CC BY
40
etative balance (45.9 %) and vagotonia (24.3 %) and only 29.7 % of patients continued sympathicotonic reaction. 1 patients group common standard therapy resulted in an increase in the number of patients with type normotonicheskim BP 10.8 % asimpatikotoniches-kim type — by 3.5 %, which contributed to a decrease by 14.3 % of patients with type gipersimpatiko-tonic autonomic reactivity.
Conclusions:
1. Conducted by standard therapy had no significant effect on the vegetative state patients with asthma sympathicotony original.
Continued gipersimpatikotonicheskaya vegetative reactivity in children is characterized by tensions adaptation reactions, which certainly requires medical correction.
2. Influenced fenibuta in patients with baseline sympathicotony positive adaptive changes occur, activation of parasympathetic ANS by reducing the activity of the sympathetic nervous system, reducing the sympathicotonic reactions by 68 % by increasing the number of patients with and hey vagotonia.
References:
1. Абазова З. Х. Взаимовлияние состояния функциональной системы дыхания и функции гипоталамо-гипофизарно-тиреодиной системы//Вестник новых медицинских технологий. - 2002. - № 4. - С. 66-68.
2. Баевский Р. М., Иванов Г. Г., Чирейкин Л. В. Анализ вариабельности сердечного ритма при использовании различных электрокардиографических систем: Методические рекомендации//Вест. аритмологии. - 2001. - № 24. - С. 66-85.
3. Балаболкин И. И. Современные подходы к терапии острой бронхиальной астмы у детей.//Аллергология и иммунология в педиатрии. - 2010. - № 3. - С. 12-19.
4. Емельянов А. В., Сергеева Г. Р. Бронхиальная астма: как улучшить отдаленные результаты лечения?//СошШит Medicum. -2010. - № 3. - С. 80-84.
5. Иллек Я. Ю., Зайцева Г. А., Погудина Е. Н. Атопическая бронхиальная астма у детей. - Киров, 2012.
6. Казначеева Л. Ф., Массерова В. В. Особенности показателей вегетативной регуляции у больных атопическим дерматитом на фоне восстановительного лечения//Сибирское медицинское обозрение. - 2010. - № 5. - С. 26-27.
7. Краева В. Бронхообструктивный синдром//Врач. - 2010. - № 10. - С. 27-29.
8. Крючков Н. А. Патогенетические аспекты бронхиальной астмы//Вестник Российской академии медицинских наук. - 2010. -№ 8. - С. 46-51.
9. Ловицкий С. В., Гоголь И. А. Оценка выраженности дисбаланса вегетативной нервной системы у больных бронхиальной астмой при нарушении внутрицентральных взаимоотношений//Вестник Российской военно-медицинской академии. - 2009. -№ 1(25). - С. 650-651.
10. Порахотько Н. А., Лаптева И. М. Патогенетические особенности хронической обструктивной болезни легких и бронхиальной астмы//Пульмонология. - 2010. - № 3. - С. 120-123.
11. Фридман И. Л., Сухова Е. В. Зависимость различных аспектов качества жизни больных бронхиальной астмой от социальных, клинических, лабораторных, функциональных показателей//Пульмонология. - 2010. - № 5. - С. 90-93.
Khegay Olga Aleksandrovna, a senior fellow of the Department of Obstetrics, Gynecology and Perinatal Medicine of the Tashkent Institute of Postgraduate Medical Education Asatova Munira Miryusupovna, MD, Professor, Head of the Department of Obstetrics E-mail: ohegay899@gmail.com
The relationship between immune and endocrine abnormalities in women with reproductive dysfunction and autoimmune thyroiditis
Abstract: The aim of the study was to examine the state of the immune and hormonal status of 90 women with reproductive dysfunction and autoimmune thyroiditis (AIT). To study the serum concentrations of the thyroid-stimulating hormone, free thyroxin, antithyroid peroxidase antibodies, antithyroglobulin antibodies and anti-inflammatory cytokines (IL-1^, IL-6, IL-18, TNF-a), depending on the stage ofAIT.
Keywords: autoimmune thyroiditis, cytokines, infertility, miscarriage.
One of the most common causes of infertility and miscarriage is a hormonal and immune imbalance occurs on the background ofthy-roid pathology [3, 14]. Carriage of antibodies to the thyroid gland is a common phenomenon among women of childbearing age (5-10 %) and well-known risk factor for hypothyroidism [12]. In women suffering with infertility, hypothyroidism diagnosis occurs in 2-34 % [11]. However, to date there is no single point ofview on the role of antithyroid autoantibodies in the formation ofreproductive disorders. On the one hand, antithyroid antibodies can serve as a marker of autoimmune
dysfunction and combined with other autoimmune process [7; 8], on the other hand, antithyroid antibodies can be an independent factor that has a direct negative impact on the fetus [10] and the implantation process [16]. There is no consensus regarding to the correction of the reproductive function in women with autoimmune thyroiditis yet. It is known that disturbances in the immune status forms to the clinical manifestations of both AIT and disorders in the reproductive system, which affects to the course of the disease, the severity of which is directly related to the intensity of the immune changes [2].
