Features of Anti- and Prooxidant Status in Women Depending on the Presence of Arterial Hypertension and Functional State of the Ovaries

The dissertation is dedicated to the study of the features of anti- and prooxidant status in women depending on the presence of arterial hypertension and the functional state of the ovaries. The work analyzes the markers of LDL oxidizability, the content of nitric oxide metabolites, and antioxidant and prooxidant activity of blood serum in healthy women and patients with arterial hypertension in the context of age, FSH and estradiol levels, and the functional state of the ovaries. The relationships of the studied parameters with the components of metabolic syndrome, including insulin resistance and abdominal fat deposition, are investigated.

Relevance of the Topic.

A lower incidence of cardiovascular events in premenopausal women compared with men of the same age is well documented. However, after its onset, cardiovascular morbidity in women reaches the same level, if not higher, than in men [127,305,167]. Simultaneously, cardiovascular mortality ranks first in the structure of mortality in this population group [364]. This is attributed to the protective role of female sex hormones [305].

A decline in estrogen-producing ovarian function is associated with the development of postmenopausal metabolic syndrome (MS), which includes an increase in the amount of central (abdominal) adipose tissue; a shift in the lipid profile toward a more atherogenic pattern with increased concentrations of LDL and TG, decreased levels of HDL, as well as the appearance of small dense LDL; impaired glucose tolerance [127], which are direct risk factors for coronary heart disease (CHD). Furthermore, postmenopausal metabolic syndrome is characterized by the obligatory presence of insulin resistance/hyperinsulinemia (IR/HI), which increase sodium reabsorption, stimulation of the sympathetic nervous system, and proliferation of vascular smooth muscle cells. This allows the authors to assert that a prominent clinical manifestation of MS in the postmenopause is arterial hypertension (AH) [351].

In the postmenopause, IR markers are greater in patients with AH compared with normotensive women with a similar body mass index [228]. A direct correlation between visceral adipose tissue and systolic blood pressure (SBP) and the HOMA-R index has been identified, with their values being significantly higher in postmenopausal than in premenopausal women [213]. The role of the insulin resistance cluster in inducing and accelerating the processes of atherogenesis has been demonstrated [42].

Hemodynamic and metabolic disturbances are largely associated with the activity of oxidative stress (OS) leading to endothelial dysfunction. A clear tendency toward intensification of OS and the severity of atherosclerotic changes has been noted with increasing duration of menopause. This fact is confirmed by measurements of malondialdehyde (MDA) concentration and intima-media thickness of the carotid arteries, as well as their direct correlation with each other and with the duration of menopause [148].

The regulatory function of the endothelium suffers in the context of hypercholesterolemia, diabetes mellitus, smoking, AH, and heart failure [13,147]. The aforementioned conditions are associated with the activation of oxidative stress processes due to excessive production of reactive oxygen metabolites (ROM) [371,376]. Oxidative stress is realized through LDL peroxidation, impaired vascular reactivity, proliferation of vascular smooth muscle cells, macrophage adhesion, activation of polymorphonuclear leukocytes (PMNs), and platelets [32,37,345].

ROM and elevated blood glucose concentration are the primary causes of LDL modification, a significant portion of which occurs in the blood with the participation of blood cells generating ROM [29]. Since PMNs do not penetrate the arterial intima, it is believed that their participation in LDL oxidation occurs in the bloodstream. The features of the catabolism of peroxidatively modified LDL characterize their high atherogenicity [28]. It has been demonstrated that peroxidatively modified LDL, due to their cytotoxicity, can damage the endothelium [70].

In vascular diseases, the ability of endothelial cells to release relaxing factors decreases while the production of constrictor factors is preserved or increased, i.e., endothelial dysfunction (ED) develops [36]. A decrease in the synthesis and release of dilator factors and/or an increase in the synthesis of constrictor factors in any segment of the vascular bed leads to local vasospasm [338], and in the case of generalization of the process - to the development of hypertension [369]. Various variants of the development of endothelial dysfunction have also been described [51].

In women, OS and ED parameters have been studied in the postmenopause either depending on the presence of clinical forms of atherosclerosis such as CHD [323], or in the context of hormone replacement therapy [247]. At the same time, such studies in the context of MS development in women with various variants of estrogen deficiency development have not been encountered in the available literature, nor has the influence of the main hormonal parameters of perimenopausal and postmenopausal endocrine imbalance (FSH, estradiol, and characteristics of the gonadal-endocrine axis) on OS and ED processes in patients with AH - at the onset of the cardiovascular continuum - been studied.

