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

Cover Page

Cite item

Full Text

Abstract

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.

About the authors

Yulia E. Dobrokhotova

N. Pirogov Russian National Research Medical University

Email: pr.dobrohotova@mail.ru
ORCID iD: 0000-0002-7830-2290

PhD, MD (Medicine), Professor, Head, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

Sabina E. Safarli

N. Pirogov Russian National Research Medical University

Author for correspondence.
Email: sabina.safarli000@gmail.com
ORCID iD: 0009-0001-7966-7486
SPIN-code: 6041-2203
Scopus Author ID: 59394037300

Obstetrician-Gynecologist, Postgraduate Student, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

Irina Yu. Ilyina

N. Pirogov Russian National Research Medical University

Email: iliyina@mail.ru
ORCID iD: 0000-0001-8155-8775

PhD, MD (Medicine), Professor, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

Metanat R. Narimanova

N. Pirogov Russian National Research Medical University

Email: safarovametanat@yandex.ru
ORCID iD: 0000-0003-0677-2952

PhD (Medicine), Associate Professor, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

Igor I. Grishin

N. Pirogov Russian National Research Medical University; N. Pirogov City Clinical Hospital No. 1

Email: igrishin.md@gmail.com
ORCID iD: 0000-0001-5839-1858

PhD, MD (Medicine), Professor, Department of Obstetrics and Gynecology, Institute of Surgery, N. Pirogov Russian National Research Medical University; Obstetrician-Gynecologist, N. Pirogov City Clinical Hospital No. 1

Russian Federation, Moscow; Moscow

Alexander P. Raksha

N. Pirogov Russian National Research Medical University; N. Pirogov City Clinical Hospital No. 1

Email: rakshadoc@yandex.ru
ORCID iD: 0009-0005-7897-5179

PhD, MD (Medicine), Professor, Department of Pathological Anatomy and Clinical Pathological Anatomy, N. Pirogov Russian National Research Medical University; Head, Pathology Department, N. Pirogov City Clinical Hospital No. 1

Russian Federation, Moscow; Moscow

Ekaterina V. Scherbak

N. Pirogov City Clinical Hospital No. 1

Email: scherbakev2@zdrav.mos.ru
ORCID iD: 0009-0006-0346-4523

Pathologist

Russian Federation, Moscow

Milana D. Kazieva

N. Pirogov Russian National Research Medical University

Email: mila1705@bk.ru
ORCID iD: 0009-0004-2567-6215

Assistant Professor, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

Amina Yu. Azimova

N. Pirogov Russian National Research Medical University

Email: aminayous@mail.ru
ORCID iD: 0000-0001-8528-9648

Obstetrician-Gynecologist, Senior Laboratory Assistant, Department of Obstetrics and Gynecology, Institute of Surgery

