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ENDOMETRIUM AND RECEPTIVITY

The endometrium is the inner layer of the uterus and is responsible for embryo implantation. It is receptive for embryo implantation for a short period, around days 19-21 in a normal menstrual cycle.

In a Hormone Replacement Therapy (HRT) treatment cycle, the receptivity is expected five days after progesterone exposure. The optimal time for endometrial receptivity and embryo hatching is called Window Of Implantation (WOI).

The WOI is displaced in approximately 30% of women. Endometrial maturation in normal and HRT treatment menstrual cycles may be individual, causing the need of personilized medicine in ART. The excact timing of WOI depends on the endometrial physiology, drug dosage and individual drug response.

A receptive endometrium is a precondition for successful embryo hatching

VALIDATION

beREADY test has been validated under clinical conditions in two independent international IVF clinics. In total, 45 HRT patients’ samples were involved in a head-to-head comparison against the leading endometrial receptivity test on the market. The concordance rate between two tests was 96%. The slight difference has two reasons. First, there is a variation in the way results are phrased- the discordant samples were worded differently, yet had identical timing recommendations according to the reports. Second, the tests use different technological platforms. beREADY applies a highly accurate TAC-seq modern sequencing technology that enables us to detect biomarker molecules at a single molecule level. The ultimate accuracy of the TAC-seq enables us to detect even the slightest differences between the studied endometrial samples.

TECHNOLOGY

The beREADY test detects 67 genes that are biomarkers of receptive endometrium. The genes are detected by patent pending and the published TAC-seq methodology that applies advanced Illumina DNA sequencing technology. The applied methodology makes endometrium biomarker profiling extremely accurate, helping detect the key molecules down to single-molecule level.

The graph on the right demonstrates the sensitivity of TAC-seq. Under controlled conditions, a set of input molecules (X-axes) with known concentration were added to the experiment, and later the same set was detected (Y-axes). The correlation was measured between input and detected molecules. Similar accuracy is ensured in every beREADY endometrial biopsy analysis, reflecting the receptivity status without distortion.

The test bases on extensive and long-term research in collaboration with research institutions and clinics. The outcome is concluded in three points:

  • Receptive endometrial biomarker genes were selected based on an original reseach and meta-analysis
  • The receptivity status of analyzed samples were confirmed by independent method in validation phase
  • Applied laboratory method was developed and published, keeping eyes the need of reliable clinical test.

Accreditation of beREADY service

The Precision Medicine Laboratory will be accredited in accordance with ISO 15189. In implementing the beREADY service, we have taken into account the ISO procedures and the current service SOPs are compliant with ISO 15189 requirements. Accreditation is in progress and due to be completed in autumn 2019. Since the method is new, we wish to use the service proving experience in ISO accreditation.

The research behind beREADY test

Krjutškov et al., Single-cell transcriptome analysis of endometrial tissue. 2016, Human Reproduction, PubMed ID 26874359

Altmäe et al., Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. 2018, Scientific Reports, PubMed ID 28855728 

Suhorutshenko et al., Endometrial receptivity revisited: endometrial transcriptome adjusted for tissue cellular heterogeneity. 2018, Human Reproduction, PubMed ID 30295736

Teder et al., TAC-seq: targeted DNA and RNA sequencing for precise biomarker molecule counting. 2018, npj Genomic Medicine, PubMed ID 30588329

Saare et al., A molecular tool for menstrual cycle phase dating in endometriosis transcriptomic studies. 2019, Biology of Reproduction, PubMed ID 31004479