IVF & FERTILITY TREATMENT FOR WOMEN OVER 40 - WHAT ARE YOUR CHANCES?

What is the ‘implantation window’ in fertility treatment and how to improve it?

Elena Santiago, MD
Fertility Specialist at VIDA Fertility

Category:
Embryo Implantation

implantation-window-and-its-importance
From this video you will find out:
  • What role does the endometrium play?
  • What is the ‘window of implantation’ and how to identify it?
  • What kinds of endometrial receptivity testing are there, and how are they performed?
  •  What are the indications for performing endometrial receptivity testing?
  • How is the endometrium prepared for Frozen Embryo Transfer & Fresh Embryo Transfer?
  • What happens during and after implantation?

What is the ‘implantation window’ in fertility treatment and how to improve it?

During this event, Dr Elena Santiago, Gynaecologist & Fertility Specialist at Clinica Tambre, Madrid, explained the implantation window, how to improve it and prepare the endometrium for the embryo transfer to achieve a positive outcome. It is essential to understand the implantation window in order to comprehend fertility treatments and general fertility. During the session, Dr Santiago covered women’s physiology, the menstrual cycle, the role of the endometrium, the window of implantation, endometrial receptivity tests, endometrial preparation for embryo transfer, the implantation process, and recommendations to take home.

Women’s Physiology & age

To begin, let’s discuss women’s physiology and how the ovarian cycle works. Women are born with all their eggs (EX) in their ovaries, typically around 2 million. Unlike men who produce new sperm every three months, women do not generate new eggs throughout their lives. It is crucial to grasp this distinction. Additionally, contrary to the belief that only one egg is lost each month, women actually lose a substantial number of eggs during each menstrual cycle, with approximately 11,000 eggs dying each month until menopause. This loss occurs even in childhood before experiencing the menstrual cycle. During puberty, which usually occurs between the ages of 10 and 16, significant changes take place in a woman’s life, including the reactivation of the gonadotropin-releasing system in the brain. This activation triggers the ovaries, initiating the menstrual cycle and maturation of the reproductive system. Bone growth and the development of secondary sexual characteristics also occur during this stage, culminating in menarche, the onset of menstruation. By the time of menarche, women typically have around 300,000 to 400,000 eggs remaining. Throughout a woman’s reproductive years, she continues to lose eggs, with approximately 1,000 eggs lost during each menstrual cycle, regardless of contraceptive use, pregnancy, or nutritional supplements. It is worth noting that lifestyle factors can affect the quality of eggs and ovarian reserve. Contrary to common belief, fertility treatments such as IVF or ovarian stimulation do not deplete eggs or impact ovarian reserve. A woman runs out of ovarian reserve when her ovaries stop producing hormones, leading to the onset of menopause, which is confirmed after a year without menstruation.

The menstrual cycle

The menstrual cycle begins with the release of gonadotropin hormones (FSH and LH) in the brain, which stimulate the ovaries. As a result of this stimulation and follicle growth, the ovaries produce estrogen, followed by progesterone after ovulation. Oestrogens play a crucial role in thickening the endometrium, while progesterone prepares the endometrium for pregnancy. The endometrium is the inner lining of the uterus and undergoes changes throughout the menstrual cycle. If pregnancy does not occur, the endometrium is shed during menstruation. During the follicular phase of the cycle, estrogen levels increase, leading to the growth of the endometrial lining. After ovulation, during the luteal or secretory phase, the endometrium becomes more receptive, facilitated by progesterone. This receptivity allows for implantation to occur. If implantation does not happen, the endometrium renews itself, resulting in menstruation. The interplay of ovarian hormones and the endometrium is vital for successful implantation and early embryo development. The term “window of implantation” refers to the limited timeframe when the endometrium is receptive to implantation. Recent studies suggest that each woman has her own personalized window of implantation due to variations in uterine receptivity. Approximately 10% to 30% of infertility patients may have a displaced window of implantation. Understanding this concept is crucial in fertility treatments like IVF because the timing of embryo transfer aligns with the receptive window. Implantation failure may occur if the window of implantation differs from expectations. The fertile window, when the endometrium is receptive, typically occurs around six to ten days after ovulation. However, this timeframe can vary among women depending on their menstrual cycle length. Women with cycles ranging from 25 to 35 days are considered to have ovulatory cycles, but the specific timing of the window of implantation differs. Tracking ovulation symptoms such as abdominal pain, changes in vaginal discharge, breast sensitivity, and changes in smell, or temperature can help identify the fertile window. Ovulation tests, which detect hormone levels in urine, are another useful tool. In fertility treatments, assessing the window of implantation or endometrial receptivity is essential. Endometrial biopsy is a common method to analyze gene expression in the endometrium. This biopsy can determine if a woman is pre-receptive, receptive, or post-receptive. The results of these tests provide valuable information for personalizing embryo transfer protocols and improving pregnancy rates. These tests are typically recommended for patients with unsuccessful embryo transfers or unsuccessful transfers of genetically normal embryos (euploid embryos) after multiple attempts. In conclusion, understanding the implantation window, the role of the endometrium, and endometrial receptivity is crucial in fertility treatments. Women’s physiology, the menstrual cycle, and the interplay between hormones and the endometrium play significant roles. Tracking ovulation symptoms and utilizing tests like endometrial biopsy can provide valuable insights for personalized embryo transfers. These approaches help optimize the chances of successful implantation and pregnancy.

