Molecular endometrial signatures associated with uterine infertility factor
AbstractThe aim of the study – to study the «receptive» and immune characteristics of the endometrium of infertile women in the “implantation window” phase.
Material and methods. 171 women were examined, with the allocation of groups with infertility: unclear genesis (n=21), with tubal-peritoneal infertility (TPI) (n=74), associated with external genital endometriosis (EGE) (n=22), with chronic endometritis (CE) (n=36), with “thin” endometrium (n=8). The control group included 10 healthy fertile women.
Serum vitamin D was evaluated, hysteroscopy and pipelle biopsy of the endometrium in the «implantation window» phase was performed to assess the pathomorphological and immunohistochemical studies of the expression of steroid hormone receptors (estradiol ER and progesterone PR), vitamin D receptors (VDR), cytokines (TNFα, IL-10). Chronic endometritis (CE) was confirmed when the CD138+ marker was detected, and the proliferative activity of the endometrium was confirmed when Ki-67 was overexpressed.
Results. After immunohistochemical examination, taking into account the hysteroscopy data and pathomorphological conclusions, the molecular signatures of the endometrium within each infertility group were heterogeneous: with impaired immune status (n=42), proliferative (n=40), dysplastic (n=47), chronic inflammation (CE) (n=30), “normal” endometrium (n=10). The “normal” endometrial variant was combined with the control group (n=22).
Significant differences in the content of 25 (OH) D in infertile women from the control group [43 (36; 52.5) were detected in the dysplastic phenotype [26.8 (24.5; 40.5); p=0.005], proliferative [23.5 (15.3; 48.0); p=0.009] and CE [28.5 (25.5; 38.8); p=0.02].
A “receptive” endometrial profile was detected in 22 women (10 fertile and 12 with a “normal” endometrial phenotype from the TPI group), a “non-receptive” profile was determined in all women with CE, 89.5% with a proliferative and dysplastic phenotype, 62.5% with a disturbed immune status. Impaired endometrial receptivity confirms a decrease in the stromal expression ratio of mean PR/ER receptor values (unlike the control group and the normal endometrial phenotype – 2.1): with proliferative – 2.6 times (p<0.05), with CE – 1.5 times (p<0.05) and dysplastic phenotype – 1.9 times (p<0.05). The level of VDR expression in the endometrium of women with all phenotypes except dysplastic was significantly higher than in the group with a “normal” endometrium in both compartments (p<0.001), with CE and impaired immune status in the epithelium of the glands – comparable, stroma – significantly lower in inflammation (p<0.001).
The molecular profile of cytokines and the immunoregulatory index of TNF-α/IL-10 at different phenotypes differed from the control (“normal” endometrium – 1.1 in the epithelium of the glands and 1:1 in the stroma): with a disturbed immune status of 1.0 and 0.94, respectively; in case of dysplastic – 1.0 and 0.7, respectively; CE – 2.5 and 2.2, respectively; proliferative – in the epithelium of the glands – 1.5.
Conclusion. The main molecular signatures of the endometrium and the determinants of its dysfunction in the uterine factor of infertility have been identified. It has been shown that the acquisition of “receptive” status by the endometrium is realized under the influence of immune responses modulated by the activity of cytokines. Impaired expression of steroid hormones (ER and PR) and indirectly affecting the receptivity of immune factors (cytokines TNF-α/IL-10, VDR) allows us to assert the revealed defects in the mechanisms of decidualization of the stroma and secretory potential of the glands, genes for controlling the processes of cellular metabolism.
The concept that favorable blastocyst implantation suggests a receptor-mediated immune dominant of a moderate pro-inflammatory decidual environment has been confirmed.
Keywords:infertility; “implantation window” phase; immunohistochemical study; molecular phenotype; cytokines; “receptive” endometrium
Funding. The study had no sponsor support.
Conflict of interest. The authors declare no conflict of interest.
For citation: Polina M.L., Radzinskiy V.E., Mikhaleva L.M., Vitiazeva I.I., Mikhalev S.A. Molecular endometrial signatures associated with uterine infertility factor. Akusherstvo i ginekologiya: novosti, mneniya, obuchenie [Obstetrics and Gynecology: News, Opinions, Training]. 2023; 11 (3): 63–73. DOI: https://doi.org/10.33029/2303-9698-2023-11-3-63-73 (in Russian)
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