Understanding Your Endometrium and Window of Implantation

As you begin your fertility journey, it’s not uncommon to feel overwhelmed by the amount of new information you are expected to learn in order to make informed decisions about your fertility treatment options. A good place to start is understanding your endometrium, and the role it plays in conception. Below, you will find a breakdown of what the endometrium is, how embryo implantation occurs, and what your window of implantation (WOI) is. We will also discuss factors that can prevent implantation or cause implantation failure, as well as options that can help improve your IVF success rate. 

What is the endometrium? 

Commonly referred to as the uterine lining, the endometrium is the layer of tissue (or mucus membrane) that lines the inside of the uterus. This is the part of the uterus where embryos physically attach themselves in the first stage of pregnancy.  

Over the course of a menstrual cycle, this mucus membrane thickens in anticipation of a possible pregnancy. Ideally, the endometrium will reach a thickness of 7 to 10mm by the time a fertilized egg descends into the uterus for implantation. 

If implantation does not occur, then the lining thins and sheds, which results in menstrual bleeding.  

What is embryo implantation?  

Embryo implantation is a multi-day, natural process when the embryo attaches itself to the uterine lining, or endometrium. This occurs during the initial period of the embryo’s development, typically around the mid-point of your menstrual cycle. If you are undergoing IVF treatment, implantation is completed about five days after your embryo transfer procedure.  

The endometrium undergoes physical changes in order to accommodate for the embryo’s implantation. Examples of such changes include an accumulation of immune cells, a restructuring of the blood cells, and secretions by certain cells in order to prepare for implantation. During IVF, the embryo transfer must take place during the time frame known as the “window of implantation,” which is when the endometrium will be most receptive to the embryo transfer.  
 

What is the window of implantation (WOI)?  

The window of implantation (WOI) is when the endometrium (the mucous tissue that lines the inside of the uterus) is most receptive to the embryo transfer. Typically, this happens between days 19 and 21 of an average menstrual cycle, some time during the luteal phase. It varies for each person, of course, but the fact that there is a window – and that it is a relatively short one – does not. 

During the WOI, the perfect concoction of hormones is created to encourage the embryo and endometrium to synchronize. It’s crucial that the embryo be implanted during this window in order to ensure a successful transfer. This is true for both frozen embryos and fresh ones. Endometrial receptivity testing (ERT) can help determine your window of implantation. 
 

What makes the endometrium receptive for implantation?  

There are several factors that contribute to endometrial receptivity. One factor is endometrial thickness, which can be tested using an ultrasound to ensure the lining is adequate for supporting embryo implantation. 

However, endometrial thickness alone cannot determine whether your endometrium is receptive and cannot be used to identify your WOI. To more accurately and precisely identify your WOI, you will need to undergo molecular testing. 

Endometrial testing can be an important part of IVF treatment. It can help to assess whether or not your endometrium has an adequate thickness, and at what time optimal receptivity occurs for you. 

Why is endometrial receptivity testing important? 

Endometrial receptivity testing can be helpful to anyone undergoing IVF treatment, but it’s especially important in the case of women who have experienced recurrent implantation failure in past IVF treatments. The test helps to determine the ideal time to undergo embryonic transfer and implantation. There are both fertility and endometrial testing options that aim to prevent implantation failure for future IVF treatments.  

Female fertility testing is also important in determining the issues preventing the embryo from implanting. Undergoing an ultrasound and uterine cavity exam, as well as blood and urine testing will provide your fertility specialist with vital information on your reproductive health.  

Endometrial receptivity tests (ERTs) are a specific type of test for women, in which a tissue sample is collected from the uterine lining and its genes analyzed to determine if they are receptive at the time of biopsy. This test is often done during a mock cycle, which is a procedure similar to an embryo transfer, and functions as a trial run to identify if there are any issues that may impede successful implantation. Typically, mock cycles are performed while taking the hormone medications your fertility specialist has prescribed for your IVF treatment.  
 

The ERT biopsy can be invasive and even painful at times since anesthetics are not typically given for the procedure. Inti Labs’ endometrial receptivity test MIRA™ uses microRNA (miRNA) instead of the more common messenger RNA (mRNA). The miRNA biomarkers used in the test correlate to more than 600 of the genes related to receptivity, and require a smaller tissue sample, making the biopsy less invasive and uncomfortable. This test also has a failure rate of <1%, making it one of the most reliable endometrial receptivity tests for women on the market.   
 

