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. 2025 Feb;6(1):55-64.
doi: 10.1016/j.xfss.2024.10.005. Epub 2024 Oct 16.

A positive ReceptivaDx result for BCL6 does not correlate with abnormal ERA results or decreased expression of receptivity-associated markers: two sides of the endometrial receptivity coin in fertility evaluation and treatment

David Huang  1 , Emily Flynn  2 , Ana Almonte-Loya  3 , Brittany Davidson  2 , Meagan Chan  4 , Amber Casillas  4 , Juan C Irwin  4 , Gabriela K Fragiadakis  5 , Hakan Cakmak  4 , Alexis J Combes  2 , Marcelle I Cedars  4 , Marina Sirota  6 , Linda C Giudice  4
Affiliations

A positive ReceptivaDx result for BCL6 does not correlate with abnormal ERA results or decreased expression of receptivity-associated markers: two sides of the endometrial receptivity coin in fertility evaluation and treatment

David Huang et al. F S Sci. 2025 Feb.

Abstract

Objective: To investigate if a positive result on ReceptivaDx for evaluation of B-cell lymphoma 6 (BCL6), a proposed marker of progesterone resistance associated with impaired uterine receptivity, correlates with a suboptimal profile of receptivity-associated markers in the window of implantation using the endometrial receptivity array and single-nucleus transcriptomic analysis.

Design: Retrospective clinical cohort study; pilot study of single-nucleus RNA sequencing of prospectively collected window of implantation endometrium undergoing ReceptivaDx BCL6 evaluation.

Subjects: Patients with infertility who underwent endometrial biopsy for concurrent endometrial receptivity array analysis (ERA; Igenomix, Valencia, Spain) and BCL6 immunostaining (ReceptivaDx; Cicero Diagnostics, Inc., Huntington Beach, CA).

Exposure: Positive BCL6 result on ReceptivaDx (histologic score >1.4).

Main outcome measures: Prereceptive ERA result; relative expression levels of endometrial receptivity-associated epithelial genes by single-nucleus sequencing.

Results: One hundred and seventy-two patients with concurrent ERA and ReceptivaDx evaluation were included in the analysis: 40 were BCL6-positive and 132 were BCL6-negative. One patient (2.5%) in the BCL6-positive group had a prereceptive ERA result, compared with 29 patients (22.0%) in the BCL6-negative group (P<.01). BCL6 positivity was associated with decreased odds of a prereceptive ERA result (odds ratio, 0.09; 95% confidence interval, 0.01-0.69; P=.02). Single-nucleus transcriptomic analysis of 5,718 epithelial cell nuclei from four individuals showed significant cell type-specific transcriptomic changes associated with a positive ReceptivaDx BCL6 result in both natural cycle (NC) and programmed cycle (PC) endometrium: there were 2,801 significantly differentially expressed genes comparing NC BCL6-positive with -negative, and 1,062 differentially expressed genes comparing PC BCL6-positive with -negative. Of the 34 receptivity-associated epithelial markers evaluated, 16 were significantly upregulated in NC BCL6-positive vs. -negative endometrium epithelial nuclei. In PC epithelial nuclei, 12 of the 34 receptivity-associated genes were significantly upregulated, whereas only one was significantly downregulated in BCL6-positive vs. -negative endometrium.

Conclusions: A positive ReceptivaDx BCL6 result does not correlate with a prereceptive ERA. Epithelial cells from BCL6-positive endometrium did not show significantly decreased expression in most of the receptivity markers evaluated. These findings demonstrate discordance between the interpretation of "endometrial receptivity" by ReceptivaDx and ERA, and highlight the need for further validation of endometrial evaluation methods in fertility treatment.

Keywords: BCL6; implantation failure; infertility; receptivity.

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Conflict of interest statement

Declaration of Interests D.H. receives current funding from the American Board of Obstetrics and Gynecology/American Association of Obstetricians and Gynecologists Foundation Scholar Award. E.F. reports support from University of California San Francisco (UCSF) Data Science CoLab (works in this group) for the submitted work; grants from Sjgren's International Collaborative Clinical Alliance: U01 DE028891-01A1, Eli Lilly (UCSF AutoImmunoprofiler Sponsored Research Agreement), and Precision Medicine in Rheumatology: P30AR070155-05 (supported by these three grants, but none pertained specifically to this work) outside the submitted work. A.A.-L. reports support from Bakar Computational Health Sciences Institute Biomedical Informatics Program (works in this group) for the submitted work; grants from National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development P50 HD055764 (supported by this grants but are not pertained specifically to this work) outside the submitted work. B.D. has nothing to disclose. M.C. has nothing to disclose. A.C. has nothing to disclose. J.C.I. has nothing to disclose. G.K.F. has nothing to disclose. H.C. has nothing to disclose. A.J.C. reports funding from UCSF ImmunoX and UCSF Department of Pathology for the submitted work; consulting fees from Foundery and Survey Genomics; patent for SCENITH assay; patent for the use of anti ITGB8 as tumor treatment outside the submitted work. M.I.C. reports grant funding from National Institutes of Health; honoraria for Editorial Duties from Up-to-Date; Past President—American Society of Reproductive Medicine; President Elect—American Gynecological and Obstetrical Society outside the submitted work. M.S. reports funding form National Institutes of Health for the submitted work; funding from P50 outside the submitted work. L.C.G. reports funding from National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development P50HD055764; stock Merck ∼$5K, Pfizer ∼$5K outside the submitted work.

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