The role of endometrium

The endometrium changes every month. Estrogen thickens the lining in the first part of the cycle, while progesterone prepares it for pregnancy. The endometrium survives and nourishes the early embryo by stimulating gland growth. The term “window of implantation” refers to the few days when the endometrium is receptive for implantation. Recent studies show that every woman has her personal window of implantation, which may be altered in infertility patients. Calculating the window of implantation is important in IVF treatments to ensure the uterus is ready for embryo transfer. Implantation failure may occur if the window differs from expectations. Generally, the window of implantation occurs after ovulation, within the secretory or luteal phase, lasting around 6 to 10 days. The length of the menstrual cycle varies among women, and the window of implantation depends on when ovulation occurs. Cycles can range from 25 to 35 days, with ovulation usually occurring within this range. Identifying symptoms of ovulation can help determine the window of implantation. Symptoms may include nausea, abdominal pain, spotting, transparent vaginal discharge, changes in smell, breast sensitivity, and temperature changes. Ovulation tests can also assist in identifying the fertile window. Regarding fertility treatments, testing the receptivity of the endometrium is crucial. Endometrial biopsy is a simple procedure that analyzes around 300 genes, determining if the endometrium is pre-receptive, receptive, or post-receptive. This personalized information guides embryo transfer at the optimal time for implantation.

Endometrial Receptivity Testing

Endometrial receptivity tests are indicated for patients who have had multiple unsuccessful high-quality embryo transfers or unsuccessful euploid embryo transfers. If a healthy chromosomic embryo transfer fails, testing is recommended. Overall, it’s advisable for any patient seeking a better approach before undergoing an embryo transfer to consider these tests. There are patients who have undergone multiple treatments, such as egg donation and are about to undergo their first embryo transfer. They want to know if their window of implantation is normal or if there are any differences. Additionally, some patients may only have one high-quality embryo for transfer and would like to undergo testing before proceeding to minimize the risk. It’s important to note that endometrial testing is typically done in preparation for frozen embryo transfers. This involves using estrogen and progesterone in a substituted cycle or a natural cycle. In less common cases, gonadotropins can be used. Ultrasounds and progesterone blood tests are crucial for monitoring the growth of the endometrium and ensuring the correct timing for the biopsy.

Implantation process

The implantation process involves different stages, including hatching, the addition of molecules to interact with the endometrium, adhesion, and the actual inversion of the embryo into the endometrium. The success of embryo implantation depends on factors such as gamete quality (egg and sperm), endometrium status, a technique used during embryo transfer, and proper luteal phase support with appropriate progesterone levels.

Take-home messages

To summarize, a good endometrium is vital for successful treatment. Personalizing each treatment for individual patients is crucial, and endometrial testing is a commonly used tool at Clinica Tambre to help patients with implantation failure. Studies have shown that this receptivity test improves pregnancy rates after embryo transfer and provides valuable insights into endometrial function and receptivity. By performing a basic examination with vaginal ultrasound and utilizing endometrial tests, we can gain a better understanding of endometrial health, including the absence of infection and a favourable microbiome. The ultimate goal is to enhance reproductive outcomes, and utilizing these tools can contribute to improved success rates in personalized cases.

I underwent an ERA (Endometrial Receptivity Analysis) test 1 and a half years ago, which showed that my endometrium was post-receptive by 12 hours. Since then, I have had 3 transfers without success. 2 months ago, during a hysteroscopy with a Curettage procedure, a septum was found to be excised). I would like to know if the previous ERA results still apply or if I need to undergo the test again.

