Immunological and immunohistochemical features of endometrial implantation factor in healthy patients of late reproductive age


Аbstract. Relevance. The number of women of older reproductive age is steadily increasing, and repeated failures of Assisted Reproductive Technologies programs during the transfer of high-quality embryos indicate the possibility of disruption of embryo implantation processes associated with impaired receptivity and functionality of the endometrium. Morphological, immunological and immunohistochemical changes in the endometrium associated with age factor may be decisive for the formation of the «implantation window» and correction of these changes and may improve the outcomes of Assisted Reproductive Technologies for a cohort of patients of older reproductive age. The aim of the study - to expand the pathogenetic understanding of the violation of the implantation ability of the endometrium in healthy patients of older reproductive age. Materials and Methods. A prospective sample study of 46 patients (group 1), aged 38 to 45 years with an officially registered diagnosis of infertility lasting no more than 4 years, with a successful gynecological and obstetric history, who were about to have their first IVF attempt, was conducted. The patients were examined according to Order № 803n of the Ministry of Health of the Russian Federation. Additionally, the level of peripheral blood melatonin, the determination of progesterone, estrogen, HLA-DR (MHC II), CD56 (NK cells), CD138, leukemia inhibiting factor receptors in the endometrium were studied. Concentrations of IL-6, IL-10, TGFß, and VGEF were determined in the cervical secretion, with the calculation of the pro-inflammatory index, as the ratio of IL-6/IL-10 cu and the ratio of TGFß1/VEGF. Statistical data processing was performed using the Statistica 10.0 application software package (StatSoft, Inc., USA). Results and Discussion. In the group of healthy patients of older reproductive age, there is an imbalance of steroid receptors and secretory transformation of the endometrium against the background of relative hyperestrogenism, with a decrease in the reception of own hormones in the endometrium. A decrease in melatonin signals a disorder of pineal and pituitary control over ovarian cycling. There is a decrease in the expression of leukemia inhibiting factor. Signs of inactive chronic endometritis with an autoimmune component are monitored, confirmed by a pro-inflammatory cytokine balance. The predominance of fibrosis processes over angiogenesis processes is confirmed by an increase in the ratio of TGFß1/VEGF and highly resistant blood flow in the uterine arteries. Conclusion. Standard pre-gravidar preparation cannot compensate for all factors that violate the implantation potential of the endometrium in this cohort of patients and requires the development of new complex techniques that directly affect the diversity of all factors that ensure the natural extinction of reproductive potential in order to increase the effectiveness of Assisted Reproductive Technologies programs.

About the authors

Elena I. Kravtsova

Kuban State Medical University

ORCID iD: 0000-0001-8987-7375
Krasnodar, Russian Federation

Natalia V. Kolesnikova

Kuban State Medical University

Author for correspondence.
ORCID iD: 0000-0002-9773-3408
Krasnodar, Russian Federation

