WHAT IS THE ‘IMPLANTATION WINDOW’ IN FERTILITY TREATMENT AND HOW TO IMPROVE IT?
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Understanding uterine lining, implantation window and how to prepare for embryo transfer?

Roksolana Semchyshyn, MD, PhD
Head of IVF department , Medicover Fertility Ukraine

Category:
Embryo Implantation, IVF process

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From this video you will find out:
  • What are the main factors of successful implantation?
  • Cooperation between endometrium and embryo: how it works?
  • What does the implantation process look like?
  • What does a thick endometrium indicate?
  • What is the Endometrial Receptivity Array (ERA) test, and when is it recommended?

Understanding uterine lining, implantation window and how to prepare for embryo transfer?

During this webinar, Dr Roksolana Semchyshyn, PhD, the Head of the IVF department, IVF specialist, and ultrasound diagnostics at Medicover Fertility Ukraine, shared insights on optimizing the thickness and quality of the endometrium and discussed techniques to diagnose and address any potential issues as well as provided practical guidance on identifying the optimal time for embryo transfer, based on individual factors and treatment protocols.

The Role of Endometrium in your success

The endometrium plays a vital part in the success of your attempts, and there is an ongoing debate about who the main player is – the embryo or the endometrium.

Endometrial competence, meaning the ability of the endometrium to successfully implant the embryo, is influenced by various factors. These factors include hormonal influences and our immune system. Understanding these factors is crucial in enhancing the chances of successful implantation. The implantation process involves a complex interaction between the endometrium and the embryo. While we may not see what is going on inside, we recognize the importance of the embryo coordinating with the endometrium for successful implantation.

There is a very hard cooperation between the endometrium and embryo, and sometimes we can’t see what is going on inside, but we understand that the embryo needs to just coordinate with endometrium and has to implant inside.

When considering successful implantation, we must evaluate the endometrium’s structure, thickness, and competence. Ultrasound scanning, especially 3D ultrasound scanning, is the most valuable diagnostic method for this purpose. It provides a comprehensive picture of the endometrium and uterus, aiding in the assessment of their condition.

 Importance of Endometrial Thickness

The thickness of the endometrium is a critical factor. It should be between 8 and 14 millimetres, with variations depending on the type of cycle (cryo cycle or medical preparation). Thick or thin endometrium can impact the chances of successful implantation.

Abnormalities such as uterine malformations (e.g., corner sutras, septal uterus) and disorders like polyps can influence endometrial competence and implantation. Screening for and addressing these issues is vital to increase the chances of a successful pregnancy.

Hysteroscopy is an essential tool for evaluating the structure of the endometrium. Office hysteroscopy, performed without general anaesthesia, is a quick and effective procedure. It allows us to diagnose and treat small polyps. Larger polyps and submucosal myomas may require general anaesthesia for surgical removal.

Hysteroscopy is beneficial in cases of negative IVF attempts or when there are indications of abnormalities detected during ultrasound scanning. It can significantly improve success rates within three months after the procedure.

Understanding the role of the endometrium and its impact on successful implantation is crucial for our fertility treatments. By evaluating and addressing factors such as endometrial thickness and abnormalities, we can enhance our chances of achieving successful pregnancies through IVF.

Importance of the Window of Implantation

The window of implantation refers to the time frame when the endometrium is most receptive to blastocyst implantation during a natural cycle. In a cycle lasting up to 28 days, the window of implantation typically occurs between days 6 to 8 after ovulation, with a duration of 48 hours. Sometimes, this window may be disrupted or altered in certain patients.

There are two methods of evaluating the window of implantation: the ERA (Endometrial Receptivity Array) test and electron microscopy. The ERA test assesses gene expression in the endometrium to determine its receptivity to implantation after starting progesterone. On the other hand, electron microscopy evaluation involves endometrial aspiration at specific intervals during progesterone preparation to detect bodies, which play a role in implantation.

It is recommended after two negative IVF attempts with good-quality embryos to investigate if the endometrium receptivity is affecting the success rate. However, the effectiveness of these tests is still a subject of investigation, and not all experts widely recommend them due to varying results and uncertainty about reproducibility.

