The ratio of hypoxic and nitrosative stress in endometrial precancer and cancer

Introduction. Endometrial hyperplasia (EH) is a pathological condition characterized by an imbalance between the glandular and stromal structures of the endometrium, as well as changes in the phenotype of proliferating cells. The key regulators of these processes are HIF-1-alpha, which is responsible for the cellular response to hypoxia, and iNOS, which is induced by inflammation and produces abnormal amounts of nitric oxide. However, the relationship between these processes in endometrial pathology requires further study. 
Study Objective. To study the structural features of oxidative, nitrosative stress and their relationship in endometrial hyperplasia (without atypia / with atypia) and endometrioid adenocarcinoma.
Materials and Methods. In a retrospective, non-randomized cohort study, four groups of women (30 participants each, aged 18–45 years) were formed based on the morphological analysis of endometrial biopsies: Group 1: endometrial endometriosis without atypia, Group 2: endometrial endometriosis with atypia, Group 3: endometrioid adenocarcinoma, and Group 4 (control): women with a normal endometrium in the secretory phase of the cycle. Patients who had taken hormonal medications in the past 6 months, or had uterine fibroids, endometriosis, or tumors in other locations were excluded. Histological and immunohistochemical (IHC) analyses were performed using antibodies to HIF-1-alpha and iNOS. Histological specimens were analyzed using QuPath and ImageJ. Statistical data processing was performed in Statistica 13 using the Kruskal–Wallis and Mann–Whitney tests. Differences were considered significant at p<0.05.
Results. In the group with HE without atypia, most cells did not demonstrate HIF-1-alpha expression, and immunopositive cells showed a weak cytoplasmic reaction localized exclusively in the glands. iNOS expression was also noted predominantly in the glands, with an increase closer to their lumina. The relationship between HIF-1-alpha and iNOS was weak. In the 2nd group, with HE with atypia, HIF-1-alpha was expressed in both glands and stroma, with localization in the cytoplasm and nuclei, and iNOS was detected in the same structures. A moderately strong relationship was observed between the markers. In the group with adenocarcinoma, HIF-1-alpha was expressed predominantly in the glands, while iNOS was limited to glandular structures, and the relationship between the markers was virtually absent. In the control group, the expression of both markers was minimal, but a strong correlation was observed between them.
Conclusion. Thus, the results indicate changes in the nature of the correlation between oxidative and nitrosative stress in normal endometrium, in uterine lining hyperplasia, and in endometrial cancer. These changes are due to specific features of metabolic processes in the endometrium and highlight the need for further study and analysis of the pathological changes accompanying uterine pathology.

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