Igenomix - Diagnosis of Endometrial Receptivity using ERA - Prof. Carlos Simón

Workshop Introduction

The workshop will cover endometrial receptivity analysis, including diagnostic tests and future developments. Four speakers will present on different aspects of the topic.

Learning Objectives

• Understand human endometrial receptivity

• Learn about the Endometrial Receptivity Analysis (ERA) test and its therapeutic options

• Discover the clinical impact of ERA test in specific indications such as endometriosis and obesity

• Explore non-invasive diagnostic methods in progress that are being developed for endometrial fluid

Understanding Human Endometrial Receptivity

This section covers the history of understanding human endometrial receptivity, starting with classical criteria from Noah's over 50 years ago.

History of Understanding Human Endometrial Receptivity

• The first piece of information found was classical criteria from Noah's over 50 years ago.

• In the late 50s, there were some news about embryo attachment and invasion.

Conclusion

This is a short transcript that introduces a workshop on endometrial receptivity analysis. It covers learning objectives for the workshop and provides an overview of what each speaker will discuss. Additionally, it briefly touches on the history of understanding human endometrial receptivity.

Introduction

The speaker discusses the limitations of the single molecule approach in determining endometrial receptivity and introduces the concept of gene signatures.

Single Molecule Approach Limitations

• Single molecule approach fails to produce productive results at the clinical level.

• Only progesterone receptor and estradiol receptor have been identified as clear indicators of endometrial receptivity.

• Blocking progesterone receptor leads to non-receptive endometrium, but activating it does not guarantee receptive endometrium.

• Ultrasound and other anatomical measures are helpful but not sufficient in determining receptivity.

Gene Signatures

• Microarray technology allows for a multi-molecule approach to identifying gene signatures that inform about endometrial function.

• Endometrial receptivity array was developed using this approach after 10 years of work.

Endometrial Receptivity Array

The speaker explains how the endometrial receptivity array works and its significance in determining endometrial receptivity.

Function of Endometrial Receptivity Array

• The array uses gene signature analysis to determine if the endometrium has acquired a phenotype that allows it to adhere to an embryo during implantation.

• This is crucial because implantation can only occur during a certain window of time when both receptive endometrium and viable embryo coincide.

Embryo Adhesion

The speaker discusses how embryos are able to adhere and emphasizes the importance of checking transfer catheters for attachment before implantation.

Embryo Adhesion

• Embryos are by definition able to adhere anywhere.

• Clinicians must check transfer catheters for attachment before implantation, as they can sometimes get attached to plastic.

Understanding Endometrial Receptivity

In this section, the speaker discusses the process of implantation and how the endometrium develops the capacity to be adhered by the blastocyst. The importance of the epithelial barrier in developing a window of implantation is also highlighted.

Implantation Process

• The endometrium develops a capacity to be adhered by the blastocyst during a specific moment in the menstrual cycle.

• Plasma membrane transformation occurs, which changes the phenotype of endometrial epithelium and allows for invasion to start.

• Experiments on animals have shown that embryos will not attach if placed in an epithelial monolayer, highlighting the importance of the epithelial barrier in developing a window of implantation.

Window of Implantation

• The moment where five days of progesterone or LH plus seven is considered as when the window of implantation will be ready.

• Currently, personalized medicine does not give equal treatment to all patients' embryos or semen. However, when it comes to endometrial receptivity, we transfer our embryos wherever they are ready because we cannot intervene except for giving progesterone to patients.

Endometrial Receptivity Diagnosis

• Endometrial dating has been done since 1950 but randomized studies have shown that normal morphology in luteal phase does not mean receptivity.

• Ultrasound patterns and endometrial thickness are not predictive indicators for receptivity.

New Technologies

• New technologies such as genomics, transcriptomics, and proteomics can be used to study endometrial receptivity.

• Transcriptomic markers have been shown to have a real impact in other specialties like oncology.