Normally, it is recommended to renew endometrial tests every year because the window of implantation can change over time. Therefore, I would recommend repeating the ERA test after 1.5 years to improve your reproductive outcomes.

What is the ideal progesterone level prior to transfer?

When you are already taking progesterone, it is advisable to measure the levels two or three days before the transfer. At Clinica Tambre, our protocol recommends a minimum of 10 nanograms per millilitre. If the progesterone level is insufficient, additional progesterone shots can be administered to correct the levels before embryo transfer and continued as a part of the treatment.

I’m 43 years old and will undergo a frozen embryo transfer with my own eggs in a few months. What can I do to maximize the implantation window?

To maximize your window of implantation, if you have only one embryo for transfer, it is important to ensure proper endometrial preparation. This includes achieving a good thickness of at least seven millimeters and a triple-line appearance. Before starting progesterone supplementation, check that the progesterone levels are below 1.0 nanogram per milliliter. Additionally, undergoing an endometrial testing can further improve your success rate. It is also recommended to check your microbiome to ensure everything is in order.

What about a modified natural cycle?

It can be an effective option. Pregnancy rates do not differ significantly between substituted or modified natural cycles. However, it is important for the woman to have regular cycles and for the ovary to function properly. Monitoring the follicle growth and the endometrium’s preparation is crucial. Ovulation should be triggered at the correct time, usually a week after the trigger for endometrial transfer.

When should the ERA test be done, and what is the name of the microbiome test?

The ERA test should be performed at the same point as the embryo transfer. This means undergoing the same endometrial preparation, but instead of transferring the embryo, a biopsy is taken. It is essential to record the time of progesterone administration for accurate calculation of the hours needed for embryo transfer. As for the microbiome test, different laboratories offer various commercial names for the test. Examples include Meta, EMMA, and ALICE. The important aspect is to check the microbiome and identify any potential endometrial infections.

When can the microbiome test be done, and is it a complicated and painful procedure?

The microbiome test can be done at any point in your cycle, except during your period. Although an endometrial biopsy can cause some discomfort, the procedure itself is not overly complicated. It is typically performed in the consultation room, and it may cause more sensation compared to embryo transfer due to a slightly thicker catheter. The cells collected for the biopsy can also cause mild discomfort. However, the procedure is relatively quick, lasting only a few minutes. To make the process less complicated, it is advised to arrive for the biopsy with a full bladder.

Can an ERA test be done 5 days after an egg retrieval?

Yes, it is possible to perform an ERA test 5 days after egg retrieval. This is when the window of implantation should be receptive, as it is the time for a fresh embryo transfer. However, at Clinica Tambre, we primarily perform frozen embryo transfers, and for ERA or window of implantation testing, it is typically done with a substituted cycle or a natural modified cycle. Performing the ERA test after ovarian stimulation is not the most common protocol. Substituted cycles involving estrogen and vaginal progesterone or natural modified cycles are generally more cost-effective and easier options.

Is the ERA test also done through biopsy? Can this test be done together with the microbiome test?

Yes, the ERA test is always done through biopsy. It can be done together with the same biopsy as the microbiome test. When undergoing the biopsy, simply inform the lab about the type of test you want, whether it is only the window of implantation or if you also want to check the microbiome for any potential infections, such as endometritis.

Does the ERA test include the CD138 test, which tests for endometriosis?

No, the ERA test is focused on the window of implantation. CD138 is an immunohistochemical test that is different from the tests normally done. The tests we discussed earlier, which involve gene and bacteria analysis, are more specific and sensitive than CD138. However, CD138 biopsy is sometimes used in fertility clinics as a cheaper alternative.

How much time does the treatment for the microbiome take place after the test?

The duration of the treatment for the microbiome depends on the findings. If endometriosis or infection is detected, antibiotic treatment is necessary, typically lasting seven to ten days. Additionally, probiotic treatment, both orally and vaginally, is usually recommended and can take around two weeks. If the treatment only involves dysbiosis, which indicates an imbalance in the microbiome, there is no need to repeat the biopsy, and probiotic treatment is continued until the next embryo transfer. The treatment should not significantly delay the transfer process.

Is endometriosis painful or can it be asymptomatic? Can it be seen by ultrasound?

Endometriosis is typically asymptomatic and chronic, and it cannot be visually observed during an ultrasound. However, in some cases, suspicions may arise when a patient is not responding adequately to the preparation of the endometrium, such as when the appearance or thickness does not meet expectations despite treatment. But visual confirmation through ultrasound is not possible.

