Window of Implantation
An important question in the treatment of infertility with IVF is this – When is an embryo able to implant into the uterus? If a normal embryo is placed into the uterus too early or too late based on its stage of development, then implantation will fail. This is known as IVF failure or implantation failure. For many years, it was believed that the “window of implantation” was a small time frame that occurred a fixed number of days after ovulation. Recent studies have shown that for some women – this may not always be true.
Before ovulation, while an egg is developing, the ovary is producing the hormone estrogen. This is called the follicular or proliferative phase. Estrogen causes the uterine lining to thicken. If an embryo were to be placed into the uterus during this time, it would not be able to implant or produce a pregnancy. After ovulation, the ovary produces the hormone progesterone. This is called the luteal or secretory phase. Progesterone causes numerous changes in the uterine lining that allow an embryo to implant. However, it seems that there are only a few days during the secretory phase in which the embryo can implant. This is known as the window of implantation.
How do scientists determine the days that the uterus is able to allow implantation? Many types of tests have been tried. The earliest attempts involved looking at the uterine lining under a microscope. Definite changes can be seen under a microscope in the uterine lining as it goes from the proliferative to the secretory phase. However, detecting the very subtle changes needed to distinguish a receptive uterine lining is very difficult. The pathologists who view the uterine lining under the microscope will often have different assessments from one another. Stated another way, microscopic analysis of the uterine lining is not accurate or reproducible. Another type of test involves looking at specific “markers” in the uterine lining. The cells of the uterine lining have a large number of structures on their surface. It was hoped that there might be a specific marker that would be present only when the lining was receptive and not at other times. The most popular of these markers is called beta-3 integrin. While there was initially great hope for the use of these marker tests as indicators for the window of implantation, they have failed to improve the outcomes in IVF cycles.
Endometrial receptivity array
Developed in 2020, the endometrial receptivity array uses some very sophisticated technology which measures the amount of RNA that the cells of the uterine lining produce.
Remember, each cell in the uterine lining has a nucleus which contains the genetic material known as DNA. DNA is the coded blueprint for the instructions that a cell needs to carry out its function. For example, if a cell’s purpose is to make a certain protein, the DNA contains the code for how to make the protein. The code is “translated” into a slightly different form called RNA and the RNA tells the cell which amino acids to combine to make the protein.
The uterine lining cells make more of a certain type of RNA at one time of the cycle and less in another time of the cycle. Scientists have used powerful computer chips to look at the amount of RNA produced at different times of the cycle. Then, using computer algorithms, they could detect patterns in the RNA production. Some RNA levels may not correlate with the window of implantation at all. Other types of RNA may be present in higher amounts and some may be present in lower amounts. In total, scientists have found 138 types of RNA (so far) that help in determining the window of implantation.
This endometrial receptivity array is very reproducible. Studies were done on patients where they took two samples at the same time of the cycle several months apart. Most often, the results of the tests were the same.
The most interesting part of the endometrial receptivity assay is that it has identified that some women might have a receptive uterus at an earlier time than expected and some might be receptive at a later time! Infertility specialists can then use this information to change the time that embryos are placed into the uterus so that it matches up better with the window of implantation!
How commonly is an abnormal test found?
In studies of women with recurrent failed IVF cycles – about 25% of the women were found to have an abnormal ERA result. In infertile women without a history of recurrent in vitro fertilization failures, about 12% of the women were non-receptive.
Of those women with a non-receptive uterine lining, most (85%) were found to have their window of implantation shifted later in the cycle. These women were said to be pre-receptive. The remaining 15% had their window of implantation shifted earlier in the cycle, these patients were called post-receptive.
How do you correct these problems with uterine receptivity?
There are some case reports and small studies in which doctors changed the timing of the embryo transfer according to the results of the endometrial receptivity assay. One such study looked at women with recurrent IVF failures using donor eggs (which means that all of the patients had high quality embryos to transfer). These patients had failed in anywhere from one to six previous attempts. Most did not become pregnant, a few became pregnant but miscarried – none had achieved a live birth. Doctors then changed the time of the embryo transfer based on the results of the endometrial receptivity assay and found that 67% achieved an ongoing pregnancy.
This was very encouraging evidence that this may be a useful test. However, as more data was collected, and larger and better studies were performed, researchers found that adjusting the time of the transfer was not improving the chance for pregnancy or live birth. As a result, in 2022, the ERA test is no longer recommended for people attempting pregnancy with IVF
How if the test performed?
The endometrial receptivity assay is performed by obtaining the tissue from the uterine lining at a very specific time. This can be done in one of two ways:
1) If a woman ovulates, she can use a home urinary ovulation predictor test to detect the LH surge. This is considered day 0. On day 7, she will go to the fertility doctor for the test.
2) Another method is to use medications to prepare the uterine lining using the hormones estrogen and progesterone. This is the method we usually use for performing a frozen embryo transfer cycle. The day the progesterone is started is day 0. The test is done on the fifth day after that.
On the appropriate day (using either method), the doctor or nurse practitioner will perform an endometrial biopsy. First, a speculum is placed into the vagina so that the cervix (opening of the uterus) can be seen. The cervix is stabilized and then a catheter (like a thin, flexible plastic straw) is advanced through the cervix into the uterine cavity. A plunger in the catheter is withdrawn. This creates suction in the catheter which draws endometrial tissue inside the catheter. The catheter is then removed.
The results are available in about three weeks.
At this time, the ERA is no longer a recommend test.