The relationship between immune and endocrine abnormalities in women with reproductive dysfunction and autoimmune thyroiditis
Objective: to study the dynamics of the parameters of immune and hormonal status in women with reproductive dysfunction and autoimmune thyroiditis.
Materials and research methods: It is surveyed 90 women who have applied to the City Perinatal Center in Tashkent (Uzbekistan) with reproductive dysfunction and autoimmune thyroiditis. The diagnosis of autoimmune thyroiditis was set on the basis of complaints, typical ultrasound picture of the thyroid gland, and increased content of antithyroid autoantibodies in the blood. The standards for inclusion ofpatients was increasing the level of antibodies to thyroid peroxidase (ATPO) and/or antibodies to thyroglobu-lin (ATG) more than 5 times with respect to the parameters specified in the test kit. Depending on the functional status of thyroid all patients with autoimmune thyroiditis were divided into 4 groups: hyperthyroidism (n = 20), subclinical hypothyroidism (n = 20), overt hypothyroidism (n = 20), euthyroidism (n = 20). The control group was consisted of 10 women with impaired reproductive function without thyroid disease.
The study of the hormonal profile was carried out in the City Perinatal Center laboratory. Determination of blood thyroid stimulating hormone (TSH), free thyroxine (fT4) was performed by method of enzyme immunodetection by using a standard set of firms «Human» (Germany). To determine the ATG and ATPO used standard «Insep» company sets (Russia). Study of cytokines: interleukin-1p (IL-1p), interleukin-6 (IL-6), interleukin-18 (IL-18) and tumor necrosis factor-a (TNF-a) was performed on the apparatus Stat Fax-2100 using standard sets of the company «Vector-Best» (Russian).
Ultrasound examination was carried out on the unit Mindray DC-3, for the study of the uterus and ovaries used Convex multi-frequency sensor (2.5-5 MHz.) and intracavitary probe (5-8 MHz.), thyroid scan used a linear multi-frequency transducer (5-10 MHz.).
Statistical processing of the results was carried out on a PC using standard packages applied statistical analysis software (Statistical Package for Social Science-22, Microsoft Excel). In order to determine the type of sample distribution of the test, Kolmogorov-Smirnov test was used. To analyze the results of the study were used nonparamet-ric tests U-test and the Mann Whitney test for independent samples, the Wilcoxon test for dependent samples, Spearman rank correlation. Results and discussions
The results of the analysis of the menstrual function of patients with AIT have shown a high frequency of oligomenorrhea (42.5 %), which was found mainly among patients in the stage of overt hypothyroidism, amenorrhea less common (10.0 %) and polymenorrhea (4.0 %). Ovulatory dysfunction was observed in 46.3 % (37) women, it was more common when the manifest hypothyroidism (in 14). The lack of the luteal phase was detected in 30.0 % (24) women and was noted more frequently in women with hyperthyroidism (9). Luteal syndrome nonovulated follicle was observed in 24.0 % (19) cases was mainly characteristic for patients in stage euthyrosis (10). Among all patients with AIT in 41.3 % of women diagnosed with early pregnancy miscarriage, at 58.7 % of infertility.
Results of the study parameters of thyroid status in women with AIT showed that in the group ofwomen with AIT in the stage ofhyper-thyroidism TSH level was 0.2 ± 0.1 mIU/L (vs. 2.2 ± 0.7 mIU/L in the control, p < 0.001), fT4 was 2.2 ± 0.3 ng/dL (vs. 1.5 ± 0.2 ng/dL in the control, p < 0.001). In women with subclinical hypothyroidism TSH was 7.6 ± 4.8 mIU/L (vs. 2.2 ± 0.7 mIU/L in controls, p < 0.001), fT4 - 1.3 ± 0.2 ng/dL (vs. 1.5 ± 0.2 ng/dL in the control, p < 0.05). In women with manifest hypothyroidism TSH level was 13.8 ± 5.5 mIU/L (vs. 2.2 ± 0.7 mIU/L in controls, p < 0.001) and fT4 - 0.5 ± 0.1 ng/dL (vs. 1.5 ± 0.2 ng/dl in controls, p < 0.001).
In women with AIT in stage euthyrosis statistically significant differences in the level of TSH and f T4 compared with the control group were found. The highest ATPO and ATG have been reported in women with autoimmune thyroiditis in the stage of subclinical hypothyroidism (1332.3 ± 927.2 U/ml and 578.5 ± 645.2 IU/mL, respectively) and overt hypothyroidism (1289.3 ± 1022.6 IU/mL and 741.8 ± 501.1 IU/ml, respectively).
