Endometrial cytokine profile in abnormal uterine bleeding among women on menopausal hormone therapy: data on interleukin-2, -6, and -15

Background. Abnormal uterine bleeding is one of the most common reasons for discontinuation of menopausal hormone therapy. However, in a significant number of cases, abnormal uterine bleeding occurs without identifiable organic causes, suggesting the involvement of functional and immunological mechanisms, including alterations in the cytokine profile of the endometrium. Particular attention is given to interleukins IL-2, IL-6, and IL-15, which play a pivotal role in regulating the innate immune response of the endometrial mucosa.

Objective. To assess the levels of interleukins IL-2, IL-6, and IL-15 in the endometrial environment of postmenopausal women receiving menopausal hormone therapy, and to evaluate their potential association with the development of abnormal uterine bleeding.

Materials and methods. A randomized controlled study was conducted involving 106 postmenopausal women. The main group (n = 72) received continuous combined menopausal hormone therapy (estradiol 1 mg + dydrogesterone 5 mg), while the control group (n = 34) did not receive hormone therapy. Levels of IL-2, IL-6, and IL-15 in uterine aspirates were measured using enzyme-linked immunosorbent assay (ELISA) prior to treatment, after 6 months of menopausal hormone therapy, and during episodes of abnormal uterine bleeding.

Results. Levels of IL-2 and IL-6 did not show statistically significant changes either after 6 months of menopausal hormone therapy or in relation to the presence of AUB. In contrast, IL-15 levels increased significantly after 6 months of therapy (p < 0.001) in both women with and without abnormal uterine bleeding. Moreover, IL-15 concentrations were significantly higher in women with abnormal uterine bleeding compared to those without (p = 0.0254).

Conclusion. The findings indicate that IL-15 is a sensitive marker of the endometrial immune response to exogenous hormonal stimulation and may be involved in the pathogenesis of abnormal uterine bleeding during menopausal hormone therapy. Conversely, IL-2 and IL-6 did not demonstrate diagnostically relevant changes, suggesting their limited role in the local inflammatory response. These results highlight the need for further studies involving an expanded panel of immune markers and functional assessment of endometrial immune cell populations.

1. Hamdaoui N., Boubli L. La gestion des effets secondaires sous traitement hormonal de la ménopause : saignements utérins anormaux. RPC Les femmes ménopausées du CNGOF et du GEMVi [Management of side effects under hormonal replacement therapy in menopausal women: Abnormal uterine bleeding. Postmenopausal women management: CNGOF and GEMVi clinical practice guidelines]. Gynecol Obstet Fertil Senol. 2021; 49 (5): 474-484. French. DOI: 10.1016/j.gofs.2021.03.028. Epub 2021 Mar 20. PMID: 33757921.

2. Marjoribanks J., Farquhar C., Roberts H., Lethaby A., Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2017; 1 (1): CD004143. DOI: 10.1002/14651858.CD004143.pub5. PMID: 28093732; PMCID: PMC6465148.

3. Dobrokhotova Yu. E., Il'ina I. Yu., Safarli S. E. Abnormal uterine bleeding and postmenopausal bleeding with menopausal hormone therapy: current evidence. Russian Journal of Woman and Child Health. 2024; 7 (3): 241-247. (In Russ.). DOI: 10.32364/2618-8430 2024-7-3-9.

4. Sriprasert I., Beydoun H., Barnabei V., Nassir R., LaCroix 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; 22 (10): 1067-1075. DOI: 10.1097/GME.0000000000000436. PMID: 25756697.

5. Hickey M., Doherty D. A., Fraser I. S., Sloboda D. M., Salamonsen L. A. Why does menopausal hormone therapy lead to irregular uterine bleeding? Changes to endometrial blood vessels. Hum Reprod. 2008; 23 (4): 912-918. DOI: 10.1093/humrep/dem418. Epub 2008 Jan 23. PMID: 18216041.

6. Okada H., Nakajima T., Sanezumi M., Ikuta A., Yasuda K., Kanzaki H. Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro. J Clin Endocrinol Metab. 2000; 85 (12): 4765-4770. DOI: 10.1210/jcem.85.12.7023. PMID: 11134140.

7. Kitaya K., Yasuda J., Yagi I., Tada Y., Fushiki S., Honjo H. IL-15 expression at human endometrium and decidua. Biol Reprod. 2000; 63 (3): 683-687. DOI: 10.1095/biolreprod63.3.683. PMID: 10952908.

8. Ahtiainen M., Pöllänen E., Ronkainen P. H., Alen M., Puolakka J., Kaprio J., Sipilä S., Kovanen V. Age and estrogen-based hormone therapy affect systemic and local IL-6 and IGF-1 pathways in women. Age (Dordr). 2012; 34 (5): 1249-1260. DOI: 10.1007/s11357-011-9298-1. Epub 2011 Aug 16. PMID: 21845403; PMCID: PMC3448994.

9. Berg G., Ekerfelt C., Hammar M., Lindgren R., Matthiesen L., Ernerudh J. Cytokine changes in postmenopausal women treated with estrogens: a placebo-controlled study. Am J Reprod Immunol. 2002; 48 (2): 63-69. DOI: 10.1034/j.1600-0897.2002.01061.x. PMID: 12389594.

10. Vitale C., Cornoldi A., Gebara O., Silvestri A., Wajngarten M., Cerquetani E., Fini M., Ramires J. A., Rosano G. M. Interleukin-6 and flow-mediated dilatation as markers of increased vascular inflammation in women receiving hormone therapy. Menopause. 2005; 12 (5): 552-558. DOI: 10.1097/01.gme.0000172267.24949.70. Epub 2005 Sep 1. PMID: 16145309.

11. Kamada M., Irahara M., Maegawa M., Ohmoto Y., Murata K., Yasui T., Yamano S., Aono T. Transient increase in the levels of T-helper 1 cytokines in postmenopausal women and the effects of hormone replacement therapy. Gynecol Obstet Invest. 2001; 52 (2): 82-88. DOI: 10.1159/000052948. PMID: 11586033.

12. Akyol S., Cınar S. A., Purisa S., Aydinli K. Relationship between lymphocytes, IL2 and the hormones E2, LH, PRG and FSH in menopausal and postmenopausal women. Am J Reprod Immunol. 2011; 66 (4): 304-309. DOI: 10.1111/j.1600-0897.2011.00990.x. Epub 2011 Mar 28. PMID: 21443747.

13. Lusty E., Poznanski S. M., Kwofie K., Mandur T. S., Lee D. A., Richards C. D., Ashkar A. A. IL-18/ IL-15/ IL-12 synergy induces elevated and prolonged IFN-γ production by ex vivo expanded NK cells which is not due to enhanced STAT4 activation. Mol Immunol. 2017; 88: 138-147. DOI: 10.1016/j.molimm.2017.06.025. Epub 2017 Jun 20. PMID: 28644973.