Introduction to Endometrial Receptivity

In this section, the speaker introduces the concept of endometrial receptivity and its importance in fertility treatment.

Understanding Endometrial Receptivity

• The ability of the endometrium to allow embryo implantation is known as endometrial receptivity.

• It is important for fertility treatments because it determines whether an embryo will successfully implant or not.

Current Diagnosis Methods

• Currently, there are no reliable methods for diagnosing endometrial receptivity.

• Endometrial dating and ultrasound patterns are not predictive indicators for receptivity.

Importance of Research

• Research on endometrial receptivity is important because it can lead to better diagnosis and treatment options for infertility.

Endometrial Receptivity Analysis

In this section, the speaker discusses the endometrial receptivity analysis (ERA) and how it is used to determine the optimal time for embryo transfer.

Gene Signature

• The ERA uses a gene signature to determine endometrial receptivity.

• This gene signature consists of 238 genes and is published in a paper from 2011.

• The ERA now uses a new technology called emitter deceptive analysis, which provides better logistics and accuracy.

Classification

• The expression of these genes is coupled with an informatic predictor in a classification system.

• This classification system gives a simple message: whether or not the endometrium is receptive yet.

• If it is not receptive, the patient needs more days of progesterone. If it is receptive, the patient can proceed with embryo transfer.

Cycle Timing

• The ERA should be done in cycles that match when the patient will transfer embryos.

• Typically, this means doing the ERA in either a natural cycle or hormonal replacement therapy cycle.

• The genomic signature used by the ERA is based on what happens in a physiologically prime endometrium.

Hormonal Treatment

• The genomic signature used by the ERA only works if the hormonal situation is consistent between cycles.

• Therefore, stimulated cycles cannot be used because they have varying levels of hormones.

Procedure

• To prime for an ERA test, patients are given six milligrams of progesterone per day for one week.

• After one week, an ultrasound is done to check the endometrial thickness. If it is sufficient, a biopsy can be taken after five days of progesterone.

Introduction

The speaker introduces the topic of molecular signature and discusses the accuracy and consistency of a test that was published in 2013.

Accuracy and Consistency of Molecular Signature Test

• The speaker compares the accuracy of the molecular signature test to two pathologists using the newest criteria.

• The Kappa value numbers are clear, with the most effective results being in the pre-receptive and post-receptive endometrium compared to pathology histology.

• The speaker discusses how they checked for consistency by analyzing donors who underwent hormonal treatment at different times, up to 40 months apart, with repeat results being consistent.

• Patients who became pregnant again after undergoing an ERA prediction were analyzed, with accumulated data showing that when a patient is receptive using this approach, it will be consistent in the future for at least 40 months.

Difficult Situations

The speaker discusses how they tested their ERA test in difficult situations such as patients with recurrent implantation failure.

Recurrent Implantation Failure

• In a prospective non-randomized study involving 80 patients with recurrent implantation failure versus 25 control patients undergoing IVF for the first time, it was found that 74% of those with implantation failure had receptive endometrium while 25% were non-receptive.

• Patients with receptive endometrium had higher implantation rates (33%) and pregnancy rates (51%) than those without.

• Patients who never became pregnant due to an endometrial factor achieved similar levels as normal population after undergoing ERA testing.

Conclusion

The speaker concludes by discussing the usefulness of ERA testing and how it can help patients achieve pregnancy.

Usefulness of ERA Testing

• Patients who underwent ERA testing were able to come back for embryo transfer at any time, with implantation and pregnancy rates being higher in those with receptive endometrium.

Personalized Embryo Transfer

In this section, the speaker discusses a diagnostic test that helps determine when to transfer an embryo regardless of the timing from biopsy to analysis. The speaker also talks about how the window of implantation can vary in patients and how personalized embryo transfer can improve pregnancy rates.

Non-Receptive Patients

• A diagnostic test helps determine when to transfer an embryo regardless of the timing from biopsy to analysis.