According Vikgem's study, the annual risk of hypothyroidism in women with elevated ATPO and euthyroid is 2.1 % [17]. The specific autoantibodies can serve as markers of the occurrence of the failure in pregnancy induced cycle [6]. The presence of high titers ATPO and ATG is associated with adverse pregnancy outcomes [13; 15], even in women with euthyroid [9].
The results of the study of pro-inflammatory cytokines, IL-1p, IL-6, IL-18 and TNF-a in patients with AIT, significantly different from the values that was obtained in the control group. It is known that IL-1^ is a leading cytokine cascade in the inflammatory response, the highest values were observed in patients with hyperthyroidism (83.2 ± 44.2 pg/ml) and euthyroid (81.1 ± 49.6 pg/ml). Less severe reactions were observed during the manifest hypothyroidism and the concentration of IL-1^ was 63.1 ± 47.7 pg/ml. A different pattern was observed in the level of IL-6, which according to the literature is both pro-inflammatory and anti-inflammatory cytokine. The highest values were found in subclinical hypothy-roidism (133.9 ± 66.2 pg/ml), relatively low — thyrotoxicosis (88.9 ± 62.5 pg/ml). IL-18, also known as IFN-y-inducing factor by itself or IFN-y stimulates apoptosis initialization process [5]. The values of IL-18, remained within the legal parameters for all patients with Hashimoto's thyroiditis, but were significantly lower compared to the control. The highest values of IL-18 were observed in patients with thyrotoxicosis (194.0 ± 82.2 pg/ml). In all patients with autoimmune thyroiditis, regardless of the phase of the autoimmune process determined reliably high levels of TNF-a, particularly in the group ofwomen with euthyroid (79.9 ± 62.0 pg/ml).
According to M. M. Orlova (2012) and E. S. Kesaeva (2013) in patients with chronic autoimmune thyroiditis development characteristic cytokine imbalances that manifest increase in the content of pro-inflammatory (IL-1p, IL-6, IL-8, TNF-a, IFN-y) and anti-inflammatory cytokines (IL-4, IL 10) [1, 2]. According to the authors at AIT indicator IL-1^ was increased 3,4 times, IL-4 is 5.3 times, IL-6, 2,2-fold, TNF-a 3 times IFN-y 2.5 times [1]. The results of our study indicate significant deviations IL-1p, IL-6 and TNF-a in all patients with Hashimoto's thyroiditis, both in the stage of hypothyroidism and hyperthyroidism and euthyrosis.
As mentioned A. A. Yunusov (2014), the degree of activation of pro-inflammatory cytokines is directly dependent on the amount of thyroid cancer in women [4]. Correlation analysis of cytokine levels with the volume of thyroid spent E. S. Kesaeva et al (2012) did not reveal any direct link between these parameters [1]. We studied the correlation between immune and hormonal parameters differentially depending on the functional state of the thyroid gland. The results are shown directly proportional relationship between IL- 1p, IL-6 and TNF-a in all patients with Hashimoto's thyroiditis, regardless of the functional state of the thyroid gland. In hyperthyroidism stage revealed a direct correlation between IL-1p and IL-6 (r = 0.84, p < 0.01), IL-10 and TNF-a (r = 0.57, p < 0.01) between IL-10 and ATPO (r = 0.48, p < 0.05), IL-6 and TNF-a (r = 0.47, p < 0.05), IL-6 and ATPO (r = 0.52, p < 0.05) and an inverse correlation between TSH levels and fT4 (r = -0.82, p < 0.001). At the stage of subclinical hypothyroidism was observed a direct correlation between IL-1^ and IL-6 (r = 0.81, p < 0.001), IL- 1p and TNF-a (r = 0.80, p < 0.001)
and IL-6 and TNF-a (r = 0.65, p < 0.05). In women with AIT in the stage of overt hypothyroidism was observed a direct correlation between IL-10 and IL-6 (r = 0.82, p < 0.001), IL-10 and TNF-a (r = 0.91, p < 0.001) between IL-6 and TNF-a (r = 0.72, p < 0.001), IL-6 and ATPO (r= 0.51, p < 0.05) and an inverse correlation between TSH levels and fT4 (r = -0.51, p < 0.05). In euthyrosis stage there was a direct correlation between IL-1^ and IL-6 (r = 0.73, p < 0.001), IL-10 and TNF-a (r = 0.78, p < 0.001), IL-10 and ATG (r = 0.44, p < 0.05) between IL-6 and TNF-a (r = 0.54, p < 0.05) and IL-18 and TNF-a (r = 0.48, p < 0.05).