Embryo selection by the endometrium  

The endometrium is fairly selective with its resources, and for good reason. It does not want to “waste” nutrients and other resources on a lower quality embryo, so it “feels out” if an embryo is healthy. When embryos are healthy, the endometrium doesn’t do anything to prevent the implantation process. However, if it detects a low-quality embryo, the endometrium will take action in order to prevent the embryo from developing further.  

Some research has shown that transferring multiple embryos can result in a higher chance of pregnancy. However, embryo quality can be tricky to accurately assess, and sometimes they appear to be healthy even though they are “flawed” inside. There is not yet enough research to confirm that implanting one good embryo and one bad one – as opposed to only one good embryo – is more conducive to successful implantation.  

The success of an implantation can be influenced by whether the embryo is frozen or fresh. After undergoing fertility testing, many women decide to freeze embryos so that they can reproduce using healthy embryos later in life. Embryos can be frozen for extended periods of time and then transferred into the endometrium when a woman is ready to conceive.  

Parents who freeze their embryos can take this opportunity to have pre-implantation genetic testing (PGT) done. If they choose to do so, there is often a higher chance that their implantation will be successful. Nevertheless, it remains critical that the window of implantation be assessed even for the transfer of a frozen embryo because its successful implantation still relies on this time frame. 
 

How immunology affects embryo implantation  

Immune cells such as natural killer (or NK) cells can help the body as it prepares for the implantation of an embryo, since they work to prevent infection throughout the body and influence embryonic implantation. During the implantation process, the endometrium uses these cells to ensure it is healthy and prepared for embryo implantation. 
 

There are two types of NK cells in the endometrium: the peripheral blood NK cells (pbNK cells), located in the blood, and the uterine NK cells (uNK cells), located in the uterus. The pbNK cells target and kill anything that is seen as a threat to the body, making their “natural killer” name a fitting one. The uNK cells do not attack potential infections; instead, they create blood vessels for implantation and promote the embryo’s development. These cells work in tandem to protect your body and the embryo during the implantation period. 
 

Why does embryo implantation fail?  

IVF cannot be successful without a successful embryo implantation, and numerous factors can influence the success or failure of this step. Some factors are based on lifestyle habits, while others are simply genetic. Here are a few common issues that can affect the IVF success rate: 

Maternal age and aneuploidy  

Maternal age is a large factor in determining the IVF success rate. From the age of 35 onwards, women begin to lose a majority of their good embryos. When embryos are of lower quality, they are more likely to be rejected by the endometrium, causing the implantation to fail. Advanced maternal age can also increase the chance of aneuploidy and results in fewer live births and more miscarriages. This is why many women opt to freeze eggs earlier. Try not to stress too much, though – with endometrial testing, fertility treatments, and new assisted reproductive technology, the opportunity of becoming a mother later in life is increasingly within reach.  

 
Lifestyle  

Despite the advancement of IVF and other assisted reproductive technologies, lifestyle habits can affect the success of embryonic implantation. For example, those with a higher BMI (>30) have less success with implantation than those with a lower BMI (<25). If someone has a BMI >40, there is a marked increase in the risk that they will have a miscarriage. So, when planning for in vitro fertilization and considering the IVF success rate, your bodyweight is something to take into account as a potential risk factor.  

Smoking has a similar effect on the success rate of embryonic implantation, reducing the chances of a live birth and increasing the chances of a miscarriage, even when fertility treatments are involved.  

Stress is another factor that can put someone at risk of a miscarriage. This can be far more difficult to manage, especially for those who have undergone the IVF process before. The IVF process itself can be stressful, and high levels of the stress hormone cortisol¹ can significantly increase the risk of miscarriage within the first three weeks of pregnancy. Therefore, finding ways to cope with the process is very important and putting yourself first is a must.  

Infection  

Infection in the endometrium can cause inflammation, which can lead to a more serious condition called chronic endometritis. This condition causes the relationship between the microorganisms and the endometrium’s immune system to break down, reducing the chance of a successful implantation. Endometritis can be caused by the sexually transmitted disease chlamydia as well as a range of other common bacteria, all of which can stall the embryo transfer process. 

