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In the search for a reliable biomarker able to diagnose immunological causes of infertility, uterine immune cells have been widely investigated. As a result, heterogeneous methods and cutoff values of what constitutes an aberrant number of immune cells have been reported, and a standardized method for quantification is needed. The objective of this study was to compare methods for quantification of immune cells visualized with immunohistochemistry in the endometrium of women in fertility treatment. Evaluation of the density of CD56 + , CD16 + and CD163 + cells by conventional microscopy on a semiquantitative scale (low, medium and high) was compared to a continuous count using digital image analysis (DIA) reported as percentage positive cells out of the total number of stromal cells and number of positive cells per mm 2 , respectively. We previously reported the CD56/CD16 ratio as a possible prognostic marker, and therefore the ratios of CD56/CD16 were compared using two different methods for selecting fields for counting with DIA: one method using principles of systematic random sampling, where glands were excluded, and one method analyzing large parts of the tissue including glands. A significant association between conventional microscopy and DIA was found when the semiquantitative scale was compared to medians of positive cells in CD56, CD16 and CD163, respectively, p < 0.001. A systematic significant difference in the ratios of CD56/CD16 was found when comparing the two methods for field selection, p < 0.001. To determine the possible use of these methods, more knowledge of the correlation to clinical outcome is warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Problem: To what extent do endocrine, immunological, gene expression and histological markers of endometrial receptivity correlate?, Method of Study: Between November 2017 and September 2019, 121 women referred to a University Hospitals Fertility Clinic consented to inclusion in this cohort study. The women underwent timed endometrial biopsy followed by blood samples in a hormone-substituted cycle. Of these, 37 women had just started IVF treatment, and the remaining 84 had experienced recurrent implantation failure following IVF/ICSI. The hormone-substituted cycle consisted of initiation with oral oestradiol followed by addition of vaginal progesterone treatment for five full days. Endometrial biopsies were subject to histological examination, immune cell markers by immunohistochemistry (CD56 + , CD16 + , CD163 + , FoxP3) and gene expression microarray analyses with the endometrial receptivity array (ERA ® ) test (Igenomix). Plasma progesterone and oestradiol were measured on the day of biopsy., Results: CD56 + uterine natural killer (uNK) cell counts correlate with transcriptional markers of endometrial receptivity assessed by the ERA test. Endometrial maturation, receptivity and immunological markers were not correlated with mid-luteal blood plasma progesterone level. Mid-luteal serum oestradiol level correlated with markers of endometrial maturation and receptivity. The tests were carried out during a standard hormone substitution cycle, and the findings may not apply in the natural cycle., Conclusion: CD56 + uNK cell counts and endometrial receptivity assessed by the ERA test appear to be linked. Mid-luteal progesterone levels were not correlated to the tested markers of endometrial receptivity. In contrast, mid-luteal oestradiol level was inversely related to markers of endometrial receptivity and maturation., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Research Question: What is the prevalence of disrupted markers of endometrial function among women experiencing recurrent implantation failure (RIF), and does the prevalence differ from a control cohort?, Design: Prospective controlled cohort study. In total, 86 women with a history of RIF and 37 women starting their first fertility treatment were recruited for this study. Endometrial and blood profiling were carried out in a hormone-substituted cycle using oestradiol and progesterone. Endometrial biopsies were analysed by histology, immune cell profiling, and the endometrial receptivity array (ERA®) test (Igenomix, Valencia, Spain). The vaginal microbiome was analysed using a NGS-based technology (ArtPRED, Amsterdam, the Netherlands). Blood tests included oestradiol, progesterone, prolactin, thyroid-stimulating hormone, vitamin D and anti-phospholipid antibody levels., Results: Patients who had experienced RIF produced a range of test abnormalities. Compared with controls, women with RIF had a higher prevalence of chronic endometritis (24% versus 6%), a lower vitamin D level and a borderline lower progesterone level. Women who had experienced RIF had a more favourable vaginal microbiome compared with controls. Although the RIF cohort was older than the controls (mean age 33.8 years versus 30.2 years), no differences between the groups were observed in immune cell profiling and the ERA test., Conclusion: These data demonstrate that a single test or treatment for the endometrial factor in RIF is unlikely to be clinically effective. Diagnosing the endometrium in women with RIF permits targeted rather than blind interventions. Relative vitamin D deficiency, lower mid-luteal progesterone and chronic endometritis are ready targets for treatment. Understanding the role and treatment of an unfavourable vaginal microbiome in RIF needs further investigation., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)