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different, i.e. Patients with bronchiectasis process of puberty occurs gradually and does not end until the end of puberty.
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Prolactin and cortisol hormones level in patients with HIV and AIDS Begisheva R.1, Merkushkina T.2, Safiullin A.3, Zalyalieva M.4 (Republic of Uzbekistan) Показатели пролактина и кортизола у пациентов с ВИЧ/СПИД Бегишева Р. Р.1, Меркушкина Т. А.2, Сафиуллин А. И.3, Залялиева М. В.4
(Республика Узбекистан)
1Бегишева Раушания Рашидовна /Begisheva Raushaniya - младший научный сотрудник; 2Меркушкина Татьяна Александровна /Merkushkina Tatyana - младший научный сотрудник; 3Сафиуллин Александр Иосифович /Safiullin Aleksandr - младший научный сотрудник; 4Залялиева Марьям Валиахмедовна / Zalyalieva Maryam - доктор биологических наук, профессор, лаборатория иммуноаллергодиагностики, Институт иммунологии Академия наук Республики Узбекистан, г. Ташкент, Республика Узбекистан
Abstract: concentration of prolactin, Cortisol, and absolute count of CD4-lymphocytes were studied in 80 HIV-infected patients. The significant increase of prolactin was found in 22,6% of patients at the 3rd stage of the disease and in 46,0% of patients at the 4th stage of the disease. Cortisol level was increased in 22,6% and 28,6% of patients respectively. Prolactin concentration in women was significantly higher than in men. Cortisol level was 1,2 - 1,4 times higher in men than in women. Prolactin level was 3,3 times higher than normal values in HIV infected patients with rapid progression of the disease. The ratio prolactin/cortisol was increased during the rapid progression of the disease, which can be used for the prognosis of HIV/AIDS course and for the optimization of the treatment of opportunistic infections and ARV (Antiretroviral) therapy.
Аннотация: в статье анализируется концентрация гормонов кортизола и пролактина в зависимости от концентрации CD4 лимфоцитов у 80 ВИЧ-инфицированных пациентов. Было обнаружено значительное повышение уровня пролактина у 22,6% пациентов на 3 стадии заболевания и у 46,0% лиц на 4 стадии заболевания. Уровень кортизола был повышен у 22,6% и 28,6% пациентов соответственно. Уровень пролактина был в 3,3 раза выше нормальных значений у лиц с быстрой прогрессией заболевания.
Keywords: AIDS, HIV, prolactin, cortisol. Ключевые слова: СПИД, ВИЧ, пролактин, кортизол.
Introduction
HIV infection causes the state of infective stress in patients, which involves in the disease all physiological systems of the body, including neuro - immune and endocrine system (NIES). The endocrine, nervous, and immune systems are interrelated in complex ways that are not yet fully understood. In recent years, the role of hypothalamic - pituitary-adrenal axis activity in stress response has been actively investigated. Among the dysfunctions of NIES during the stress the important role is given to changes in the level of prolactin and cortisol. It is well known that prolactin level is strongly correlated with the state of the hypothalamus and pituitary gland [1, 2, 3, 4]. Prolactin affects the cell growth of tissues and the immune function [5, 6]. Cortisol is considered the "primary", active glucocorticoid synthesized by the adrenal cortex and is essential for the adaptation and maintenance of stress homeostasis during critical illness. Its secretion is stimulated by ACTH (adrenocorticotropic hormone) and controlled by corticotropin releasing factor, which is synthesized in the hypothalamus. Increased levels of cortisol is observed during bodily stresses such as infection, depression, inflammation, pain, fear, emotional distress and etc [1, 2, 7, 8, 9]. However, the studies that show the role of prolactin and cortisol in the progression of HIV infection and AIDS are almost absent.
The aim of the study was to research the concentration of prolactin and cortisol in HIV-infected patients depending on the absolute number of CD4 lymphocytes.
Material and Methods
The study involved 80 HIV-infected patients aged between 22 and 52 years (men number - 28, women - 52). Patients were at the stage of secondary manifestations of HIV infection and at the AIDS stage. The control group consisted of 20 healthy adults of comparable age and sex. All patients were registered in the Republican AIDS Center. Diagnosis of HIV and AIDS was established by ELISA and confirmed by immunoblotting methods. Patients at the 3rd and 4th clinical stages were receiving antiretroviral therapy. To estimate the stage of the disease, in addition to clinical examination there were determined the absolute number of CD4-lymphocytes by flow cytometry. Concentration of the hormones was determined by using a commercial standard reagent kits (Human, Germany) according to the manufacturer's instructions. Blood was taken from the patients in the morning on an empty stomach in the first tube and in the second dry tube with EDTA. Blood with EDTA was used to determine CD4 lymphocytes count. Cortisol and prolactin level were determined in the serum, which was stored in the deep freeze before analysis.
