What to Know About Endometrial Receptivity Analysis (ERA Tests)

When it comes to fertility treatments, couples often seek procedures or add-ons to increase their chances of conceiving. One such procedure that has gained popularity is the Endometrial Receptivity Analysis (ERA) test. However, a recent randomized controlled trial presented at the 2021 American Society for Reproductive Medicine (ASRM) Scientific Congress & Expo has raised concerns about its effectiveness.

Despite the new findings, it’s important to understand the ERA test, how it works, and what benefits it may provide. This article provides a comprehensive overview of the ERA test and what you need to know if you consider it part of your IVF treatment.

The Role of Endometrial Receptivity Testing in Fertility Treatment

Endometrial Receptivity Analysis (ERA) claims to help individuals undergoing In Vitro Fertilization (IVF) determine the optimal time of progesterone exposure before an embryo transfer, in hopes of increasing the likelihood of embryo implantation into the endometrium (uterine lining), and eventually a successful pregnancy and live birth.

The delicate process of implantation involves a complex interactions between the endometrium and the embryo that can only occur during a special window of time, also known as “the window of receptivity” or “the window of implantation.”

This section covers the basics of endometrial receptivity and how it relates to fertility treatment, starting with the endometrium’s role in pregnancy.

What is the endometrium?

The uterus or womb is lined with a special tissue called the endometrium. This tissue plays a vital role in pregnancy by serving as the site for embryo implantation and nourishing the developing fetus.

The endometrium consists of two layers: the first layer, stratum basalis, remains constant throughout the menstrual cycle, while the second layer, stratum functionalis, grows thicker, changes in response to hormonal fluctuations, and is eventually sloughed off during menstruation.

Hormones like estrogen and progesterone help regulate the thickness and texture of the endometrium, creating an ideal environment for an embryo to grow.

If a fertilized egg (blastocyst) implants in the endometrium, it can lead to pregnancy. If not, the endometrium is shed during menstruation.

What is endometrial receptivity?

Although embryo development and endometrial preparation are separate processes, they must align for successful implantation and pregnancy to occur. For this to happen, the endometrium must reach a receptive state in which it’s ready to receive and support an embryo. This is known as endometrial receptivity.

During this window of receptivity (between days 20 and 24 of an average 28-day menstrual cycle), the endometrium undergoes changes in gene expression, secretion of molecules, and structural modifications to facilitate embryonic implantation.

Additionally, the embryo must be mature enough to implant (the blastocyst stage, which is day 5 or 6 of growth) and be chromosomally normal (euploid) to successfully implant and lead to an ongoing pregnancy, as abnormal embryos (aneuploid) usually fail to implant or result in an early miscarriage.

Pregnancy will not occur if:

• the window is missed
• the embryo is not mature enough to implant
• the embryo is chromosomally abnormal
• the endometrium is not expressing the correct genes or is not in a receptive state

This window of receptivity exists in both natural conception and IVF.

Recurrent Implantation Failure (RIF)

Repeated or recurrent implantation failure (RIF) occurs when an embryo fails to implant following multiple IVF cycles with high-quality embryos or after natural conception attempts.

There’s no standard for how many failed IVF cycles or embryos transferred constitute recurrent implantation failure (RIF). As a result, different fertility centers may have varying definitions for RIF.

However, given the success rates of IVF and the average number of embryos transferred per cycle, it’s recommended to define RIF as failure of implantation in at least three consecutive IVF attempts where one-to-two high-quality embryos are transferred per cycle.

How Endometrium Plays a Role in Implantation

As mentioned earlier, the blastocyst implants and grows throughout pregnancy in the endometrium. This means the endometrium or lining of the uterus must be receptive and healthy for successful implantation and pregnancy.

Several factors can impair endometrial receptivity and lead to implantation failure, including:

• Hormonal imbalances: Hormones such as estrogen and progesterone help prepare the endometrium for implantation. An imbalance in these hormones can lead to an unprepared endometrium.
• Uterine abnormalities: Structural problems in the uterus, such as fibroids, polyps, or adhesions, can prevent the endometrium from developing normally and interfere with implantation.
• Inflammation: Chronic inflammation in the endometrium can alter the expression of genes and affect the secretion of molecules essential for implantation.
• Infection: Infections such as bacterial vaginosis or sexually transmitted infections (STIs) can disrupt the natural microbiome of the reproductive tract and lead to inflammation, impairing endometrial receptivity.
• Autoimmune disorders: Certain autoimmune conditions, such as antiphospholipid syndrome or Lupus, can cause abnormal blood clotting and lead to recurrent miscarriages or implantation failure.
• Age: Over time, the endometrium undergoes changes that may make it less receptive to implantation. This may be due to changes in gene expression and cellular function in the endometrium.

Endometrial receptivity exists on a spectrum, and defects can range from mild to severe. Mild defects can lead to placental abnormalities and issues like pre-eclampsia or low birth weight, while more severe defects can cause early pregnancy loss.

Complete loss of receptivity can lead to infertility.

What is an endometrial receptivity analysis (ERA)?

An endometrial receptivity analysis (ERA) test is a diagnostic test that some fertility clinics claim can help determine whether or not an individual’s endometrium is ready to receive an embryo.

RMA does not offer ERA testing, as current scientific evidence does not support its use in routine clinical practice.

What IVF Patients Need to Know about ERA Testing

ERA testing involves an endometrium biopsy followed by gene expression analysis in the endometrial tissue. The test claims to provide clinicians with information on the receptivity of the endometrium to an embryo at the time of biopsy based on the genes being expressed.