Role of immune system and thyroid gland in receptivity

The presentation highlights the potential impact of the immune system and thyroid gland on endometrial receptivity. Factors such as higher NK cell activity, HLA compatibility, and the presence of antibodies may affect implantation. While some recommendations support addressing these factors, the overall influence on IVF success is not strongly established.

There are three methods of preparation: the long protocol, modified cycles with estrogens only, and natural cycles. The long protocol is considered the gold standard and involves blocking internal hormones, followed by estrogen and progesterone administration. Ultrasound monitoring is essential during preparation. The choice of protocol depends on medical conditions and individual patient factors. There are three main protocols: the long protocol, modified protocols with estrogens only, and the natural cycle.

Pros and Cons of the Long Protocol

The long protocol is considered the gold standard and is used for patients with endometriosis or irregular cycles. Doctors find it easier to control and plan embryo transfer with this protocol. However, it may lead to complications during pregnancy, such as preeclampsia, and could result in bigger babies after birth.

The modified protocol, which uses only estrogens, is employed for patients with thin endometrium or irregular cycles. It allows for follicular growth as the ovaries are not suppressed by agonists. Hormonal and ultrasound monitoring is crucial during this protocol.

The natural cycle protocol is considered patient-friendly as it does not involve additional medications. Patients may use hCG triggering for ovulation. However, the main challenge is that the exact day of ovulation cannot be predicted, leading to potential scheduling issues for embryo transfer.

The protocol depends on the patient’s medical conditions and specific needs. For instance, using the long protocol for patients with thin endometrium may not yield desired results. Patient adherence to medication and timing is essential for successful outcomes. Following the prescribed dosages and scheduling ultrasound scans diligently is crucial. Photos of the endometrium are helpful for doctors to assess its thickness and structure accurately.

Dr Semchyshyn emphasized that believing in successful outcomes is also considered a key factor. Patients are encouraged to have faith in the process. For those who struggle with this belief, psychological support from a psychologist is recommended.

In conclusion, the presentation emphasizes the importance of choosing the appropriate endometrial preparation protocol based on individual patient factors. Patient adherence to medications and follow-up is critical for achieving successful results. Moreover, having a positive outlook and belief in the success of the treatment can contribute significantly to the overall outcome.

- Questions and Answers

n a patient with estrogen resistance evidenced by a thin endometrium, which options are available to investigate further? How can these scenarios be addressed in the endometrium? PRP use on the endometrium. Do you have any experience with that?

To understand if there is true estrogen resistance, we need to perform an aspiration from the endometrium and test for endometrial receptivity. If the estrogen receptors’ percentage is normal, this is not estrogen resistance. If the endometrium doesn’t respond to estrogens, it could be due to damage to the basal layer, possibly seen in Asherman syndrome. In such cases, we may try to dissect adhesions or use gel or intrauterine contraceptives to open the cavity. PRP (Platelet-Rich Plasma) injections have been used experimentally, but they are not proven and are not recommended by official guidelines.

How can you thicken your lining in the most natural way?

In a natural cycle, we don’t measure progesterone levels on the day of embryo transfer. Progesterone is usually measured before ovulation to ensure adequate production. For treatment cycles, vaginal progesterone is typically used, and the dosage can vary from 300 to 400 mg per day, depending on the patient’s situation.

Does ESHRE not recommend the ERA test anymore as an indicator of endometrial receptivity?

ESHRE guidelines do not recommend the ERA test or other immune system and antibody tests for endometrial receptivity.

If the ERA test shows that my implantation window is not-standard, can this be considered “the cause” of our infertility and cannot work without a personalized embryo transfer?

The ERA test doesn’t provide an exact day for endometrial receptivity, so repeating the test after modifying the progesterone can give a clearer result. The practice of double embryo transfer has shown promising results in certain cases of recurrent implantation failure.  

Is there anything we can do to adjust our lifestyle or diet to influence the endometrial receptivity, or is it just as it is?

Lifestyle and diet changes will not significantly influence endometrial receptivity. Embryo quality is the main factor for successful implantation.

What are your best tips about preparing for embryo transfer beyond the protocol and medication aspect of things?

