Predicting Endometrial Receptivity for Optimal Reproductive Management

Endometriosis Clinical Trial

— PERFORM  

Official title:

Predicting Endometrial Receptivity for Optimal Reproductive Management (PERFORM)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04107129
• Other study ID #: 51702
• Secondary ID: 4R44HD097750-02
• Status: Active, not recruiting
• Start date: July 1, 2020
• Est. completion date: July 30, 2024

Study information

• Verified date: July 2023
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 76
• Est. completion date: July 30, 2024
• Est. primary completion date: July 1, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 42 Years

Eligibility

Inclusion Criteria:

1. Age - 18 to 42

2. AMH = 1

3. Planning to undergo IVF with delayed embryo transfer

4. Must have blastocyst(s) by day 6 that were biopsied for PGT-A

5. BMI 18-35

Exclusion Criteria:

1. Uterine fibroids > 4 cm in size

2. Polycystic ovary syndrome (PCOS) according with the Rotterdam criteria.

3. Ovarian failure and subjects receiving donor oocytes/embryos

4. Anti-cardiolipid and/or lupus anti-coagulant abnormalities by history

5. Diabetes mellitus (Type I or Type II)

6. Untreated hypothyroidism

7. Hyperprolactinemia

8. Uncorrected uterine anomaly

Related Conditions & MeSH terms

• Endometriosis
• Infertility
• Infertility, Female

Intervention

Procedure:
• Endometrial Biopsy
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

Other:
• Euploid embryo transfer
Patients undergoing IVF and Preimplantation genetic testing will undergo delayed euploid frozen embryo transfer per clinical protocol and standard of care.

Diagnostic Test:
• Blood sample
Estradiol and Progesterone levels in the blood will be checked

Locations

Country	Name	City	State
United States	Stanford Fertility and Reproductive Health	Sunnyvale	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

References & Publications (18)

Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, Flowers JL, McCarty KS Jr. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986 Oct;46(10):5419-25. — View Citation

Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20. — View Citation

Endometriosis exerts "profound" economic burden in the US. (2007). PharmacoEconomics & Outcomes News. https://doi.org/10.2165/00151234-200705230-00025

Evans-Hoeker E, Lessey BA, Jeong JW, Savaris RF, Palomino WA, Yuan L, Schammel DP, Young SL. Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis. Reprod Sci. 2016 Sep;23(9):1234-41. doi: 10.1177/1933719116649711. Epub 2016 May 24. — View Citation

Fox C, Morin S, Jeong JW, Scott RT Jr, Lessey BA. Local and systemic factors and implantation: what is the evidence? Fertil Steril. 2016 Apr;105(4):873-84. doi: 10.1016/j.fertnstert.2016.02.018. Epub 2016 Mar 3. — View Citation

Lensen S, Osavlyuk D, Armstrong S, Stadelmann C, Hennes A, Napier E, Wilkinson J, Sadler L, Gupta D, Strandell A, Bergh C, Vigneswaran K, Teh WT, Hamoda H, Webber L, Wakeman SA, Searle L, Bhide P, McDowell S, Peeraer K, Khalaf Y, Farquhar C. A Randomized Trial of Endometrial Scratching before In Vitro Fertilization. N Engl J Med. 2019 Jan 24;380(4):325-334. doi: 10.1056/NEJMoa1808737. — View Citation

Lessey BA, Metzger DA, Haney AF, McCarty KS Jr. Immunohistochemical analysis of estrogen and progesterone receptors in endometriosis: comparison with normal endometrium during the menstrual cycle and the effect of medical therapy. Fertil Steril. 1989 Mar;51(3):409-15. doi: 10.1016/s0015-0282(16)60545-9. — View Citation

Lessey BA, Palomino WA, Apparao KB, Young SL, Lininger RA. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol. 2006;4 Suppl 1(Suppl 1):S9. doi: 10.1186/1477-7827-4-S1-S9. — View Citation

Likes CE, Cooper LJ, Efird J, Forstein DA, Miller PB, Savaris R, Lessey BA. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet. 2019 Mar;36(3):483-490. doi: 10.1007/s10815-018-1388-x. Epub 2019 Jan 4. — View Citation

Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril. 2005 Dec;84(6):1574-8. doi: 10.1016/j.fertnstert.2005.02.059. — View Citation

Meyer WR, Lessey BA, Castelbaum AJ. Hydrosalpinx and altered uterine receptivity. Fertil Steril. 1997 Nov;68(5):944-5. doi: 10.1016/s0015-0282(97)90360-5. No abstract available. — View Citation

Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998 Apr 30;17(8):857-72. doi: 10.1002/(sici)1097-0258(19980430)17:83.0.co;2-e. — View Citation

Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997 May;67(5):817-21. doi: 10.1016/s0015-0282(97)81391-x. No abstract available. — View Citation

Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8. doi: 10.1038/nprot.2008.73. — View Citation

Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, Brodszky V, Canis M, Colombo GL, DeLeire T, Falcone T, Graham B, Halis G, Horne A, Kanj O, Kjer JJ, Kristensen J, Lebovic D, Mueller M, Vigano P, Wullschleger M, D'Hooghe T. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 2012 May;27(5):1292-9. doi: 10.1093/humrep/des073. Epub 2012 Mar 14. Erratum In: Hum Reprod. 2014 Sep;29(9):2073. — View Citation

Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, Le Shay N, Nezhat CN, Kempson R, Lessey BA, Nayak NR, Giudice LC. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006 Mar;147(3):1097-121. doi: 10.1210/en.2005-1076. Epub 2005 Nov 23. — View Citation

Vitagliano A, Di Spiezio Sardo A, Saccone G, Valenti G, Sapia F, Kamath MS, Blaganje M, Andrisani A, Ambrosini G. Endometrial scratch injury for women with one or more previous failed embryo transfers: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2018 Sep;110(4):687-702.e2. doi: 10.1016/j.fertnstert.2018.04.040. — View Citation

Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP, Young SL, Jeong JW, Lessey BA. KRAS Activation and over-expression of SIRT1/BCL6 Contributes to the Pathogenesis of Endometriosis and Progesterone Resistance. Sci Rep. 2017 Jul 28;7(1):6765. doi: 10.1038/s41598-017-04577-w. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	SIRT1 gene expression in the endometrium	Endometrial biopsy specimens will be stained for SIRT1 using immunostaining and Hscore assignment.	2-3 years
Secondary	BCL6 expression in the endometrium	Endometrial biopsy specimens will be stained for BCL6 using immunostaining and Hscore assignment.	2-3 years
Secondary	Number of patients who have a positive pregnancy test (HCG level > 5) 9 days after embryo transfer	pregnancy rate	2-3 years
Secondary	Number of embryo transfers that lead to live births	live birth rate	2-3 years