Embryo implantation-related molecules 

There are a lot of molecules involved with the implantation process, so having higher or lower levels of any of them can affect the success of an embryo transfer. Examples of these molecules include LIF, altered expressions of CAMs, altered Th1/Th2 cytokine environments, and prostaglandins. Abnormalities in the levels of these molecules can result in unsuccessful implantation. 

Anatomical abnormalities 

A person undergoing IVF may have unique anatomical abnormalities. For example, the formation of polyps or fibroids in the endometrium can prevent the embryo’s ability to implant. Their presence can misshape the endometrial cavity, stopping the embryo transfer process altogether. Assessing for endometrial abnormalities is another reason why endometrial testing and fertility testing are so important. 

Genetics 

When trying to have kids, the genetic material present in the embryo can play a strong role in successful implantation and live birth rates. Specifically, translocations or inversions inherited by the embryo can increase the chance of miscarriages or unsuccessful implantation. 

Some parents may have concerns about passing on genetic disorders. Older parents also have a greater risk of aneuploidy, which occurs when the chromosomes don’t equal 46. Typically, humans have 46 chromosomes, receiving 23 from each parent. Having fewer or more than 46 can affect the outcome of pregnancy. In both cases, pre-implantation genetic testing can be done to determine the genetic health of your embryos. 

Additionally, there are genetic markers that can indicate the overall health of your endometrium. Tests like MIRA™ (miRNA-based Receptivity Analysis) can tell you whether your WOI is displaced or non-standard. 

Treatments for implantation failure or recurrent loss related to the endometrium 

Whether or not you have experienced implantation failure or miscarriage, there are still many female fertility testing and treatment options you can try to increase the likelihood of successfully conceiving – everyone’s body responds to the IVF process differently. Before undergoing any fertility treatments, talk to your doctor and have the proper fertility tests done to see which option is best for you.  

Embryo glue 

Embryo glue is essentially what it sounds like: a substance that makes embryos more “sticky.” It contains hyaluronic acid, which helps increase the likelihood of embryos sticking to and implanting in the endometrium.  

A benefit of this option is that it can be used before or during the development of the embryo. Some research has indicated that it results in more live births and a higher pregnancy rate overall. However, there is still a fair amount of debate over whether or not embryo glue provides any benefit at all. There are no known adverse side effects to embryo glue, so there is minimal fertility testing required to determine eligibility for this treatment. 
 

Endometrial scratch 

Another treatment to support implantation is the endometrial scratch, which has a literal name: a device is inserted into the endometrium to scratch the tissue. The damaged tissue then becomes inflamed, promoting an environment that is actually better for implantation. There appears to be an increase in live births and pregnancy rates among those who opt for this treatment; however, more research needs to be done to prove its validity.  

Immunotherapy (IVIG, intralipids, prednisone or prednisolone)  

Immunotherapy works to suppress the immune system, specifically NK cells. This technique is widely disputed, as there is still very little research that supports the idea that NK cells are harmful to the IVF process. However, it’s an available option that you can discuss with your doctor.  

IVIG, or intravenous immunoglobulin, is a treatment in which the mother receives infusions of human-derived antibodies. As a form of immunotherapy, it works to suppress immune cells. There is little research to support this method.  

Intralipids are another fertility treatment option. An intralipid infusion consists of emulsified fat that is given to the mother via IV. Essentially, this is a safer and more widely recommended version of IVIG and, once again, it works to suppress immune cells.  

Finally, the use of prednisone (a prodrug) or prednisolone (the active drug) is also a fertility treatment option. These are glucocorticoid medications that simultaneously suppress the immune system and reduce inflammation. This treatment is used to encourage embryonic implantation as well as to reduce the chances of miscarriages.  

MIRA™: miRNA-based Receptivity Analysis 

MIRA™ is a miRNA-based endometrial receptivity test that helps healthcare providers determine a patient’s window of implantation for optimized embryo transfer. It does this by assessing a combination of miRNA biomarkers to find the status of a patient’s endometrial receptivity, information your fertility specialist can use to help increase the chances of successful IVF treatment. 

You’re going to encounter a lot of medical terms and scientific jargon on the road ahead of you. Having a good understanding of your window of implantation, and the essential role the endometrium plays in conception, will help you feel more comfortable making the important decisions about your fertility treatment options. Whatever form your fertility journey takes, you have many tools at your disposal to address any challenges you meet along the way.