The effectiveness of local cytokine therapy for chronic endometritis in patients with infertility
Objective: To evaluate the effectiveness of the complex of natural antimicrobial peptides and cytokines (preparation Superlymph, rectal suppositories) in the complex treatment of chronic endometritis (CE) in infertile patients. Materials and methods: This was a prospective (n=64) randomized, placebo-controlled, blinded study on the effectiveness of the complex of natural antimicrobial peptides and cytokines (Superlymph) in the complex treatment of CE in infertile patients aged 28 to 37 years (mean age was 31.88±2.65 years). Endometrial microbiota was studied. After screening and randomization, patients were categorized into the main group (n=32) and the control group (n=32). All patients received doxycycline monohydrate treatment. Additionally, patients of the main group received two courses of Superlymph with an interval of three weeks. Before and after the treatment, the microflora of the uterine cavity was evaluated and immunohistochemical examination of endometrial biopsy samples was performed. Results: After the analysis of microbiology data, it was found that the addition of local cytokine therapy contributes to the elimination of 84.04% of identified microorganisms from the uterine cavity, but in the control group this indicator was 59.13% (χ2=13.075, p<0.001). There was also a statistically significant decrease in the severity of CE in the main group (χ2=10.563, p=0.002). Conclusion: Adjuvant cytokine therapy in the combination treatment of CE increases a rate of elimination of microbial agents from the uterine cavity and significantly reduces the severity of CE.Tapilskaya N.I., Tolibova G.Kh., Savicheva A.M., Kopylova A.A., Glushakov R.I., Budilovskaya O.V., Krysanova A.A., Gorskii A.G., Gzgzyan A.M., Kogan I.Yu.
Keywords
chronic endometritis
idiopathic infertility
local chemotherapy
Superlymph
References
- Puente E., Alonso L., Laganà A.S., Ghezzi F., Casarin J., Carugno J. Chronic endometritis: old problem, novel insights and future challenges. Int. J. Fertil. Steril. 2020; 13(4): 250-6. https://dx.doi.org/10.22074/ijfs.2020.5779.
- Pirtea P., Cicinelli E., De Nola R., de Ziegler D., Ayoubi J.M. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis. Fertil. Steril. 2021; 115(3): 546-60. https://dx.doi.org/10.1016/j.fertnstert.2020.12.010.
- Espinós J.J., Fabregues F., Fontes J., García-Velasco J.A., Llácer J., Requena A. et al. Impact of chronic endometritis in infertility: a SWOT analysis. Reprod. Biomed. Online. 2021; 42(5): 939-51. https://dx.doi.org/10.1016/j.rbmo.2021.02.003.
- Тапильская Н.И. Роль иммунной системы в патогенезе невынашивания беременности. Предпосылки для фармакологической коррекции. Обзоры по клинической фармакологии и лекарственной терапии. 2002; 1(2): 15-26. [Tapilskaya N.I. The role of the immune system in the pathogenesis of pregnancy failure. Prerequisites for pharmacological correction. Reviews on clinical pharmacology and drug therapy. 2002; 1(2): 15-26. (in Russian)].
- Dabee S., Passmore J.A.S., Heffron R., Jaspan H.B. The complex link between the female genital microbiota, genital infections, and inflammation. Infect. Immun. 2021; 89(5): e00487-20. https://dx.doi.org/10.1128/IAI.00487-20.
- Тапильская Н.И., Будиловская О.В., Крысанова А.А., Толибова Г.Х., Копылова А.А., Цыпурдеева Н.Д., Гзгзян А.М., Савичева А.М., Коган И.Ю. Микробиота эндометрия женщин с хроническим эндометритом и идиопатическим бесплодием. Акушерство и гинекология. 2020; 4: 72-81. [Tapilskaya N.I., Budilovskaya O.V., Krysanova A.A. et al. Endometrial microbiota of women with chronic endometritis and idiopathic infertility. Akusherstvo i ginekologiya/ Obstetrics and Gynecology. 2020; 4: 72-81. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.4.72-81.
- Swidsinski A., Loening-Baucke V., Mendling W., Dörffel Y., Schilling J., Halwani Z. et al. Infection through structured polymicrobial Gardnerella biofilms (StPM-GB). Histol. Histopathol. 2014; 29(5): 567-87. https://dx.doi.org/10.14670/HH-29.10.567.
- Koo H., Allan R.N., Howlin R.P., Stoodley P., Hall-Stoodley L. Targeting microbial biofilms: current and prospective therapeutic strategies. Nat. Rev. Microbiol. 2017; 15(12): 740-55. https://dx.doi.org/10.1038/nrmicro.2017.99.
