The efficacy of selective cyclooxygenase 2 inhibitors in the treatment of genital endometriosis

Cover Page

Abstract


External genital endometriosis is characterized by the processes of angiogenesis, neurogenesis, impaired apoptosis, local inflammation of the tissues, secretion of estradiol, and cell proliferation. In a similar manner, prostaglandin E2 affects  tissues. The safest drugs that overwhelm COX-2 activity and inhibit the expression of prostaglandin E2 are selective COX-2 inhibitors. As a mediator of inflammation, prostaglandin E2 is involved in all inflammatory processes. It induces the expression of local P450 aromatase and the anti-apoptotic gene Bcl-2. E2 also possesses immunosuppressive-mediated activity and inhibits the synthesis of cytokines IFNγ, TNFα, and IL-12, IL-1β-mediated expression of chemokines, the proliferation of T- and B-cells and reduces the cytotoxic activity of NK cells, creating a background of the immunosuppressive characteristic of endometriosis [1–3].

This study included 100 patients of reproductive age (aged 22−35 years) with a confirmed diagnosis of external genital endometriosis of degree II–IV. Fifty patients received 100 mg of celecoxib in monotherapy and in combination with 2 mg of dienoguest. The control group included 50 people receiving monotherapy with 2 mg of dienogest. The effectiveness of therapy was assessed using the visual analog scale (VAS) and on the basis of the dynamics of algodismenorrhea, pain during coitus, clinical examination, and the patient’s subjective assessment of the degree of irritability and severity of depressive syndrome. The effectiveness of the treatment was evaluated according to MRI and ultrasound of the pelvic organs throughout the study. To control for possible complications of the therapy, the patients performed a comprehensive dynamic survey assessing the indicators of general blood analysis and the blood coagulation system. In the group with the combined application of celecoxib and dienoguest, a clinically significant reduction in pain syndrome and a decrease in the degree of irritability and depressive syndrome were noted relative to the control group. No side effects of celecoxib on the body systems were identified throughout the study. Thus, celecoxib can be recommended as a safe and effective combination therapy for endometriosis.


Nikolay G. Samoshkin

Author for correspondence.
djep@yandex.ru
Central Clinical Hospital No 2
Russian Federation, Velikiy Novgorod

Multidepartment

Maria I. Yarmolinskaya

m.yarmolinskaya@gmail.com
Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Russian Federation, St. Petersburg

Professor of Russian Academy of Sciences, Head of Department of Endocrinology of Reproduction, Doctor of Medical Sciences

Victoria O. Polyakova

vopol@yandex.ru
Research Institute of Obstetrics, Gynecology and Reproductology named after D.O. Ott
Russian Federation, St. Petersburg

