If you have had implantation failure, we can help you
1. ERA: Endometrial Receptivity Analysis. What is it?
The ERA Endometrial Receptivity Analysis is a state-of-the-art diagnostic method that has been developed and patented in 2009 by IGENOMIX after over 10 years of research. This technique helps evaluate the woman’s endometrial receptivity from a molecular perspective.
The lack of synchronisation between the embryo ready to be implanted and endometrial receptivity is one of the causes of recurring implantation failure. This is why it is imperative to assess the endometrium in order to determine the optimal day for embryo transfer.
The ERA test requires an endometrial biopsy that should be carried out on day LH+7 (natural cycle) or day P+5 (HRT cycle). This biopsy is quickly and easily taken by a gynaecologist in their consultation room. After being sent away, the sequencing expression of 236 genes involved in the endometrial receptivity is analysed. An in-house designed computational predictor analyses the data obtained, classifying the endometrium as Receptive or Non-Receptive.
The ERA Endometrial Receptivity Analysis is a personalized genetic test to diagnose the state of endometrial receptivity in the window of implantation.
This molecular diagnostic tool is used to analyze the expression levels of 236 genes linked to the status of endometrial receptivity, using RNA sequencing taken from the endometrial tissue. Following the analysis, a specific computational predictor classifies the samples according to their expression profile as Receptive or Non-Receptive. The Endometrial Receptivity Anaysis (ERA®) has been designed, developed and patented by IGENOMIX (PCT/ES2009/000386).
2. What is the Endometrial Receptivity Analysis used for?
The analysis reveals the personalised window of implantation of each woman. This data will enable a personalised embryo transfer (pET), synchronising endometrial receptivity with a blastocyst prepared for implantation.
The results from the analysis will determine if the woman was receptive or not at the time of sampling. If she is receptive, this implies that her window of implantation falls on the day of the cycle during which the biopsy was performed and the embryo could therefore be transferred to the uterus during this period.
A non-receptive status may imply a displaced window of implantation. The procedure will be performed once again according to the computational predictor, which will provide an estimate of the woman’s personalised window of implantation. This will facilitate the successful implantation of the embryo in a subsequent cycle with what is known as personalised Embryo Transfer (pET).
3. Who is the ERA Endometrial Receptivity Analysis for?
This test has been performed on patients who have had recurring implantation failure with embryos of good morphological quality. This test is recommended for patients with seemingly normal uterus and normal endometrial thickness (≤6 mm), in which no problems are detected.
The ERA test can also be performed in patients with an atrophic endometrium, whose thickness never reaches 6 mm consistently. However, if a patient with normal endometrial thickness presents a punctual cycle with growth below 6mm we recommend canceling the cycle and starting a new one.
A displaced window of implantation is detected in approximately 25% of these patients.
This analysis helps determine the personalised window of implantation, enabling personalized embryo transfer (pET) to be performed on the basis of these results.
This ERA test must be recommended by a gynaecologist and the result will be sent to the doctor. Under no circumstances will the result be sent to the patient. The doctor will be responsible for sending the report to the patient.
4. What technology is used with ERA?
The ERA test is performed with Next Generation Sequencing technology. The change in technology used in ERA, from Arrays to NGS, not only increases the sampling capacity to be processed, but it also implies the development of a new and improved predictor, which will allow us to enhance the effectiveness of the diagnosis and to add other additional tests.
The data obtained from analysing more than 12,000 samples with ERA was used to develop this new predictor. This enables us to define more clearly each one of the endometrial profiles and their subcategories in relation to the clinical objective of pregnancy and the birth of a child.
Meanwhile, the degree of flexibility in the analyses with NGS technology is a lot higher. This enables the addition of extra tests, such as the endometrial microbiome, which will soon be performed on the same sample, in turn supplementing and improving the data obtained from the ERA test.
5. What are the advantages of the ERA Endometrial Receptivity Analysis?
As an endometrial receptivity diagnostic method, the ERA determines the personalized window of implantation of each patient before she begins an assisted reproductive treatment.
The ERA test has proven highly sensitive and accurate in detecting gene expression profiles associated with receptivity.
Other endometrial status dating methods are based on histological criteria. However, these methods show a high degree of subjectivity and do not differentiate between slight yet significant molecular changes in the acquisition of the receptive phenotype.
1. In which kind of cycle could the ERA test be performed?
The ERA Endometrial receptivity analysis should be performed during a HRT cycle or natural cycle. The receptivity diagnosis is valid just for the type of cycle during which the test is performed, therefore, the embryo transfer must be carried out in the same kind of cycle with which the receptive result is obtained.
2. How is the endometrial biopsy taken?
The biopsy of the uterine fundus is performed following a standard procedure with a Pipelle catheter or similar. About 70 milligrams of tissue are enough. For illustration purposes, this equates to a cube with sides measuring 7 millimetres. Once the endometrial biopsy is taken, the tissue must be inserted into the ERA cryotube. Under no circumstances should the tissue volume exceed 1/3 of the total volume of the cryotube so as to ensure successful preservation.
