Elevated Periimplantation Uterine Natural Killer Cell Density in Human Endometrium Is Associated With Impaired Corticosteroid Signaling in Decidualizing Stromal Cells

Abstract

Background:Decidualizing human endometrial stromal cells (HESCs) profoundly up-regulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), the enzyme that converts inert cortisone to active cortisol. We postulated that the induction of a cortisol gradient upon decidualization of the periimplantation endometrium may impact on the uterine natural killer (uNK) cell population and on local expression of corticosteroid-dependent target genes.Methods:Midluteal endometrial biopsies (n = 55) were processed for uNK cell (CD56) analysis and primary HESC cultures. The cultures remained either untreated or were decidualized for 4 or 8 days. A tissue microarray was constructed from endometria with normal (n = 18) and elevated uNK cell (n = 18) scores. An abnormal uNK cell test was defined as greater than 5% CD56+ cells in the subluminal stroma.Results:Increased uNK cell density was associated with lower endometrial expression of 11βHSD1 and mineralocorticoid receptor (MR) but not glucocorticoid receptor in vivo. Elevated uNK cell density also corresponded to impaired induction of key decidual markers (11βHSD1, prolactin, and insulin-like growth factor binding protein-1) and MR-dependent enzymes (dehydrogenase/reductase member 3 and retinol saturase) in differentiating HESC cultures. Increased uNK cell density in vivo was not associated with increased in vitro expression of either IL-15 or IL-11, two cytokines implicated in uNK cell regulation.Conclusions:Elevated levels of uNK cells in the stroma underlying the surface epithelium are associated with inadequate cortisol biosynthesis by resident decidualizing cells and suboptimal induction of key MR-dependent enzymes involved in lipid biogenesis and the retinoid transport pathway. Our observations suggest that uNK cell testing identifies those women at risk of reproductive failure due to relative uterine cortisol deficiency.

Uterine NK cells: active regulators at the maternal-fetal interface

“…More recently, commercial tests for quantifying numbers of eNK cells in the luteal phase have been introduced, and steroid therapy is prescribed to those women with "high" levels (97,103,104). How numbers of mucosal NK cells might relate to their functions is not clear, particularly as there is a day-to-day increase during the luteal phase due to uNK cell proliferation.…”

Recurrent pregnancy loss is associated with a pro-senescent decidual response during the peri-implantation window

“…Approximately 15% of clinical pregnancies result in miscarriage 1 , most often during the first 37 trimester. Fetal chromosomal abnormalities account for 50-60% of sporadic miscarriages 2 , 38 although the incidence is lower in recurrent pregnancy loss (RPL) 3,4 , defined as two or more 39 losses 5,6 . Further, with each additional miscarriage, the frequency of euploid loss increases 40 whereas the likelihood of a successful pregnancy decreases 7 , indicating that uterine factors 41 drive higher-order miscarriages.…”

Natural killer cells and reproductive health

“…That 57% of women with three or more consecutive miscarriages involved in the study did not have an elevated uNK cell count demonstrates the complex nature of assessing the role of uNK cells in patients with RM. 34 Kuroda et al 16 demonstrated a difference in glucocorticoid signalling in patients with RM, and a higher proportion of uNK cells close to the luminal epithelium. uNK cells are normally found in surrounding perivascular cells and glands in the endometrial stroma.…”

“…Instead, the actions of progesterone on uNK cells are mediated via the glucocorticoid receptor (GR) . Progesterone enhances the expression and activity of 11BHSD type 1 in decidualising human endometrial stromal cells, thus increasing the conversion of cortisone to cortisol . Cortisol has a direct effect on the preparation of epithelial endometrial cells for implantation .…”