д-р биол. наук, профессор, проф. РАН

  • Денисова В.М., Ярмолинская М.И., Потин В.В., Тимофеева Е.М. Активность овариальной ароматазы при эндометриозе // Журнал акушерства и женских болезней. — 2013. — Т. 62. — № 2. — С. 17–22. [Denisova VM, Yarmolinskaya MI, Potin VV, Timofeeva EM. Ovarian aromatase activity in endometriosis. Journal of Obstetrics and Women’s Diseases. 2013;62(2):17-22. (In Russ.)]
  • Прозорова В.К., Вертким А.Л., Сычев Д.А. Нестероидные противовоспалительные средства // Клиническая фармакология. Учебник для вузов / Под ред. В.Г. Кукеса. — М.: ГЭОТАР-Медиа, 2006. [Prozorova VK, Vertkim AL, Sychev DA. Nonsteroidal anti-inflammatory drugs. In: Clinical pharmacology. Textbook for high schools. Ed by V.G. Kukes. Moscow: GEOTAR-Media; 2006. (In Russ.)]
  • Efstathiou JA, Sampson DA, Levine Z, et al. Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil Steril. 2005;83(1):171-181. doi: 10.1016/j.fertnstert.2004.06.058.
  • Целебрекс — специфический ингибитор циклооксигеназы 2: эффективность и переносимость // Научно-прак тическая ревматология. — 2000. — Т. 38. — № 2. — С. 80–82. [Shchekina EG. Celebrex-specific cyclooxygenase 2 inhibitor: efficacy and tolerability. Science-practical rheumatology. 2000:38(2):80-82. (In Russ.)]. doi: 10.14412/1995-4484-2000-1241.
  • Ярмолинская М.И., Молотков А.С., Беженарь В.Ф., и др. Комбинированная терапия распространенных форм генитального эндометриоза с применением ингибиторов ароматазы // Журнал акушерства и женских болезней. — 2013. — Т. 62. — № 1. — С. 64–70. [Yarmolinskaya MI, Molotkov AS, Bezhenar’ VF, et al. Combined therapy of extensive genital endometriosis with aromatase inhibitors. Journal of Obstetrics and Women’s Diseases. 2013;62(1):64-70. (In Russ.)]
  • Молотков А.С. Подходы к оценке ароматазной активности в эндометриоидных гетеротопиях // Вестник Российской военно-медицинской академии. — 2013. — № 2. — С. 25–28. [Molotkov AS. Approaches to evaluation of aromatase activity in endometriosis heterotopies. Vestnik Rossiiskoi voenno-meditsinskoi akademii. 2013;2(42):25-28. (In Russ.)]
  • Ярмолинская М.И., Айламазян Э.К. Генитальный эндо метриоз. Различные грани проблемы. — СПб.: Эко-Вектор, 2017. [Yarmolinskaya MI, Aylamazyan EK. Genital endometriosis. Different aspects of the problem. Saint Petersburg: Eko-Vektor; 2017. (In Russ.)]
  • Bally M, Dendukuri N, Rich B, et al. Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data. BMJ. 2017;357:j1909. doi: 10.1136/bmj.j1909.
  • Bulun SE, Zeitoun K, Takayama K, et al. Estrogen production in endometriosis and use of aromatase inhibitors to treat endometriosis. Endocr Relat Cancer. 1999;6(2):293-301. doi: 10.1677/erc.0.0060293.
  • Allen C, Hopewell S, Prentice A. Non-steroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2005;(4):CD004753. doi: 10.1002/14651858.CD004753.pub2.
  • Денисова В.М., Потин В.В., Ярмолинская М.И. Значение активности овариальной ароматазы для выбора метода терапии эндометриоза // Архив акушерства и гинекологии им. В.Ф. Снегирева. — 2015. — Т. 2. — № 4. — С. 41. [Denisova VM, Yarmolinskaya MI, Potin VV. Value of the acti vity of ovarian aromatase to choose the method of endo metriosis treatment. Arkhiv akusherstva i ginekologii im. V.F. Snegireva. 2015;2(4):41. (In Russ.)]
  • Биохимия: учебник для вузов / Под ред. Е.С. Северина. — М.: ГЭОТАР-Медиа, 2003. [Biochemistry: textbook for high schools. Ed by E.S. Severin. Moscow: GEOTAR-Media; 2003. (In Russ.)]
  • Каратеев А.Е., Яхно Н.Н., Лазебник Л.Б., и др. Применение нестероидных противовоспалительных препаратов: клинические рекомендации. — М.: ИМА-ПРЕСС, 2009. [Karateev AE, Yakhno NN, Lazebnik LB, et al. Use of non-steroidal anti-inflammatory drugs: clinical recommendations. Moscow: IMA-PRESS; 2009. (In Russ.)]
  • Лебедева В.В., Гмошинский И.В., Мазо В.К., Муравь ев Ю.В. Повышение проницаемости слизистой оболочки тонкой кишки при длительном применении нестероидных противовоспалительных препаратов у больных ревматическими заболеваниями // Экспериментальная и клиническая гастроэнтерология. — 2008. — № 2. — С. 16–21. [Lebedeva VV, Gmoshinskiy IV, Mazo VK, Murav’ev YV. Increased permeability of the mucosa of the small intestine with prolonged use of NSAIDs in patients with rheumatic diseases. Experimental and clinical gastroenterology. 2008;(2):16-21. (In Russ.)]
  • ab01.ru [интернет]. Целебрекс [доступ от 24.08.2017]. Доступ по ссылке: http://www.ab01.ru/rls/c4.html. [ab01.ru [Internet]. Celebrex [cited 2017 Aug 24]. Available from: http://www.ab01.ru/rls/c4.html. (In Russ.)]
