises questions about impartiality.
Improving the endometrium
So if the endometrium is so important, what can you do to improve it? This is the million dollar question.
Presently, we do not have any proven method to improve pregnancy rates. Studies have compared fresh versus frozen cycles and found that the pregnancy rates are similar. Countless different regimens exist to prepare the endometrium for a frozen cycle including natural cycle, modified natural cycle and medicated cycles using a variety of different estrogens (tablets, patches, gels) and progesterone. No regimen has been shown to be more effective than another.
Therefore, the experience of the clinician comes into play. Fertility treatment is often just as much art as it is science. However, without proper research, it’s never possible to know if the successful outcome was a result of changing the treatment strategy, or due to more throws of the dice and getting lucky.
- Craciunas L, Gallos I, Chu J, Bourne T, Quenby S, Brosens JJ, Coomarasamy A. Conventional and modern markers of endometrial receptivity: a systematic review and meta-analysis. Hum Reprod Update. 2019 Mar 1;25(2):202-223.
- Simón C, Gómez C, Cabanillas S, Vladimirov I, Castillón G, Giles J, Boynukalin K, Findikli N, Bahçeci M, Ortega I, Vidal C. A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF. Reproductive BioMedicine Online. 2020 Sep 1;41(3):402-15.
- Lensen S, Wilkinson J, van Wely M, Farquhar C. Comments on the methodology of an endometrial receptivity array trial. Reproductive BioMedicine Online. Volume 42, Issue 1, 2021. Page 283.