Predicting Endometrial Receptivity for Optimal Reproductive Management

Study Overview
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Brief Summary
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The purpose of this study is to understand why some women are infertile (unable to conceive a child). The investigators hope to learn if an endometrial biopsy after egg retrieval is feasible for detecting biomarkers for endometriosis and predicting implantation and pregnancy rate after embryo transfer. This study design will provide for the first time, an opportunity to compare endometrial biopsy material from hyperstimulated (gonadotropin treated) subjects after egg retrieval. If successful, it would provide a new protocol for women with unexplained infertility or those with known endometriosis to avoid poor IVF outcomes.

Detailed Description
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The investigators will recruit 100 women who are undergoing IVF with egg retrieval and delayed embryo transfer to consent to endometrial biopsy 1 week after egg retrieval. Currently most women in the Stanford's IVF program undergo egg retrieval with delayed embryo transfer (ET) with preimplantation genetic testing of embryos. This delay allows most to avoid the condition known as ovarian hyperstimulation and allows time for genetic screening (PGT-A) performed on embryos. Such a delay also opens the window for endometrial assessment for proteins like SIRT1 and BCL6 that have been suggested to be associated with endometriosis. Endometriosis is thought to cause IVF failure (Littman et al., 2002); by treating endometriosis in the future, clinicians might avoid IVF failure due to an unexpected non-receptive endometrium (Littman et al., 2002). This study design will provide for the first time, an opportunity to compare endometrial biopsy material from hyperstimulated (gonadotropin treated) subjects after egg retrieval. If successful, it would provide a new protocol for women with unexplained infertility or those with known endometriosis to avoid poor IVF outcomes. There is some evidence that endometrial scratching (biopsy) may enhance embryo attachment in future cycles (Vitagliano et al., 2018), although not all studies agree (Lensen et al., 2019). The endometrial biopsy taken in the secretory phase will be tested for BCL6 and SIRT1 expression, two proteins highly associated with the presence of endometriosis (Yoo et al., 2017). The samples of endometrium will be processed (put into formalin and paraffin blocks or saved in RNA later and not be analyzed until after completion of the ART cycle. Patients as well as the clinicians will be blinded to results and until the conclusion of the ART cycle following embryo transfer and subsequent pregnancy testing. This will be done to avoid interfering with the current ART cycle and to avoid the introduction of bias. Patients will be provided with test results after completion of the first embryo transfer if they wish to know.

Official Title
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Predicting Endometrial Receptivity for Optimal Reproductive Management (PERFORM)

Conditions
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Infertility, Female, Endometriosis

Intervention / Treatment
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* Procedure: Endometrial Biopsy
* Other: Euploid embryo transfer
* Diagnostic Test: Blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age - 18 to 42 AMH ≥ 1 Planning to undergo IVF with delayed embryo transfer Must have blastocyst(s) by day 6 that were biopsied for PGT-A BMI 18-35 Exclusion Criteria: Uterine fibroids > 4 cm in size Polycystic ovary syndrome (PCOS) according with the Rotterdam criteria. Ovarian failure and subjects receiving donor oocytes/embryos Anti-cardiolipid and/or lupus anti-coagulant abnormalities by history Diabetes mellitus (Type I or Type II) Untreated hypothyroidism Hyperprolactinemia Uncorrected uterine anomaly

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 42 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Known Endometriosis<br>Known Endometriosis undergoing IVF with PGTA | Procedure: Endometrial Biopsy<br>* An endometrial biopsy is the removal of a small piece of tissue from the endometrium, which is the lining of the uterus. Endometrial tissue will be tested for BCL6 and SIRT1 Biomarkers<br>Other: Euploid embryo transfer<br>* Patients undergoing IVF and Preimplantation genetic testing will undergo delayed euploid frozen embryo transfer per clinical protocol and standard of care.<br>Diagnostic Test: Blood sample<br>* Estradiol and Progesterone levels in the blood will be checked<br>|
| Unexplained Infertility<br>Unexplained Infertility undergoing IVF with PGTA | Procedure: Endometrial Biopsy<br>* An endometrial biopsy is the removal of a small piece of tissue from the endometrium, which is the lining of the uterus. Endometrial tissue will be tested for BCL6 and SIRT1 Biomarkers<br>Other: Euploid embryo transfer<br>* Patients undergoing IVF and Preimplantation genetic testing will undergo delayed euploid frozen embryo transfer per clinical protocol and standard of care.<br>Diagnostic Test: Blood sample<br>* Estradiol and Progesterone levels in the blood will be checked<br>|
| Low Risk Controls<br>Low Risk Controls undergoing IVF with PGTA | Procedure: Endometrial Biopsy<br>* An endometrial biopsy is the removal of a small piece of tissue from the endometrium, which is the lining of the uterus. Endometrial tissue will be tested for BCL6 and SIRT1 Biomarkers<br>Other: Euploid embryo transfer<br>* Patients undergoing IVF and Preimplantation genetic testing will undergo delayed euploid frozen embryo transfer per clinical protocol and standard of care.<br>Diagnostic Test: Blood sample<br>* Estradiol and Progesterone levels in the blood will be checked<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SIRT1 gene expression in the endometrium | Endometrial biopsy specimens will be stained for SIRT1 using immunostaining and Hscore assignment. | 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BCL6 expression in the endometrium | Endometrial biopsy specimens will be stained for BCL6 using immunostaining and Hscore assignment. | 2-3 years | 
| Number of patients who have a positive pregnancy test (HCG level > 5) 9 days after embryo transfer | pregnancy rate | 2-3 years | 
| Number of embryo transfers that lead to live births | live birth rate | 2-3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infertility, Endometriosis, BLC6, SIRT1, In Vitro Fertilization (IVF), Embryo Transfer (ET), Frozen Embryo Transfer (FET), Assisted Reproductive Technology (ART), PERFORM