Recent studies have shown that ERA receptivity tests do not increase the chances of live birth. However, I had 2 ERA tests a month apart with different results, and my PGT-tested embryo transfers were unsuccessful. Is there anything you can add to this?

There is ongoing debate regarding the effectiveness of ERA receptivity tests. However, it is important to consider that not all patients require this type of testing. When studying every patient, the results may not show significant improvements. However, when performed specifically on patients with implantation failure, ERA can improve outcomes. It is unclear why your results differed within a month, and I’m sorry to hear that your transfers were unsuccessful. Other factors may be affecting implantation, and further investigation is needed.

Can menopausal women have embryo transfers, and how can we determine the implantation window?

Menopausal women can undergo embryo transfers without issues by supplementing with estrogen and progesterone. The uterus will respond as if the ovaries were still functioning. The implantation window can be determined based on the hormonal stimulation and preparation of the endometrium. Initially, the endometrium is prepared with estrogen, and once it reaches the desired thickness and appearance, progesterone is added. The duration of progesterone supplementation typically lasts five days before the embryo transfer.

Is the window of implantation different each time? Should the endometrial test be done during the preparation for implantation? What is the test for bacteria called?

The best method of progesterone supplementation depends on the patient’s preference. Injections are considered the most effective because they ensure complete absorption and precise progesterone levels. However, vaginal pessaries are commonly used initially, and the progesterone levels are monitored. Not all patients will require injections. It is a personal choice, considering factors such as comfort and cost.

Can a problem with the microbiome affect implantation and increase the risk of miscarriage?

Yes, a problem with the microbiome can affect implantation rates and increase the risk of miscarriage. Recent studies have shown the impact of the microbiome on implantation and the development of a pregnancy. It is particularly important to check the microbiome in cases of recurrent miscarriages to identify potential factors that may be preventing successful pregnancies.

If ERA is not done in the clinic where I have the last embryo frozen, would it still be helpful to do it in another clinic for the next endometrial preparation?

If ERA is not done in the clinic where I have the last embryo frozen, would it still be helpful to do it in another clinic for the next endometrial preparation?

What supplements or preparations are needed before embryo implantation, and how long does it take to be ready?

The specific supplements and preparations needed before embryo implantation can vary depending on the individual case. However, commonly recommended supplements include folic acid to prevent neurological problems in the fetus and vitamin D, which is beneficial for pregnancy. The duration of preparation may differ, but typically one month of treatment is sufficient for vitamin D supplementation. Other supplements, such as probiotics, may be prescribed based on individual needs and the results of endometrial testing. Probiotics are usually taken for at least one month before the transfer and may continue for three to six months, depending on the situation.

How can the morphology of the uterus be checked?

The morphology of the uterus can be checked using non-invasive techniques such as three-dimensional ultrasound, which provides detailed images of the uterus and its cavity. Another option is hysteroscopy, a slightly more invasive procedure where a camera is inserted vaginally into the uterus to directly visualize the uterine cavity. Both methods are valuable for assessing the morphology of the uterus.

Which route is better for probiotics, oral or vaginal?

The choice between oral or vaginal probiotics depends on various factors, including the results of microbiome testing. Vaginal probiotics are generally preferred as they can directly reach the uterus due to proximity. However, oral probiotics may also be recommended to improve the overall flora of the bowel. In some cases, both oral and vaginal probiotics may be prescribed, but if a choice must be made, vaginal probiotics are often preferred.

If the endometrial thickness and progesterone levels were good during the preparation for embryo transfer, does ERA still need to be done?

If the endometrial thickness and progesterone levels were satisfactory and the transfer date was set, ERA (endometrial receptivity analysis) may not be necessary. ERA is usually recommended in cases of implantation failure or when there are concerns about the timing of implantation.
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Authors
Elena Santiago, MD

Elena Santiago, MD

Dr. Elena Santiago is a Specialist in Fertility. She obtained her Degree in Medicine and Surgery at Universidad Autónoma de Madrid and she was a Residential Doctor of Gynaecology and Obstetrics at Severo Ochoa University Hospital, also located in Madrid. Dr. Santiago also holds a Masters in Human Reproduction from the Universidad Rey Juan Carlos in Madrid, and she has been one of the members of the Tambre (Former clinic) medical team. Those who have been with her in the consultation room highlight the doctor's kindness, her eagerness to personalise each patient's case and her professionalism. Dr. Santiago speaks fluent Spanish, English and French.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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