Menstrual cycle distribution of uterine natural killer cells is altered in menorrhagia

Abstract

Menorrhagia affects 30% of women, is the reason for >50% hysterectomies and significantly interferes with quality of life. Altered endometrial vascular maturation is seen in menorrhagia and recurrent miscarriage, the latter with increased uterine natural killer (uNK) cells. This study compared endometrial leukocyte populations in controls and women with menorrhagia. Endometrial biopsies from controls, without endometrial pathology, and women with menorrhagia (proliferative, early-secretory, mid-secretory, late-secretory; n=5 each group) were formalin fixed and paraffin embedded. Serial sections were immunostained for CD14 (macrophages), CD56 (uNK cells), CD83 (dendritic cells) and CD8 (T cells). Leukocyte numbers were assessed as a percentage of total stromal cells in 5 randomly selected areas in each sample. Fisher's test followed by unpaired Student's t-test was used and differences were considered statistically significant at P<0.05. In controls 2-4% of total stromal cells were CD8+ T cells and 6-8% were CD14+ macrophages, with numbers remaining stable during the menstrual cycle. CD83+ dendritic cells were scarce throughout the normal menstrual cycle. 2% of the stromal cell population in proliferative endometrium were CD56+ uNK cells, increasing to a peak of 17% in the late secretory phase. In menorrhagia, CD56+ uNK cells were increased in proliferative (5%, P=0.01) and early secretory (4%, P=0.01) phases, but were reduced (10%, P<0.001) in the late secretory phase compared with controls. This study demonstrates altered uNK cells in menorrhagia, which may reflect altered endometrial expression of cytokines/growth factors affecting leukocyte recruitment and/or in situ differentiation and proliferation. The functional consequence of altered uNK cell numbers in menorrhagia may impact on endometrial vascular development and/or endometrial preparation for menstruation.