Thus, the study of the dynamics of the parameters of immune and hormonal status and the results of correlation analysis indicate a close relationship between hormonal disorders and immunological changes in patients with Hashimoto's thyroiditis and reproductive dysfunction.
Conclusions:
1. Identification of high levels of pro-inflammatory cytokines and dynamics, depending on the phase of the AIT confirms the role of immune disorders in the development and progression of thyroid dysfunction at AIT. The results of the analysis of correlation showed a directly proportional relationship between IL-1p, IL-6 and TNF-a in all patients with Hashimoto's thyroiditis, regardless of the functional state of the thyroid gland. There was a direct correlation between IL- 1p and ATPO, IL-6 and ATPO underway thyrotoxicosis, between IL-6 and ATPO underway between overt hypothyroidism and IL-1p and ATG in phase euthyrosis. The data may serve as inputs in assessing the dynamics of the autoimmune process and the effectiveness of the therapy.
2.
3.
4.
7.
9.
10.
References:
Kesaeva E. S., Basieva O. O. Screening for thyroid diseases and cytokine status in young adults/Bul. of new med. tech. - 2012. - 19(2): 46-48. Orlov M. M., Rodionova T. I. The proinflammatory cytokine shift in patients with manifest hypothyroidism//Basic research. -2012. - 8: 402-406.
Tereshin A. T., Gryazyukova L. A., Laguna B. I. Clinical and hormonal relationship with autoimmune thyroiditis in women with reproductive dysfunction//Bulletin of new medical technology. - 2010. - 17(1): 184 -187.
Yunusov A. A. Status cytokine system in autoimmune thyroiditis in women ofreproductive age/Herald KRSU. - 2014. - 14(4): 168-170. Yakushenko E. V., Lopatnikova Y. A., Sennikov S. V. Interleukin-18 and its role in the immune response//Medical Immunology. -2005. - 7(4): 355-364.
Geva E., Vardinon N., Lessing J. B., Lerner-Geva L., Azem F., Yovel I., Burke M., Yust I., Grunfeld R., Amit A. Organ-specific autoantibodies are possible markers for reproductive failure: a prospective study in an in-vitro fertilization-embryo transfer programme// Hum Reprod. - 1996, Aug. - 11(8): 1627-1631.
Glinoer D. Thyroid immunity, thyroid dysfunction ad the risk ofmiscarriage Text./D. Glinoer//Am. J. Reprod. Im. - 2000. - 43: 202-203. Glinoer D. Thyroidal and immune adaptation to pregnancy Text.: abstract/D. Glinoer//The thyroid and reproduction: European thyroid symposium. - May 22-25, 2008. - Riga, 2008. - P. 13.
Kim C. H., Chae H. D., Kang B. M., Chang Y. S. Influence of antithyroid antibodies in euthyroid women on in vitro fertilization-embryo transfer outcome//Am J Reprod Immunol. - 1998, Jul. - 40(1): 2-8.
Konishi J. Radioiodine treatment of Graves' disease for its wider indication and application in Japan Text./J. Konishi//Nippon. Rinsho. - 2006. - 64(12): 2257-2261.
11. Krassas G. E. Thyroid disease and female reproduction//Fert. Steril. - 2000. - 74(6): 1063-1070.
12. Lazarus J. H., Obuobie K. Thyroid disorders - an update//Postgr. Med. J. - 2000. - 76: 529-536.
13. Matalon S. T., Blank M., Ornoy A., Shoenfeld Y. The association between anti-thyroid antibodies and pregnancy loss// Am J Reprod Immunol. - 2001, Feb. - 45(2): 72-77.
14. Poppe K. The role of thyroid autoimmunity in fertility and pregnancy//Nat. Clin. Pract. Endocrinol. Metab. - 2008. - 4: 394-405.
15. Stagnaro-Green A., Glinoer D. Thyroid autoimmunity and the risk ofmiscarriage//Best Pract Res Clin Endocrinol Metab. - 2004,Jun. -18(2): 167-181.
16. Thyroid autoimmunity and thyroid dysfunction in women with endometriosis/C. A. Petta et al.//Hum. Reprod. - 2007. - 10: 2693-2697.
17. Vanderpump M. P., Tunbridge W. M., French J. M. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickam Survey//Clin. Endocrinol. - 1995. - 43: 55-68.
Khudaykulov Atabek Tillaevich, National Cancer Research Center, Tashkent, Uzbekistan, Doctoral candidate of the Republican cancer research center
E-mail: dr.tilla@yandex.ru
The impact of demographic change on the incidence of breast cancer in Uzbekistan
Abstract: In the cancer incidence breast cancer (BC) ranks first with a specific gravity of11.7 % among the female population in Uzbekistan. The areas of increased and reduced disease risk are identified. The incidence of breast cancer is associated with the peculiarities of medico-demographic situation in the regions. The incidence of breast cancer among the population is
