The role of uNK сells in pathogenesis of abnormal uterine bleeding in women receiving menopausal hormone therapy

Abnormal uterine bleeding (AUB) is frequently observed during menopausal hormone therapy (MHT), thus significantly impairing the quality of life of postmenopausal women and reducing their adherence to treatment. In most cases, AUB associated with MHT is not linked to pathological changes of endometrium. Of note, the role of uterine natural killer (uNK) cells in this process remains unexplored. Our objective was to evaluate the role of uNK cells in pathogenesis of AUB in women receiving MHT. A randomized controlled trial was conducted at the N. Pirogov City Clinical Hospital No. 1 from November 2022 to October 2024, involving 75 postmenopausal women. The participants were divided into three groups: women receiving MHT with AUB (n = 27); females receiving MHT without AUB (n = 25), and postmenopausal women not receiving MHT (n = 23). To perform immunohistochemical analysis and flow cytometry, endometrial samples obtained via pipelle biopsy were examined in a control group (not receiving MHT), and in the study group before MHT initiation, after 6 months of MHT treatment, and during AUB episodes. Women with AUB during MHT exhibited a statistically significant increase in uNK cells in endometrial samples compared to those without AUB (CD3-/CD16+/CD56+: 1.7 (1.46-1.85) vs. 0.66 (0.5-0.79), p 0.001). Immunohistochemical analysis revealed an increased density of CD56+ cells in endometrial stroma of patients with AUB during MHT. These findings confirm a role of uNK cells in pathogenesis of AUB in women receiving MHT. Further research may contribute to the development of new approaches for prevention and treatment of AUB by means of modulating the uNK cell activity.