- Толибова Г.Х., Траль Т.Г., Клещев М.А. Эндометриальная дисфункция: алгоритм клинико-морфологического исследования. Санкт-Петербург; 2016. 44с. [Tolibova G.Kh, Tral’ T.G, Kleshchev M.A. Endometrial dysfunction: an algorithm for clinical and morphological studies. SPb; 2016. 44p. (in Russian)].
- Wira C.R., Fahey J.V., Rodriguez-Garcia M., Shen Z., Patel M.V. Regulation of mucosal immunity in the female reproductive tract: the role of sex hormones in immune protection against sexually transmitted pathogens. Am. J. Reprod. Immunol. 2014; 72(2): 236-58. https://dx.doi.org/10.1111/aji.12252.
- Доброхотова Ю.Э., Боровкова Е.И., Скальная В.С., Ильязов Т.К., Рассохина О.В. Клинико-иммунологические параллели у пациенток с бесплодием и хроническим эндометритом до и после экзогенной цитокинотерапии. Акушерство и гинекология. 2019; 12: 154-60. [Dobrokhotova Yu.E., Borovkova E.I., Skalnaya V.S., Ilyazov T.K., Rassokhina O.V. Clinical and immunological parallels in patients with infertility and chronic endometritis before and after exogenous cytokine therapy. Akusherstvo i ginekologiya/ Obstetrics and Gynecology. 2019; 12: 154-60. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.12.154-160.
- Доброхотова Ю.Э., Ганковская Л.В., Боровкова Е.И., Зайдиева З.С., Скальная В.С. Модулирование локальной экспрессии факторов врожденного иммунитета у пациенток с хроническим эндометритом и бесплодием. Акушерство и гинекология 2019; 5: 125-32. [Dobrokhotova Yu.E., Gankovskaya L.V., Borovkova E.I., Zaidieva Z.S., Skalnaya V.S. Modulation of the local expression of innate immune factors in patients with chronic endometritis and infertility. Akusherstvo i ginekologiya/ Obstetrics and Gynecology. 2019; 5: 125-32. (in Russian)]. https://dx.doi.org/10.18565/aig.2019.5.125-132.
- Доброхотова Ю.Э., Ганковская Л.В., Боровкова Е.И., Нугуманова О.Р. Экзогенная цитокинотерапия в лечении пациенток с хроническим эндометритом. Акушерство и гинекология. 2021; 2: 119-26. [Dobrokhotova Yu.E., Gankovskaya L.V., Borovkova E.I. Nugumanova O.R. Exogenous cytokine therapy in the treatment of patients with chronic endometritis. Akusherstvo i ginekologiya/ Obstetrics and Gynecology. 2021; 2: 119-26. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.2.119-126.
- Базанов П.А., Кузнецова И.А., Павлухина С.С., Горская О.С., Митюшина Н.Г. Эффективность программ вспомогательных репродуктивных технологий у пациенток с хроническим эндометритом после лечения путем нормализации локальной экспрессии факторов врожденного иммунитета. Проблемы репродукции. 2020; 26(5): 86-90. [Bazanov P.A., Kuznetsova I.A., Pavlukhina S.S., Gorskaya O.S., Mityushina N.G. The effectiveness of ART programs in patients with chronic endometritis after treatment by normalizing the local expression of innate immunity factors. Russian Journal of Human Reproduction. 2020; 26(5): 86-90. (in Russian)]. https://dx.doi.org/10.17116/repro20202605186.
- Cicinelli E., Vitagliano A., Loizzi V., De Ziegler D., Fanelli M., Bettocchi S. et al. Altered gene expression encoding cytochines, grow factors and cell cycle regulators in the endometrium of women with chronic endometritis. Diagnostics (Basel). 2021; 11(3): 471. https://dx.doi.org/10.3390/diagnostics11030471.