Russian Federation, Moscow

References

  1. Доброхотова Ю.Э., Ильина И.Ю., Сафарли С.Э. Аномальные маточные кровотечения и кровотечения в по стменопаузе на фоне приема менопаузальной гормональной терапии: современные данные // РМЖ. Мать и дитя, 2024. Т. 7, № 3. С. 241-247. [Dobrokhotova Yu.E., Il’ina I.Yu., Safarli S.E. Abnormal uterine bleeding and postmenopausal bleeding with menopausal hormone therapy: current evidence. RMZh. Mat i ditya = Russian Journal of Woman and Child Health, 2024, Vol. 7, no. 3, pp. 241-247. (In Russ.)]
  2. Зайдиева Я.З., Казанцева В.Д. Сравнительный анализ распространенности аномальных маточных кровотечений у женщин в постменопаузе на фоне различной менопаузальной гормональной терапии (систематический обзор) // Российский вестник акушера-гинеколога, 2021. Т. 21, № 6. С. 51-58. [Zaidieva Ya.Z., Kazantseva V.D. Comparative analysis of the prevalence of abnormal uterine bleeding in postmenopausal women against the background of various menopausal hormone therapy (systematic review). Rossiyskiy vestnik akushera-ginekologa = Russian Bulletin of Obstetrician-Gynecologist, 2021, Vol. 21, no. 6, pp. 51-58. (In Russ.)]
  3. Arbuckle R., Humphrey L., Abraham L., Dennerstein L., Simon J.A., Mirkin S., Bonner N., Walmsley S., Tatlock S., Symonds T. Qualitative cross-cultural exploration of vaginal bleeding/spotting symptoms and impacts associated with hormone therapy in post-menopausal women to inform the development of new patient-reported measurement tools. Maturitas, 2014, Vol. 78, no. 3, pp. 219-227.
  4. Archer D.F. Endometrial bleeding during hormone therapy: the effect of progestogens. Maturitas, 2007. Vol. 57, no. 1, pp. 71-76.
  5. Carugno J. Clinical management of vaginal bleeding in postmenopausal women. Climacteric, 2020, Vol. 23, no. 4, pp. 343-349.
  6. Critchley H.O.D., Maybin J.A., Armstrong G.M., Williams AR.W. Physiology of the endometrium and regulation of menstruation. Physiol. Rev., 2020, Vol. 100, no. 3, pp. 1149-1179.
  7. Dudley A.C., Griffioen A.W. Pathological angiogenesis: mechanisms and therapeutic strategies. Angiogenesis, 2023, Vol. 26, no. 3, pp. 313-347.
  8. Gasteiger G., Hemmers S., Firth M.A., Le Floc’h A., Huse M., Sun J.C., Rudensky A.Y. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med,. 2013, Vol. 210, no. 6, pp. 1167-1178.
  9. Gu Y., Han F., Xue M., Wang M., Huang Y. The benefits and risks of menopause hormone therapy for the cardiovascular system in postmenopausal women: a systematic review and meta-analysis. BMC Womens Health, 2024, Vol. 24, no. 1, 60. doi: 10.1186/s12905-023-02788-0.
  10. Hapangama D.K., Bulmer J.N. Pathophysiology of heavy menstrual bleeding. Womens Health, 2016, Vol. 12, no. 1, pp. 3-13.
  11. Hickey M., Ameratunga D., Marino J.L. Unscheduled bleeding in continuous combined hormone therapy users. Maturitas, 2011, Vol. 70, no. 4, pp. 400-403.
  12. Hickey M., Crewe J., Goodridge J.P., Witt C.S., Fraser I.S., Doherty D., Christiansen F.T., Salamonsen L.A. Menopausal hormone therapy and irregular endometrial bleeding: a potential role for uterine natural killer cells? J. Clin. Endocrinol. Metab., 2005, Vol. 90, no. 10, pp. 5528-5535.
  13. Kolatt T.S., Shufaro Y., Mashiach S., Czernobilsky B., Aviel-Ronen S., Apel-Sarid L., Dahan M., Or Y. Revealing the uterine blood vessel network via virtual pathology. Reprod. Fertil., 2023, Vol. 4, no. 1, e220135. doi: 10.1530/RAF-22-0135.
  14. Li T., Li R.H.W., Ng E.H.Y., Yeung W.S.B., Chiu P.C.N., Chan R.W.S. Interleukin 6 at menstruation promotes the proliferation and self-renewal of endometrial mesenchymal stromal/stem cells through the WNT/β-catenin signaling pathway. Front. Immunol., 2024, Vol. 15, 1378863. doi: 10.3389/fimmu.2024.1378863.
  15. Marjoribanks J., Farquhar C., Roberts H., Lethaby A., Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst. Rev., 2017, Vol. 1, no. 1, CD004143. doi: 10.1002/14651858.CD004143.pub5.
  16. Middelkoop M.A., Don E.E., Hehenkamp WJ.K., Polman N.J., Griffioen A.W., Huirne J.A.F. Angiogenesis in abnormal uterine bleeding: a narrative review. Hum. Reprod. Update, 2023, Vol. 29, no. 4, pp. 457-485.
  17. Sriprasert I., Beydoun H., Barnabei V., Nassir R., La Croix A.Z., Archer D.F. Incidence of endometrial spotting or bleeding during continuous-combined estrogen-progestin therapy in postmenopausal women with and without hypertension. Menopause, 2015, Vol. 22, no. 10, pp. 1067-1075.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2026 Dobrokhotova Y.E., Safarli S.E., Ilyina I.Y., Narimanova M.R., Grishin I.I., Raksha A.P., Scherbak E.V., Kazieva M.D., Azimova A.Y.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).