Некоторые параметры иммунной системы у женщин с гиперандрогенией

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Introduction

Hyperandrogenism (HA) is a medical condition characterized by excessive levels of androgens, in a woman’s blood. Major androgens that may be elevated include testosterone, dihydrotestosterone, androstenedione, and others. This imbalance of hormones can occur for a variety of reasons and have different consequences for a woman’s body [1, 3, 5, 6].

HA occurs in 17-18% of women of childbearing age. The disease affects 16-22% of patients with infertility and 55-62% – with endocrine disorder of reproductive functions, which determines the urgency of this problem in modern gynecology since the frequency of this pathology continues to be quite high and does not have a clear tendency to decrease [4].

The study of menstrual and generative function in hyperandrogenic female patients has significance in the context of scientific, social and clinical aspects of women’s health care. This investigation is important for maintaining reproductive health, secondary prevention of reproductive dysfunction, and identification of patients at increased risk for such dysfunction in the future. According to the literature, the character of generative function in women with hyperandrogenism is closely related to their age, the specific causes of this condition, the effectiveness of therapy and other factors [8, 9].

Such patients often have altered psychoemotional status, increased risk of hyperplastic processes in target organs and endocrine diseases [4]. One of the main challenges is to identify the source of excessive androgen secretion, develop pathogenesis, diagnostic methods, and select effective rehabilitation measures [9]. Several obstetric aspects of this problem, taking into account the form of hyperandrogenism, need scientific substantiation, and their solution is of great practical importance: for predicting the features of reproductive function and hormone-dependent organs in women in the distant periods of observation [6, 9].

According to modern data, immunocompetent cells are equipped with receptors to hormones, which determines the possibility of their modulating effect on the functions of immunocompetent cells. According to the literature, the results obtained about the effect of androgens on immune processes are quite controversial [7].

The present study aimed to investigate the state of the immune system in women suffering from hyperandrogenism.

Materials and methods

Within the framework of this study, 58 women of reproductive age, diagnosed with hyperandrogenism, who were under observation at the Women’s Health Center “AyolCare” in Tashkent were examined. All of the women underwent a comprehensive clinical and laboratory examination. The control group consisted of 35 practically healthy women of reproductive age. Immunological examinations were carried out in the Laboratory of Reproduction Immunology of the Institute of Human Immunology and Genomics of the Academy of Sciences of the Republic of Uzbekistan.

Immunologic research was performed by quantitative determination of lymphocytes with CD3⁺, CD4⁺, CD8⁺, CD16⁺, CD20⁺, CD25⁺, CDHLA-DR, CD95⁺ phenotype in peripheral blood using monoclonal antibodies of LT series ("Sorbent", Moscow, Russia). The level of immunoglobulins IgA, IgM, and IgG in blood serum was determined by solid-phase enzyme-linked immunosorbent assay using test systems of CJSC "Vector-Best" (Russia) by the manufacturer’s recommendations.

Statistical processing of the results of the studies was carried out by methods of variation statistics, implemented by the standard package of applied programs “BioStat LE 7.6.5”. The data were processed using conventional approaches and the results are presented as sample mean (M) and standard error of the mean (m). The reliability of the differences between the means (P) of the compared indicators was assessed by Student’s criterion (t).

Results and discussion

As is widely known, cellular immunity is represented by different populations of T and B lymphocytes, the ratio of which plays an important role in assessing the state of this link of immunity. Immunologic researches revealed the following peculiarities of immune status [7].

The analysis of the relative number of mature T lymphocytes established the suppression of the immune system in the studied group of HA women compared to that of the control group. Thus, the total pool of Т lymphocytes (CD3⁺), «responsible» for the reactions of cellular immunity and carrying out immunological surveillance of antigenic homeostasis in the group of women with GA revealed a slightly reduced level of the relative number of CD3⁺ lymphocytes compared to control values (48.5±2.24% vs 59.9±1.01%) (р < 0.001) (Figure 1).

 

Figure 1. Certain immune system parameters in women with hyperandrogenism

Note. *, statistically significant compared to the control group data (*, р < 0.05; **, р < 0.01; ***, р < 0.001).

 

Т helper cells (CD4⁺) are inducers that regulate the strength of the body’s immune response to foreign antigen, control antigen homeostasis and cause increased antibody production. Т helper/inducers (CD4⁺) are regulatory cells, without which the transformation of B lymphocytes into antibody-producing plasma cells is impossible. They are also capable of enhancing cellular responses of the immune system [6].

When studying the number of subpopulation composition of Т lymphocytes, a tendency to decrease CD4⁺ lymphocytes was revealed in women with HA of the main group 29.3±2.09%, while in women of the control group, this indicator amounted to 38.2±0,97% (р < 0.001) (Figure 1).