Received 05.02.2022
Accepted 17.02.2022
About the Authors
Natalya I. Tapilskaya, MD, PhD, DSci (Medicine), Professor, Leading researcher at the Department of Reproduction, D.O. Ott Research Institute of Obstetrics,Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Professor of the Department of Obstetrics and Gynecology,
Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, 194100, Russia, St. Petersburg, Litovskaya str., 2,
+7(812)328-98-22, tapnatalia@yandex.ru, https://orcid.org/0000-0001-5309-0087
Gulrukhsor Kh. Tolibova, MD, PhD, DSci (Medicine), Head of the Department of Pathomorphology, Leading researcher, D.O. Ott Research Institute of Obstetrics,
Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Associate professor, S.N. Davydov Department of Obstetrics and Gynecology, North-Western State Medical University named after I.I. Mechnikov, Ministry of Health of Russia, 191015, Russia, St. Petersburg, Kirochnaya str., 41,
+7(812)328-98-22, gulyatolibova@yandex.ru, https://orcid.org/0000-0002-6216-6220
Alevtina M. Savicheva, MD, PhD, Professor, Head of the Department of Medical Microbiology, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Head of the Department of Clinical Laboratory Diagnostics, Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, 194100, Russia, St. Petersburg, Litovskaya str., 2, +7(812)328-98-22, savitcheva@mail.ru, https://orcid.org/0000-0003-3870-5930
Ruslan I. Glushakov, MD, PhD, DSci (Medicine), Head of the Department (medical and biological research) of the Research Center, S.M. Kirov Military Medical Academy, Ministry of Defense of the Russian Federation, 194044, Russia, St. Petersburg, Akademika Lebedeva str., 6; Associate professor of the Department of Pharmacology,
Medical Faculty, St. Petersburg State University, 199034, Russia, St. Petersburg, Universitetskaya nab., 7-9,
+7(812)292-32-53, glushakovruslan@gmail.com, https://orcid.org/0000-0002-0161-5977
Olga V. Budilovskaya, Researcher at the Department of Medical Microbiology, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology,
199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Assistant of the Department of Clinical Laboratory Diagnostics, Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, 194100, Russia, St. Petersburg, Litovskaya str., 2, +7(812)328-98-22, o.budilovskaya@gmail.com, https://orcid.org/0000-0001-7673-6274
Anna A. Krysanova, Researcher at the Department of Medical Microbiology, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology,
199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Assistant of the Department of Clinical Laboratory Diagnostics, Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia, 194100, Russia, St. Petersburg, Litovskaya str., 2, +7(812)328-98-22, krusanova.anna@mail.ru
Anton G. Gorskii, 6th year student of the Medical Faculty, North-Western State Medical University named after I.I. Mechnikov, Ministry of Health of Russia,
191015, Russia, St. Petersburg, Kirochnaya str., 41, +7(812)303-51-36, antong9988@mail.ru
Alexander M. Gzgzyan, MD, PhD, DSci (Medicine), Head of the Department of Reproduction, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Professor of the Department of Obstetrics, Gynecology and Reproduction, Medical Faculty,
St. Petersburg State University, 199034, Russia, Saint Petersburg, Universitetskaya nab., 7-9, +7(812)328-98-22, iagmail@ott.ru, https://orcid.org/0000-0003-3917-9493
Igor Yu. Kogan, MD, PhD, DSci (Medicine), Professor, Corresponding Member of RAS, Director of the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034, Russia, St. Petersburg, Mendeleyevskaya Line, 3; Professor of the Department of Obstetrics, Gynecology and Reproduction,
Medical Faculty, St. Petersburg State University, 199034, Russia, St. Petersburg, Universitetskaya nab., 7-9, ikogan@mail.ru, https://orcid.org/0000-0002-7351-6900
Corresponding author: Natalya I. Tapilskaya, tapnatalia@yandex.ru
Authors’ contributions: Tapilskaya N.I., Glushakov R.I. – developing research design, performing statistical analysis of the obtained data, article writing; Tolibova G.Kh. – performing histological and immunohistochemical studies; Kopylova A.A., Gzgzyan A.M. – obtaining the data for analysis, reviewing publications on the topic of the article; Savicheva A.M., Budilovskaya O.V., Krysanova A.A. – all stages of performing nucleic acid amplification methods; Gorskii A.G. – statistical processing of research results; Kogan I.Yu. – general management of the clinical trial, staff coordination, article writing.
Conflicts of interest: The authors declare that they have no competing interests.
Funding: The study was performed with the financial support of Immunotherapy Center “Immunohelp”, LLC.
Ethical approval: The study was reviewed and approved by the Local Ethics Committee of the D.O. Ott Research Institute of Obstetrics, Gynecology and Reproduction.
Patient Consent for Publication: All patients provided informed consent for the publication of their data.
Authors' Data Sharing Statement: The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Tapilskaya N.I., Tolibova G.Kh., Savicheva A.M., Kopylova A.A., Glushakov R.I., Budilovskaya O.V., Krysanova A.A., Gorskii A.G., Gzgzyan A.M., Kogan I.Yu. The effectiveness of local cytokine therapy for chronic endometritis in patients with infertility.
Akusherstvo i Ginekologiya / Obstetrics and gynecology. 2022; 2: 91-100 (in Russian)
https://dx.doi.org/10.18565/aig.2022.2.91-100