Here’s a breakdown of the ERA process:

1. The patient undergoes a “prep” or “mock” cycle, taking oral and self-injected medications to stimulate the uterine lining. Transvaginal ultrasounds and bloodwork visits monitor medication response.
2. At the end of the prep cycle, at the time an embryo transfer would typically be performed, a doctor performs a biopsy, collecting tissue from the endometrial lining. The procedure takes about two minutes and does not require sedation.
3. A third-party laboratory tests the tissue sample for the expression of hundreds of genes.
4. The doctor determines if the endometrium is receptive or non-receptive to an embryo during the biopsy based on the test results.
5. If the results indicate non-receptivity, the doctor adjusts the patient’s exposure to progesterone and transfer timing for the patient’s next cycle to increase the chances of a successful pregnancy.

The Cost of Endometrial Receptivity Analysis

ERA testing costs vary by clinic and region but typically range from $800 to $1,500 in the United States. In addition to the cost of the test itself, patients should also factor in the cost of a prep cycle, which involves taking medications and monitoring ultrasounds and bloodwork.

Patients should discuss the cost of ERA testing with their clinic and insurance provider, if applicable, and consider whether it’s necessary for their fertility treatment journey.

ERA Fertility Test Success Rates

Research on the effectiveness of the endometrial receptivity assay (ERA) in improving pregnancy outcomes for IVF patients has yielded mixed results.

In a 2021 study, ERA testing did not significantly improve outcomes for single euploid frozen blastocyst transfer (FBT) in an unselected population. The study included 767 participants randomly divided into a study group and a control group. The study group received FBT based on ERA test results, while the control group followed the standard timing protocol.

Another randomized clinical trial conducted in 2022 found that routine use of ERA to guide the timing of FBT is not supported. The study included 978 participants and found no statistically significant difference in live birth rates between the endometrial receptivity timed group and the standard timing group.

Overall, while ERA testing may be helpful for some women, further research is needed to determine its benefits, particularly for women with recurrent implantation failure.

Understanding ERA Test Results

The ERA test can yield three potential results:

1. Receptive result: This means that the endometrium is in the best state for embryo implantation, and the patient had the correct amount of progesterone exposure. The same protocol can be used for the frozen embryo transfer (FET) cycle following the mock cycle.
2. Pre-receptive result: This result indicates that the patient did not receive enough progesterone, and the endometrium was not receptive to the embryo. In this case, future FET may require a longer duration of progesterone exposure. The ERA results will determine the number of hours of progesterone support required before embryo transfer, which could mean additional 12 or 24 hours before the transfer.
3. Post-receptive result: This result suggests that the timing of progesterone exposure was beyond the optimal window before the biopsy (transfer). This indicates that the patient started taking progesterone too early before the biopsy. In this case, a repeat biopsy is necessary to confirm the correct timing of progesterone initiation relative to embryo transfer. The repeat biopsy results will determine the number of hours of progesterone support required before the transfer, which may be 12 or 24 hours less than usual.

In rare cases, an inconclusive result may occur.

What is the window of implantation?

The “window of implantation” or “window of receptivity” is a brief window or timeframe in which the uterus is ready to receive and support an embryo. This stage is crucial for pregnancy to occur.

The endometrium needs to be just the right thickness and have the right genes activated to signal to the embryo that it’s ready for implantation.

Is every woman’s window of receptivity the same?

No, this window is not universal for all women and can vary depending on the woman’s progesterone level and the genes expressed by her endometrium.

What should I know about my window of receptivity?

IVF patients most likely do not need to worry about missing their window of receptivity.

According to RMA research, women with three normal embryos have a 95% chance of pregnancy. This means that almost all women will have success on their third IVF cycle with a normal, euploid embryo that met the window of implantation.

Women who undergo Pre-implantation Genetic Testing (PGT-A) can determine if their embryos are normal or abnormal.

For the small percentage of women who do not get pregnant after multiple attempts with normal, good-quality embryos, fertility doctors may investigate whether the reason for their RIF is related to missing the window of receptivity.

Benefits of an Endometrial Receptivity Analysis

ERA testing is a relatively new technology and its benefits are not yet fully understood. While ERA testing is marketed as a way to help personalize fertility treatment and increase the chances of pregnancy, there’s still limited research on its efficacy.

Some studies have shown that ERA testing may be helpful for women who have experienced recurrent implantation failure or had multiple failed IVF cycles. However, other studies have questioned the reliability of the test and its ability to accurately predict the optimal time for embryo transfer.

Additionally, the cost of the test can be prohibitive for some patients.

Is an endometrial receptivity analysis right for me?

While ERA testing may not be effective in improving pregnancy rates in the general IVF population, some fertility clinics may still offer it for women who have experienced RIF. Some evidence suggests that the test may be helpful for this specific group of patients, but further research is needed to determine its efficacy fully.

If you’re considering the ERA test or have experienced RIF, it’s important to talk to your fertility doctor. They can help you weigh the potential benefits and costs of the test so you can make an informed decision based on your unique medical history and treatment goals.

A Word from Reproductive Medicine Associates (RMA)

At Reproductive Medicine Associates (RMA), we understand that making decisions about your fertility can be overwhelming, and we’re here to help.

Our experienced fertility specialists can provide personalized guidance on whether ERA testing is right for you based on your unique medical history and treatment goals. We also offer a wide range of fertility testing and treatment options to help you achieve your dreams of starting or expanding your family.

Please call us or fill out our online form to learn more about our services and schedule a consultation with one of our specialists. We look forward to partnering with you on your fertility journey.