Questioning of the patients was conducted on a specially designed questionnaire with their informed consent. Data were also obtained from a medical examinations and medical histories. Opportunistic diseases were diagnosed on the basis of clinical signs of the disease and the results of laboratory and instrumental studies. When the number of CD4 lymphocytes was from 500 to 200 cells/mcL, there were observed pneumonia of unknown etiology (28,2%), oral candidiasis (54,8%) lesions caused by Herpes simplex (12,3%), Herpes zoster (7,8%), CMV (5,2%), chronic diarrhea of unknown etiology (17,2%), as well as other disorders such as chronic viral hepatitis B (3,6%) and chronic viral hepatitis C (5,8% ).
As the number of cells was less than 200 cells/mcL, there were observed Pneumocystis pneumonia (6,8%), disseminated herpes infection (9,7%), Candida esophagitis (38,9%), pulmonary tuberculosis (8,9%), chronic diarrhea of unknown etiology (78,7%), chronic viral hepatitis B (6,8%), chronic viral hepatitis C (3,6%), HIV encephalopathy (38,6%), and cachexia (47,8%). Patients had various injuries and multiple markers of infections at the 3 rd and the 4th stages of the disease.
The mathematical processing of the obtained results was performed by using the Statistic 6,0 program. In analysis of the results there were determined the average values and the standard error (M ± m), coefficients of pair correlation and the reliability by the Student criterion.
Results
The results are shown in Tables 1 and 2.
It was found a wide range of individual values of prolactin in patients and in healthy individuals. HIV-infected patients had higher levels of prolactin than control group. Prolactin levels
were above the norm in 22,6% of HIV-infected patients at the stage of secondary diseases and in 46,0% of patients with AIDS. Nobody among patients had reduced level of prolactin.
Cortisol levels were higher than normal in 22,6% of patients at the stage of secondary diseases and in 28,6% of patients with AIDS. These data point out the significant changes in the concentration of prolactin and cortisol in HIV infection compared with the normal levels.
In average, prolactin levels were 3 times higher than the control values (p <0,001) in patients at the 3rd stage of the disease and 3,3 times higher (p <0,001) in patients at the 4th clinical stage. Significant differences of cortisol level were not identified at the 3rd clinical stage, but cortisol level was 12% higher (p> 0,005) at the 4th stage of the disease.
We have analyzed the content of prolactin and cortisol separately in men and women. Patients were divided into two groups depending on the level of prolactin; one of them had normal levels and the other increased level of the hormone. Prolactin level with its contents in the normal range was in average 13,3 ± 0,63 ng/mL in women and 9,2 ± 1,09 ng/mL in men.
The average level of prolactin was significantly higher in women than in men (p<0,01). The average level of prolactin was 48,1 ± 12,7 ng/mL (p <0,01) in women, who had increased level of the hormone and 36,2 ± 8,9 ng/mL (p <0,01) in men. Women had prolactin level 1,4 times higher than men (p> 0,05).
In HIV-infected women with prolactin level within the normal values, cortisol concentrations was 1,2 times lower than in the group with high level of prolactin (p> 0,05). The similar results were found in men: cortisol level in a group with high level of prolactin exceeded its level in the group with normal range of prolactin (p<0,05). It should be noted that cortisol level in both groups of men was higher than in women (p> 0,05).
Discussion
The obtained results show that the development of opportunistic infections was accompanied by changes in the endocrine system in almost half of the patients. Activation of the pituitary-adrenal axis in HIV-infected patients is confirmed by published data which indicate that the synthesis of cortisol and prolactin increases as response to stress [2, 9, 10, 11]. Thus, the prolactin is stimulating cellular and humoral immune response as well as the phagocytic activity and production of cytokines that occurs at the 1st and the 2nd stages of the disease [5, 10, 12]. Immunoreactivity of the organism decreases with a decrease of the number of CD4-lymphocytes. Perhaps this occurs due to the fact that severity of the stress reaction in early clinical stages of the disease leads to the depletion and disruption of the adaptive reserves and a more rapid progression of the disease.