Analysis of the literature data indicates that endothelial dysfunction serves as the basis of the pathogenesis of atherosclerosis [200,238]. Overproduction or impaired neutralization of free radicals is considered the beginning of oxidative stress, which is realized through LDL modification, disruption of nitric oxide metabolism, and endothelial cell metabolism [238]. Given the sharp increase in cardiovascular risk in women in the postmenopause, the relevance of studying the mechanisms of OS and ED in the process of formation of the postmenopausal syndrome is beyond doubt.

Objective: To evaluate the features of anti- and prooxidative status in women depending on the presence of arterial hypertension and the functional state of the ovaries. Research tasks:

1. To study the antioxidant and prooxidant activity of blood serum, the oxidizability of low-density lipoproteins, and the content of nitric oxide metabolites in blood serum in healthy women depending on age and the functional state of the ovaries.

2. To evaluate the markers of antioxidant and prooxidant activity of blood serum, the oxidizability of low-density lipoproteins, and the content of nitric oxide metabolites in blood serum in women with arterial hypertension depending on age and the functional state of the ovaries.

3. To conduct a comparative analysis of the studied parameters in healthy women and patients with arterial hypertension.

4. To investigate the relationships of the studied parameters with the components of metabolic syndrome, markers of the functional state of the ovaries, and age.

Scientific Novelty of the Research.

For the first time, the features of the formation of imbalance of the anti- and prooxidant blood systems in healthy women depending on age and the functional state of the ovaries have been determined. It has been shown that surgical menopause in young women is associated with a decrease in antioxidant activity of blood serum, and the formation of pronounced estrogen deficiency in this group of women determines its further decrease and a reduction in nitric oxide metabolite levels. Natural menopause is associated with a decrease in nitric oxide metabolite levels and an increase in LDL peroxidation, which is intensified with the formation of pronounced estrogen deficiency. A decrease in antioxidant activity of blood serum after menopause, in the presence of pronounced estrogen deficiency, transforms into an increase in prooxidant activity of blood serum, indicating the activation of oxidative stress in this category of women.

In women with arterial hypertension of young and middle age, under conditions of surgical and natural menopause, no changes occur in the studied markers of anti- and prooxidant status; pronounced estrogen deficiency is accompanied by an increase in nitric oxide metabolite levels and LDL oxidizability, which indicates the realization of oxidative stress in them, pointing to an aggravating rather than initiating role of estrogen deficiency in the imbalance of anti- and prooxidant status in this category of women.

For the first time, a reliable correlation dependence of the increase in nitric oxide metabolites on FSH levels has been identified in women with arterial hypertension. In women with arterial hypertension and natural menopause, a reliable negative correlation of nitric oxide metabolite levels with estradiol has been found.

Reliable positive correlation relationships between basal insulinemia markers, glucose/insulin indices, HOMA-R, and prooxidant activity of blood serum have been recorded in women with arterial hypertension and natural menopause, indicating a close relationship between insulin resistance and prooxidant status in the context of postmenopausal metabolic syndrome formation.

For the first time, the priority influence of insulin resistance and abdominal fat deposition among other metabolic and hemodynamic components of metabolic syndrome on LDL oxidizability and the magnitude of NOx markers in women with arterial hypertension has been demonstrated. The sequence of their influence depends on the functional state of the ovaries.

Practical Significance.

Studying LDL oxidizability, the content of nitric oxide metabolites in blood serum, and antioxidant and prooxidant activity of blood serum depending on age and the functional state of the ovaries in healthy women and patients with arterial hypertension will make it possible to identify the imbalance of anti- and prooxidant blood systems, as well as to evaluate its nature.

The data obtained on the priority influence of local fat deposition indices on LDL oxidizability and the magnitude of NOx markers within the complex of MS features confirm the necessity of careful diagnosis and correction of abdominal obesity and emphasize the role of WC and WHR as important prognostic markers of oxidative stress realization, the determination of which is accessible to practitioners.

The identified correlation relationships between prooxidant activity (POA) and insulinemia and the HOMA-R index expand the possibilities for predicting the development of anti- and prooxidant blood system imbalance using basal insulin-glucose markers.

Positions to be Defended.

1. The conditions of menopause onset and age in healthy women determine the features of the formation of the imbalance of anti- and prooxidant blood systems.

2. In women with arterial hypertension, regardless of age and the functional state of the ovaries, markers of oxidative stress are identified.

3. In the context of postmenopausal metabolic syndrome formation and pronounced estrogen deficiency, a close relationship exists between hyperinsulinemia/insulin resistance and prooxidant status.

4. The functional state of the ovaries determines the contribution of various components of the metabolic syndrome cluster (anthropometric, metabolic, and hemodynamic) to the realization of oxidative stress in women with arterial hypertension.