Tips for preparing for embryo transfer are not strongly influential, but maintaining a healthy body mass index and monitoring your overall health is essential.

in a cryo cycle when do you decide to initiate progesterone treatment? Exactly at what ultrasound picture do you begin progesterone?

It depends on the way of preparation is performed. If it is a natural cycle then we monitor the follicle in case we have a follicle at the size of 20, we use triggering and then relying on the LH peak and the progesterone levels we are calculating the day of embryo transfer in that case we use progesterone from the day after the hCG trigger. In case we have the modified cycle or cryo cycle, we start progesterone when the endometrium is at least 8 millimetres, this is day 12.

I had a long protocol, I had to take contraceptive pills before stimulation, and we only got 3 follicles. I also had a short protocol where stimulation started on the 2nd day of my period, I had oocytes. Now, the doctor suggests the long protocol again. What do you advise?

The protocol choice depends on your AMH level and follicle count. The short protocol with agonist can be suitable for AMH levels less than 1. We use long protocols for stimulation when the AMH level falls between 1.5 and 2.5, which represents the average level of ovarian reserve. If the AMH level is below one, we avoid the long protocol because it may lead to excessive down-regulation of the ovaries. In such cases, we opt for other stimulation methods to promote ovarian response. The choice of the protocol depends on the number of follicles, the AMH level, and your individual response to stimulation. However, it’s important to note that the AMH level and ovarian reserve primarily determine the approach rather than the specific protocol itself.

Can we change the Prednisone and Clexane to ensure good blood coagulation during the preparation of the embryo transfer and the first three months of pregnancy? 

Prednisone and Clexane are not recommended by ESHRE for routine use in embryo transfer preparation. Prednisolone may be used for certain conditions like autoimmune thyroid issues.

Do follicles that were not retrieved during egg retrievals continue to grow after the egg retrieval if no medicine is taken? I had an ultrasound four days after the retrieval and saw numerous follicles, some measuring up to 20 millimeters. Is it possible to benefit from dual stimulation to retrieve the rest of the follicles in the next cycle?

Some follicles may continue to grow after egg retrieval, but follicles measuring 14 millimetres or less usually need hormonal stimulation to grow further. Follicles over 15–16 millimetres typically grow on their own without additional stimulation. Dual stimulation can be considered to push the growth of antral follicles, which are typically less than 10 millimetres in size.

My gyneacologist said my microbiome is 40% normal, and it should be 90%. The doctor suggested treatment of Lactobacillus probiotics for 20 days. How can I maintain a good endometrial microbiome to improve the chances of successful IVF?

The use of lactobacillus probiotics for 20 days is an option to improve the endometrial microbiome, although evidence of its effectiveness is not strong. There is no clear evidence to support specific interventions to improve the endometrial microbiome beyond probiotics.

Regarding the protocols for IVF, my AMH is less than one, and the doctor wants me to be on the contraceptive pill to prepare for the procedure. Is this a good idea?

For AMH levels less than 1, estrogen pre-treatment can be used instead of contraceptive pills to synchronize follicle growth in a short protocol with agonists.

How can I know if I need antibiotics to improve my endometrial microbiome? Are there any tests to determine this?

Testing the endometrial microbiome can determine the percentage of good and bad bacteria, as well as their sensitivity to antibiotics.

If I had a modified protocol for Frozen Embryo Transfer and had 2 failed FET, I have also failed fresh transfer. Would it be better to do the transfer after 6 days of progesterone instead of 5?

Embryo transfer is typically done on day six of progesterone, but the timing can be adjusted based on individual factors like age and embryo quality. Further testing may be required to understand why previous attempts were negative.
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Authors
Roksolana Semchyshyn, MD, PhD

Roksolana Semchyshyn, MD, PhD

Dr Roksolana Semchyshyn, MD, PhD, is a Head of IVF department at Medicover Fertility Ukraine, an experienced IVF and ultrasound diagnostics specialist. She has over 11 years of practical experience in the field of IVF. Dr. Roksolana is also a member of ESHRE (European Society of Reproductive Medicine) as well as a member of UARM (Member of the Ukrainian Association of Reproductive.
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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