Individual dynamics of uterine natural killer cells in natural and stimulated cycles monitored using a new endometrial dating method

Joachim Alfer, Amir Fattahi, Nathalie Bleisinger, Sophia Antoniadis, Jürgen Krieg, Ralf Dittrich, Matthias W. Beckmann, Arndt Hartmann, Roxana M. Popovici, Kelton Tremellen

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Problem: It is important to evaluate the dynamics of uterine natural killer (uNK) cells in hormone replacement therapy (HRT) cycles, given their potential role in implantation and the common usage of HRT cycles with in vitro fertilization (IVF). 

Method of study: A total of 132 subfertile patients were evaluated during the secretory phase of either natural ovulation (OV) or HRT cycles, with two biopsies taken on approximately days 5 and 10 after ovulation/progesterone administration in a single menstrual cycle. Immunohistochemical Personal Endometrial Maturation Analysis (PEMA) was used to better quantify secretory-phase endometrial development, in combination with subsequent evaluation of uNK cell density. 

Results: uNK cell density increased rapidly from the early to mid-secretory phase, with mean uNK densities of 113 and 117 per mm2 in first biopsies and 315 and 387 per mm2 in second biopsies for OV and HRT cycles, respectively. After reassessment of endometrial development with PEMA, the first and second biopsies in HRT and OV cycles were histologically dated to developmental ranges between days 15–20 (first biopsy) and days 19–25 (second biopsy). 

Conclusion: Subfertile women showed variable endometrial development in PEMA assessment, with uNK cell density correlating with the dating results. Overall, comparable levels of uNK cell density were observed in OV and HRT cycles. Importantly, uNK cell density depends on the histological maturation stage, with similar low coefficients of determination. This observation suggests that aberrant uNK cell results more likely reflect displaced endometrial maturation, rather than an intrinsic anomaly in uNK cell trafficking.

Original languageEnglish
Article numbere13620
Number of pages8
JournalAmerican Journal of Reproductive Immunology
Issue number5
Early online date23 Sept 2022
Publication statusPublished - Nov 2022


  • CD56
  • dating
  • endometrium
  • reproduction
  • subfertile
  • uNK cells


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