Thus, on the basis of the obtained data, we can say, that very high levels of prolactin as well as increased level of cortisol in blood with predictive point of view are unfavorable signs of the disease progression, even against the ongoing antiretroviral therapy. Considering the potential prognostic value of the studied stress hormones, we conducted detailed statistical analysis of the obtained data.
We performed a pair correlation analysis between investigated hormones and a number of CD4-lymphocytes. We found weak direct correlation between the levels of prolactin and cortisol (r = + 0,17) as well as between prolactin level and the number of CD4-lymphocytes (r = + 0,21); besides that a weak inverse correlation was found between cortisol level and absolute number of CD4-lymphocytes (r = - 0,23) at the 3rd clinical stage of the disease.
At the 4th clinical stage we found the following results: no correlation between the prolactin and cortisol levels, inverse correlation between the prolactin level and the number of CD4-lymphocytes(r = - 0,41) and the same correlation as at the 3rd clinical stage between cortisol and absolute number of CD4-lymphocytes (r = - 0,22). Analysis of the data according to the high level of prolactin separately in men and women identified a weak inverse correlation in men (p = - 0,23) and positive correlation in women (p = + 0,42). These data was different from those of patients with normal level of prolactin. We did not find the close correlation between the studied parameters in the control group of healthy adults.
Calculation of prolactin/cortisol ratio in HIV-infected patients with slow progression of the disease did not differ from the control values (0,07 ± 0,005 in the control; 0,05 ± 0,01 in patients; p>0,05). The same ratio prolactin/cortisol was 4 times higher in patients with high level of prolactin
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than in the control group (p <0,001). Moreover, the ratio of prolactin/cortisol was 0,26 ± 0,06 in women, while 0,16 ± 0,05 in men. Thus, the ratio prolactin/cortisol stays the same as in control group during the slow progression of the disease, whereas the ratio increases during the rapid progression of the disease. Increased level of prolactin and the ratio prolactin/cortisol can be used to evaluate the progression of HIV infection and AIDS.
According to the literature, a high content of prolactin prevents the development of stress-induced immunosuppression, stimulates cellular and humoral immunity. However, excessive activity of neuroendocrine mechanisms that involved in stress pose a threat to homeostasis and determine the status of the high risk, which increases the probability of disease [13, 14, 15].
Presumably, this occurs during the development of opportunistic infections: as their clinical manifestations increase, high levels of stress hormone cortisol and prolactin are no longer capable to stimulate an immune response. Thus, the activation of the pituitary -adrenal axis as a result of HIV infection leads to depletion of adaptive reserves and a more rapid progression of HIV and AIDS.
Conclusions
26% of HIV-infected patients had increased level of prolactin and 22,6% had increased level of cortisol at the 2nd clinical stage of the disease. 48% of adults had high level of prolactin and 28,6% had high level of cortisol at the 4th stage of the disease.
The average value of prolactin was 48,1 ng/mL in women and 36,2 ng/mL in men with the high level of this hormone. Increased level of prolactin correlated with increased level of cortisol as well as with more quick progression of HIV infection AIDS.
The ratio prolactin/cortisol increases with rapid progression of the disease, which can be used for prognosis of HIV infection and for optimization of treatment of opportunistic infections and receiving antiretroviral therapy.
Table 1. The content of CD4-lymphocytes, prolactin and Cortisol levels in HIV-infected patients, M ± m
Indicator Clinical stage of HIV Control values
3rd 4th
prolactin, ng/mL 21,26±4,04* 23,74±7,14* 7,2±1,7
cortisol, ng/mL 176,47±15,03 212,72±42,68 189,27±33,59
CD4-lymphocytes, cells/mcL 323±17,2* 151±16,4* 676±58,0
Footnote: * р<0,001 compared with control.
Table 2. Concentration of hormones in the blood of HIV-infected men (numerator) and female (denominator) depending on the concentration of prolactin, M ± m
Indicator Range of normal values Range above the normal values
prolactin, ng/mL 9,2±1,09 13,2±0,63 36,2±8,9 48,1±12,7
cortisol, ng/mL 186,3±23,2 158,9±10,9 266,8±28 196,8±30
Acknowledgements
This work was supported by grant from Academy of Sciences of the Republic of Uzbekistan. We are indebted to the patients and the uninfected control individuals for their participation in the study. Conflicts of Interest
The authors declare that they have no conflicts of interest concerning this article.
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