Features of steroid hormone and receptor content in the mitochondria of endometrial adenocarcinoma according to tumor differentiation grade and the presence of type 2 diabetes mellitus

Mitochondria play a key role in cellular metabolism, steroid hormone synthesis, and the regulation of redox homeostasis. However, the role of mitochondrial steroidogenesis in the progression of endometrial adenocarcinoma (EA), particularly in the presence of type 2 diabetes mellitus (T2DM), remains poorly understood.

Purpose of the study. To determine the concentrations of steroid hormones and their receptors in the mitochondrial fraction of G1–G3 endometrial adenocarcinoma tissue compared with intact endometrium and to evaluate the modifying effect of type 2 diabetes mellitus on these parameters.

Patients and methods. Mitochondria were isolated by differential centrifugation from tumor tissue obtained from 92 patients with endometrial adenocarcinoma (G1–G3) and from morphologically normal endometrium (control group). Standard enzyme-linked immunosorbent assay (ELISA) kits were used to determine the concentrations of estradiol (E2), estriol (E3), estrone (E1) and their receptors (ERα, ERβ), testosterone (T) and the androgen receptor (AR), progesterone (P4) and the progesterone receptor (PR), as well as cortisol and cholesterol. Statistical analysis was performed using Statistica 10 software.

Results. In the mitochondria of G1–G2 endometrial adenocarcinomas, the estradiol level was approximately twofold higher than in the control group, whereas G3 tumors demonstrated an approximately twofold increase in estriol concentration. Testosterone and cortisol levels were elevated in the mitochondria of all tumors by 1.6-fold and more than twofold, respectively. Progesterone content was increased by 2.3–3.8-fold in the mitochondria of G1–G2 tumors but decreased by 4.3–5.9-fold in comparison with the control mitochondria. The levels of androgen and estrogen receptors were elevated in the mitochondria of all tumors, whereas the ERα/ERβ ratio decreased by 1.7–3.6-fold. Progesterone receptor levels were increased in G1–G2 mitochondria only in patients with T2DM, whereas in G3 tumors they were elevated regardless of T2DM status. Type 2 diabetes mellitus was associated with cholesterol accumulation in the mitochondria of all tumors.

Conclusion. Regardless of tumor differentiation grade and the presence of type 2 diabetes mellitus, endometrial adenocarcinoma mitochondria are characterized by increased levels of testosterone, cortisol, and sex hormone receptors, reflecting profound metabolic reprogramming of these organelles. Estradiol predominates in G1–G2 tumors, whereas estriol is the dominant estrogen in G3 tumors, which may contribute to increased tumor aggressiveness. Type 2 diabetes mellitus is associated with mitochondrial cholesterol accumulation, which may partly explain the more severe clinical course of endometrial adenocarcinoma in these patients.

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