Another group of regulatory Т lymphocytes – Т suppressors (CD8⁺) are able to inhibit immunologic reactions that are too strong and too prolonged. Т suppressors inhibit the production of antibodies (of various classes) due to delayed proliferation and differentiation of B lymphocytes, and the development of delayed-type hypersensitivity [7].

At the same time, the content of the relative number of CD8⁺ lymphocytes in women with HA was significantly increased with an average of 26.8±1.73% compared to the data of the control group 21.2±0.83% (р < 0.01).

NK cells are distinguished as a special class of lymphocytes due to their unique ability to rapidly and without prior immunization lysate foreign or their own altered cells in the absence of major histocompatibility complex class I molecules, regardless of antibodies and complement, which confirms their name “natural killer cells” [7].

It was also found that the percentage of CD16⁺ cells in the peripheral blood of women with a history of HA amounted to 19.6±1.84, while in women of the control group, it was determined 15.4±0.52% (р < 0.01) (Figure 1).

CD20⁺ lymphocytes are cells of humoral immunity responsible for antibody synthesis [5]. Analysis of the content of the number of circulating CD20⁺ cells in the peripheral blood tended to increase compared to the control group. So the relative quantity. Thus, according to the obtained data, the estimate of the relative content of CD20⁺ in the group of women with HA averaged 36.5±2.12 % vs 23.7±0.47% (р < 0.001) (Figure 1).

The number of lymphocytes expressing activation markers CD25⁺, CDHLA-DR, indicating the activity of the process was higher in women with a history of hyperandrogenism.

The number of cells with receptor to interleukin 2 (IL-2)-CD25⁺, a marker of autocrine cell proliferation suppressor cells, was increased in the group of women with hyperandrogenism So the percentage of CD25⁺ in the group of women with GA averaged 27.2±1.33% against controls 16.9±1.04% (р < 0.001) (Figure 2).

 

Figure 2. Level of lymphocytes with activation marker in women with a history of hyperandrogenism

Note. As for Figure 1.

 

In women of the main group the number of CDHLA-DR⁺ cells was significantly higher than the values of the control group (24.7±2.09% vs 16.3±0.58%) (p < 0.001). The quantitative study of lymphocytes expressing the apoptosis antigen CD95⁺ showed a tendency to increase them in the peripheral blood of women with hyperandrogenism compared to the values of healthy women (34.1±0.97% vs 22.4±0.94% in controls) (р < 0.001).

The level of serum immunoglobulins is an integral indicator of humoral immunity. Synthesis of IgG (p < 0.001) and IgA (p < 0.05) in women with a history of hyperandrogenism was significantly higher than in the control group, and the level of IgM did not differ from that of practically healthy women and was not significant (р > 0.05) (Figure 3).

 

Figure 3. Humoral immunity indicators in women with hyperandrogenism

Note. As for Figure 1.

 

Therefore, the results suggest that women with altered hormonal balance, including HA status, have specific changes in the immune system. Studies have shown that the levels of Т lymphocytes and Т helper/inducers decrease, while the number of Т killers, CD25⁺ cells (carrying receptor for IL-2) and CD95⁺ cells (carrying apoptosis signaling receptor) increase. The increased content of CD95⁺ cells indicates increased activation of apoptosis processes, which fulfill the protective function of Т killers. This increase in lymphocyte activation is likely due to increased levels of mature activated macrophages and several cytokines they produce that directly stimulate lymphocytes. The observed imbalance of immunologic parameters probably indicates that in hyperandrogenism the elimination of activated Т helper clones is either absent or impaired, which usually leads to the formation of immune response suppression. An increase in the number of activated Т lymphocyte clones is observed with a reduced process of their apoptosis, which is probably enhanced by androgen exposure.

Conclusions

1. A significant decrease in the number of Т lymphocytes (p < 0.001), Т helper/inducers (p < 0.001) in women with hyperandrogenism compared to the similar indicators of the control group was established.
2. A considerable increase of CD8⁺ suppressor cells (p < 0.001) and CD16⁺ (p < 0.001) in the group of women with GA, compared to those of the control group, was determined.
3. Substantial increase in the level of activation markers CD25⁺ (p < 0.001), CDHLA-DR⁺ (p < 0.001), and CD95⁺ lymphocytes (p < 0.001) in women with hyperandrogenism compared to the parameters of healthy women in the control group was revealed.
4. Comparative analysis of humoral immunity indicators revealed a significant increase in the level of IgG (p < 0.001) and IgA (p < 0.05) in women with hyperandrogenism.

Об авторах

У. К. Юлдашев

Институт иммунологии и геномики человека Академии наук Республики Узбекистан

Email: salima-m@list.ru

самостоятельный соискатель

Узбекистан, г. Ташкент

С. А. Музафарова

Центр женского здоровья AyolCare

Автор, ответственный за переписку.
Email: salima-m@list.ru

д.м.н., ведущий специалист

Узбекистан, г. Ташкент

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