• Majority of non-receptive patients become receptive again (84%).

• Window of implantation can vary in patients, with some having a narrow window due to uterine abnormalities.

• Personalized embryo transfer improves pregnancy rates by transferring embryos at the right moment.

Case Study

• A patient with two failed cycles underwent personalized embryo transfer using two day five blastocysts and had a successful twin pregnancy.

• Seventeen patients undergoing organ donation had lousy implantation and pregnancy rates until they underwent personalized embryo transfer.

Overall, personalized embryo transfer can improve pregnancy rates by determining the optimal time for transferring embryos based on individual factors such as uterine abnormalities and receptivity.

Personalized Embryo Transfer

In this section, the speaker discusses personalized embryo transfer as a treatment and emphasizes the importance of a personalized medicine approach. The window of implantation is also discussed.

Importance of Personalized Medicine Approach

• Personalized embryo transfer is used as a treatment because every patient is different and requires a personalized medicine approach.

• The window of implantation can go from three days of progesterone up to seven days of progesterone or LH perspective, but it's not about what is the best day; it's about what is the best day for your patient.

Timing Matters

• Timing matters more than the route or dosage when it comes to giving progesterone.

• If a premature elevation of progesterone occurs during a fresh cycle, embryos should be frozen instead of transferred to avoid decreasing implantation rates.

Receptive vs Non-Receptive Patients

• More than 8,000 patients have been analyzed with 30% being non-receptive and 70% being receptive.

• Pre-receptive patients need more days of progesterone while receptive patients need less.

• In difficult cases, doctors should double-check if patients are pre-receptive by adding 8 plus 7 mm.

Narrow Windows in Difficult Patients

This section focuses on narrow windows in difficult patients and how they can be identified.

Identifying Narrow Windows

• Narrow windows have been identified in some difficult cases where transfers must occur within 12 hours.

• In 5% of cases, a narrow window is present, and doctors should double-check to avoid problems with repetition.

Test Usefulness in Difficult Patients

This section discusses the usefulness of tests in difficult patients.

Exploring Test Usefulness

• The speaker wants to explore whether tests could be useful in difficult patients.

Introduction to IBF Patient Cycle

In this section, the speaker introduces the first IBF patient cycle and explains the inclusion criteria for patients.

Inclusion Criteria

• Patients must be under 38 years old.

• Patients must have an end body vaccine.

• Patients can go through a fresh embryo transfer or a frozen embryo transfer.

Personalized Embryo Transfer

The speaker discusses personalized embryo transfer and how it is done.

Frozen Embryo Transfer

• A frozen embryo transfer is done.

• The ERA test is conducted to determine when to transfer embryos.

• Embryos are transferred accordingly.

Ongoing Research

• Personalized embryo transfer is ongoing in many groups worldwide.

• A randomized study is underway to determine if ERA will be cost-effective as the first diagnostic line for endometrial factor.

Endometrial Receptivity Analysis (ERA)

The speaker talks about ERA and its significance in determining the best day for embryo transfer.

Endometrial Factor

• Endometrial factor is responsible for at least one in four patients with implantation failure.

• Transcriptomics signature of endometrial receptivity using ERA test reveals endometrial factor.

Personalized Embryo Transfer Results

• Personalized embryo transfer normalizes clinical results.

Future of ERA Test

• The test has some problems, including invasiveness and timing issues.

• Work is being done to make it non-invasive and able to be done 24 hours before embryo transfer.

Conclusion and Acknowledgments

The speaker concludes by discussing future work on ERA and acknowledging the team behind it.

Future Work

• The speaker hopes that in two years, they will have made significant progress on ERA.

• The goal is to make the test non-invasive and able to be done 24 hours before embryo transfer.

Acknowledgments

• The work on ERA is a result of a huge lab at the basic level.

• A biotech company has been created to translate and give products to colleagues and patients.

• The company has received funding from an EU grant.