3. How is the timing of the endometrial biopsy calculated?
If it is determined in urine or serum, the LH surge is considered as LH+0. The endometrial biopsy is taken at LH+7 (approx. 168 hours). If the ovulation is determined by ultrasound, the day of ovulation is taken as Ov+0. The endometrial biopsy is taken six days later at Ov+6 (approx. 144 hours).
Hormone Replacement Therapy cycle
Upon starting the HRT cycle, the endometrial biopsy is taken after five full days of progesterone exposure (approx. 120 hours). The day in which progesterone treatment begins is considered as P+0 and the biopsy is taken at P+5.
In this type of cycle it is important to check that the progesterone level in blood is <1ng/ml before starting the progesterone intake.
4. How is ovulation detected in a natural cycle?
The time of ovulation in natural cycles can be measured using LH urine test strips, by direct measurement of LH in blood serum, or by monitoring follicle rupture by ultrasound.
5. Which is the strategy to follow according to the ERA result obtained?
An endometrial biopsy is taken during a natural cycle or a HRT cycle to perform the ERA test.
If the patient has frozen eggs or embryos, or has fresh eggs or embryos from a donor, these may be transferred in the same type (natural or HRT) and day of cycle in which the ERA test was performed and a receptive result was obtained.
If the patient does NOT have frozen eggs or embryos and wants to use their own eggs, a cycle of ovarian stimulation for egg or embryo cryopreservation will be performed. Embryo transfer will be performed in a subsequent cycle of the same type (natural or HRT) and on the same day in which a receptive ERA test result was obtained.
Result: Result: “Non-Receptive” with a recommendation of a new window of implantation
If the result of the first ERA test is non-receptive and the expression profile analysis suggests that the window of implantation may be displaced, it is necessary to validate the new window with a second ERA test.
Where there is a displaced window of implantation that has been validated with a second ERA, the thawing of eggs or embryos and their transfer must be scheduled to coincide with the specific day for which the woman’s receptive result has been obtained.
7. Other scientific documents
Endometrial receptivity array: Clinical application.
J Hum Reprod Sci.2015 Jul-Sep;8(3):121-9. doi: 10.4103/0974-1208.165153. PMID: 26538853 [PubMed] PMCID: PMC4601169. [Epub ahead of print]
Human Endometrial Transcriptomics: Implications for Embryonic Implantation.
Gómez E, Ruíz-Alonso M, Miravet J, Simón C.
Cold Spring Harb Perspect Med. 2015 Mar 27. pii: a022996. doi: 10.1101/cshperspect.a022996. [Epub ahead of print]
The genomics of the human endometrium.
Ruiz-Alonso M, Blesa D, Simón C.
Biochim Biophys Acta. 2012 Dec;1822(12):1931-42.
Profiling the gene signature of endometrial receptivity: clinical results.
Garrido-Gómez T, Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Vilella F, Simón C.
Fertil Steril. 2013 Mar 15;99(4):1078-85.
Impact of final oocyte maturation using gonadotropin-releasing hormone agonist triggering and different luteal support protocols on endometrial gene expression.
Bermejo A, Cerrillo M, Ruiz-Alonso M, Blesa D, Simón C, Pellicer A, Garcia-Velasco JA.
Fertil Steril. 2014 Jan;101(1):138-146.e3.
The impact of using the combined oral contraceptive pill for cycle scheduling on gene expression related to endometrial receptivity.
Bermejo A, Iglesias C, Ruiz-Alonso M, Blesa D, Simón C, Pellicer A, García-Velasco J.
Hum Reprod. 2014 Jun;29(6):1271-8. doi: 10.1093/humrep/deu065. Epub 2014 Apr 4.
Clinical management of endometrial receptivity.
Blesa D, Ruiz-Alonso M, Simón C.
Semin Reprod Med. 2014 Sep;32(5):410-3. doi: 10.1055/s-0034-1376360. Epub 2014 Jun 24.
Transcriptomics of the human endometrium.
Díaz-Gimeno P, Ruíz-Alonso M, Blesa D, Simón C.
Int J Dev Biol. 2014;58(2-4):127-37. doi: 10.1387/ijdb.130340pd.
Timing the window of implantation by nucleolar channel system prevalence matches the accuracy of the endometrial receptivity analysis.
Nejat EJ, Ruiz-Alonso M, Simón C, Meier UT.
Fertil Steril. 2014 Sep 17. pii: S0015-0282(14)02025-1. doi: 10.1016/j.fertnstert.2014.07.1254.
Deciphering the proteomic signature of human endometrial receptivity
Hum Reprod. 2014 Sep;29(9):1957-67. doi: 10.1093/humrep/deu171. Epub 2014 Aug 8