Irina N. Lukoshkina

Kuban State Medical University

ORCID iD: 0000-0001-6214-8404
Krasnodar, Russian Federation

Kristina V. Uryupina

Kuban State Medical University

ORCID iD: 0000-0001-8113-2790
Krasnodar, Russian Federation

Veronika A. Avakimyan

Kuban State Medical University

ORCID iD: 0000-0002-4946-6640
Krasnodar, Russian Federation


  1. Orazov MR, Silantieva ES, Orekhov RE, Kamillova DP, Mikhaleva LM. Repeated implantation failures: etiology and possibilities of physiotherapy. A difficult patient. 2020;8–9:20–24. doi: 10.24411/2074-1995-2020-10055. (In Russian).
  2. Lapides L, Klein M, Belušáková V, Csöbönyeiová M, Varga I, Babál P. Uterine Natural Killer Cells in the Context of Implantation: Immunohistochemical Analysis of Endometrial Samples from Women with Habitual Abortion and Recurrent Implantation Failure. Physiol Res. 2022;27(71 Suppl 1): S99-S105. doi: 10.33549/physiolres.935012
  3. Ota K, Takahashi T, Mitsui J, Kuroda K, Hiraoka K, Kawai K. A case of discrepancy between three ERA tests in a woman with repeated implantation failure complicated by chronic endometritis. BMC Pregnancy Childbirth. 2022;22(1):891. doi: 10.1186/s12884-022-05241-6
  4. Prokhorova OV, Olina AA, Tolibova GH, Tral TG. Progesterone- induced blocking factor: from molecular biology to clinical medicine (literature review). Obstetrics and Gynecology. 2021;5:64–71. doi: 10.18565/aig.2021.5.64-71. (In Russian).
  5. Adamczak R, Ukleja- Sokołowska N, Lis K, Bartuzi Z, Dubiel M. Progesterone- induced blocking factor 1 and cytokine profile of follicular fluid of infertile women qualified to in vitro fertilization: The influence on fetus development and pregnancy outcome. Int J Immunopathol Pharmacol. 2022;36:3946320221111134. doi: 10.1177/03946320221111134
  6. Raghupathy R, Szekeres-B artho J. Progesterone: A Unique Hormone with Immunomodulatory Roles in Pregnancy. Int J Mol Sci. 2022;23(3):1333. doi: 10.3390/ijms23031333
  7. Sogoyan NS, Kozachenko IF, Adamyan LV. The role of AMH in the reproductive system of women (literature review). Reproduction problems. 2017;23(1):37–42. doi: 10.17116/repro201723137-42. (In Russian).
  8. Meczekalski B, Czyzyk A, Kunicki M, Podfigurna-S topa A, Plociennik L, Jakiel G, Maciejewska-J eske M, Lukaszuk K. Fertility in women of late reproductive age: the role of serum anti-M üllerian hormone (AMH) levels in its assessment. J Endocrinol Invest. 2016;39(11):1259–1265. doi: 10.1007/s40618-016-0497-6
  9. di Clemente N, Racine C, Rey RA. Anti- Müllerian Hormone and Polycystic Ovary Syndrome in Women and Its Male Equivalent. Biomedicines. 2022;10(10):2506. doi: 10.3390/biomedicines10102506.
  10. Khabarov SV, Sterlikova NA. Melatonin and its role in circadian regulation of reproductive function (literature review). Bulletin of New Medical Technologies. 2022;29(3):17–31. doi: 24412/1609-2163-20 22-3-17-31. (In Russian).
  11. Cosme P, Rodríguez AB, Garrido M, Espino J. Coping with Oxidative Stress in Reproductive Pathophysiology and Assisted Reproduction: Melatonin as an Emerging Therapeutical Tool. Antioxidants (Basel). 2022;12(1):86. doi: 10.3390/antiox12010086
  12. Yong W, Ma H, Na M, Gao T, Zhang Y, Hao L, Yu H, Yang H, Deng X. Roles of melatonin in the field of reproductive medicine. Biomed Pharmacother. 2021;144:112001. doi: 10.1016/j.biopha.2021.112001
  13. Rudenko YuA, Kulagina EV, Kravtsova OA, Tselkovich LS, Balter RB, Ibragimova AR, Ivanova TV, Ilchenko OA, Tyumina OV, Ryabov EY. Endometrial readiness for in vitro fertilization: prognosis according to ultrasound and morphological studies. Genes and cells. 2019;14(3):142–146. doi: 10.23868/201906025. (In Russian).
  14. Krylova Y, Polyakova V, Kvetnoy I, Kogan I. Dzhemlikhanova L, Niauri D, Gzgzyan A, Ailamazyan E. Immunohistochemical criteria for endometrial receptivity in I/II stage endometriosis IVF-treated patients, Gynecological Endocrinology. 2016;32(Sup2):33–36, doi: 10.1080/09513590.2016.1232576
  15. Enciso M, Aizpurua J, Rodríguez-E strada B, Jurado I, Ferrández-R ives M, Rodríguez E, Pérez-Larrea E, Climent AB, Marron K, Sarasa J. The precise determination of the window of implantation significantly improves ART outcomes. Sci Rep. 2021;11:13420. doi:

Copyright (c) 2023 Kravtsova E.I., Kolesnikova N.V., Lukoshkina I.N., Uryupina K.V., Avakimyan V.A.

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

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies