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International journal of endocrinology 5 (69) 2015

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Status of indicators characterizing the state of apoptosis and angiogenesis in patients with inactive pituitary adenomas

Authors: Kholova D.Sh., Khalimova Z.Yu., Urmanova Yu.M., Alieva D.A., Alimukhamedova G.O. - Republican Specialized Scientific-Practical Medical Center of Endocrinology MoH of Uzbekistan, department of neuroendocrinology; Tashkent Pediatric Medical Institute, Department of Endocrinology and Pediatric Endocrinology, Tashkent

Categories: Endocrinology

Sections: Clinical researches

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The aim is to study the activity of eNOS, indicators characterizing the process of apoptosis (cytochrome C, p53) and angiogenesis (ET-1, VEGF, VEGFR-2) in patients without a family history of inactive pituitary adenomas (IPA).

Material and methods. The study included 71 patients with IPA with intrasellar microadenoma - tumor size up to 10 mm. Patients’ age was from 18 to 70 years (mean age 44.5±3.85 years), females prevailed: 41 (57.7%), there were 30 males (42.3% cases). The average age of the control group was 43.6±4.5 years (10 male and 10 female). According to the aim and objectives of the study, patients with IPA were divided into two groups: the 1st group – 50 (70.4%) patients with environmental factors without burdened family history, and the 2nd – 21 (29.6%) with a family history, including panmixia – 9 (2.7%) and inbreeding – 12 (16.9%) patients. The diagnosis of IPA was verified on the basis of carefully collected history, exploring the dynamics of complex treatment of the disease, the results of magnetic resonance imaging (MRI). Concentration of PRL, LH, FSH, GH, ACTH, and TSH was measured in blood serum using ELISA analyzer. Genetic polymorphism of eNOS was assessed in serum. Genomic DNA from venous blood of examined patients was isolated using the method of chloroform extraction. The MRI-parameters were studied on the instrument «SIEMENS-1.5T» (Germany). Statistical calculations were performed in the software environment using Microsoft Windows software packages Microsoft Excel-2003 and Statistica version 6.0, 2003.

Results. Observations have shown that the reduction in eNOS by 15.3% (p <0.05) increase in ET-1 by 8.3% (p> 0,05), VEGF by 11.6% (p> 0.05), VEGFR-2 by 7.6% (p> 0.05), cytochrome C by 9.6% (p> 0.05), p53 4.2% (p> 0.1) in 9 patients with microadenomas (up to 10 mm) without a family history of IPA correlated with disease symptoms such as sexual disorders, headache, and autonomic crises. With the increase in tumor size in 11 patients this relationship has increased. The data obtained in patients with IPA differs from the controls: in IPA interrelation parameters of eNOS and VEGFR2 reverses sign from the "positive" to "negative". This connection is absent in control, and in patients with IPA it is strong one. In the control group, there is also no link between VEGF, p53, and VEGFR-2, whereas in IPA patients it is strong. Thus, we may conclude that in patients with IPA there is a dysregulation of NO production, because the activity of eNOS in inhibited. Reduction of eNOS activity does not depend on changing values of VEGF and VEGFR-2, since we found a correlation between these indicators. At the same time it draws attention to the fact that patients with IPA have increased p53 proapoptotic factor on the background of high correlation of eNOS with p53 which apparently inhibits tumor progression in patients with IPA.

Conclusions: eNOS activity is inhibited in patients with IPA, which may underlie the endothelial dysfunction. Inhibition of eNOS activity occurs on a background of activation of pro- and anti-apoptotic factors – increase of p53, minor changes of factors regulating angiogenesis (VEGF, VEGFR-2). The absence of correlation between the decline in the activity of the enzyme eNOS and indicators of pro- and anti-apoptosis and angiogenesis regulation, indicating the independence of these processes in the mechanisms of IPA formation. It was found that correlation of eNOS and VEGFR-2 increases in IPA patients, which indicates an increase in the processes of angiogenesis and inhibition of proliferative activity of tissues. The presence of high-performance connection of VEGF and VEGFR-2 with indicators of apoptosis protein p53 is found, which testifies their importance in the mechanisms of inhibition of tumor process. This is presumably achieved due to preservation of values of angiogenesis regulators VEGF and VEGFR-2 within the control range in the blood plasma of patients with IPA. It was found an imbalance in the contents of factors of endothelial function (eNOS), angiogenesis (VEGF and VEGFR-2), and proapoptosis (p53) in plasma of patients with IPA. These data demonstrate their importance in mechanisms of formation of IPA and the need for their assessment in monitoring, differential diagnosis, prognosis and development of individualized treatment tactics.


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