  • Евсеев М.А. Гепато-и гастротоксичность нестероидных противовоспалительных препаратов: возможные точки пересечения // РМЖ. — 2007. — Т. 15. — № 26. — С. 75–79. [Evseev MA. Hepato- and gastro-toxicity of non-steroidal anti-inflammatory drugs: possible intersection. Russkii meditsinskii zhurnal. 2007;15(26):75-79. (In Russ.)]
  • Каратеев А.Е., Новикова Д.С., Насонов Е.Л. Новые данные, касающиеся безопасности нестероидных противовоспалительных препаратов: представление о «класс-специфическом» высоком кардиоваскулярном риске селективных ингибиторов циклооксигеназы 2 устарело // Научно-практическая ревматология. — 2017. — Т. 55. — № 2. — С. 218–223. [Karateev AE, Novikova DS, Nasonov EL. New data on the safety of nonsteroidal anti-inflammatory drugs: the concept of the high class-specific cardiovascular risk of selective cyclooxygenase-2 inhibitors is outdated. Science-practical rheumatology. 2017;55(2):218-223. (In Russ.)]
  • Каратеев А.Е., Насонов Е.Л., Яхно Н.Н., и др. Клинические рекомендации «Рациональное применение нестероидных противовоспалительных препаратов (НПВП) в клинической практике» // Современная ревматология. — 2015. — Т. 9. — № 1. — С. 4–23. [Karateev AE, Nasonov EL, Yakhno NN, et al. Clinical guidelines “Rational use of nonsteroidal anti-inflammatory drugs (NSAIDs) in clinical practice”. Sovremennaia revmatologiia. 2015;9(1):4-23. (In Russ.)]
  • Каратеев А.Е. Целекоксиб, эторикоксиб, мелоксикам и нимесулид: сравнение достоинств и недостатков // Современная ревматология. — 2011. — № 2. — С. 9–19. [Karateev EA. Celecoxib, etoricoxib, meloxicam, and nimesulide: comparison of their merits and demerits. Sovremennaia revmatologiia. 2011;(2):9-19. (In Russ.)]
  • Shimizu Y, Mita S, Takeuchi T, et al. Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. Steroids. 2011;76(1-2):60-67. doi: 10.1016/j.steroids.2010.08.010.
  • Ding S, Zhu T, Tian Y, et al. Role of Brain-Derived Neurotrophic Factor in Endometriosis Pain. Reprod Sci. 2017:1933719117732161. doi: 10.1177/1933719117732161.
  • Ebert AD, Bartley J, David M. Aromatase inhibitors and cyclooxygenase-2 (COX-2) inhibitors in endometriosis: new questions — old answers? Eur J Obstet Gynecol Reprod Biol. 2005;122(2):144-150. doi: 10.1016/j.ejogrb.2005.04.017.
  • Olivares C, Ricci A, Bilotas M, et al. The inhibitory effect of celecoxib and rosiglitazone on experimental endometriosis. Fertil Steril. 2011;96(2):428-433. doi: 10.1016/j.fertnstert.2011.05.063.
  • Moore RA, Derry S, McQuay HJ. Discontinuation rates in clinical trials in musculoskeletal pain: meta-analysis from etoricoxib clinical trial reports. Arthritis Res Ther. 2008;10(3):R53. doi: 10.1186/ar2422.
  • Olivares CN, Bilotas MA, Ricci AG, et al. Anastrozole and celecoxib for endometriosis treatment, good to keep them apart? Reproduction. 2013;145(2):119-126. doi: 10.1530/REP-12-0386.
  • Guan Z, Baier LD, Morrison AR. p38 Mitogen-activated protein kinase down-regulates nitric oxide and up-regulates prostaglandin E2 biosynthesis stimulated by interleukin-1β. J Biol Chem. 1997;272(12):8083-8089. doi: 10.1074/jbc.272.12.8083.
  • studfiles.net [интернет]. Селективные ингибиторы ЦОГ-2 диарилсульфоны [доступ от 24.08.2017]. Доступ по ссылке: https://studfiles.net/preview/6011048/page:35/. [studfiles.net [Internet]. Selective Cox-2 inhibitors diarisulphone [cited 2017 Aug 24]. Available from: https://studfiles.net/preview/6011048/page:35/. (In Russ.)]
  • clinvest.ru [интернет]. Фармакоэкономические аспекты побочных эффектов и осложнений лекарственной терапии [доступ от 23.08.2017]. Доступ по ссылке: http://clinvest.ru/news/item/farmakoekonomicheskie-aspekty-pobochnyh-effektov-i-oslozhnenij-lekarstvennoj-terapii. [clinvest.ru [Internet]. Pharmacoeconomic aspects of the side effects and complications of drug therapy [cited 2017 Aug 23]. Available from: http://clinvest.ru/news/item/farmakoekonomicheskie-aspekty-pobochnyh-effektov-i-oslozhnenij-lekarstvennoj-terapii. (In Russ.)]
  • Барканова О.В. Методики диагностики эмоциональной сферы: психологический практикум. — Красноярск: Литера-принт, 2009. [OV Barkanova. Methods of diagnostics of emotional sphere: psychological practice. Krasnoyarsk: Litera-print; 2009. (In Russ.)]
  • Chan FK, Lanas A, Scheiman J, et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010;376(9736):173-179. doi: 10.1016/S0140-6736(10)60673-3.
  • Данилов А.Б. Управление болью. Биопсихосоциальный подход. — М.: АММ ПРЕСС, 2012. [Danilov AB. Pain management. Biopsychosocial approach. Moscow: AMM PRESS; 2012. (In Russ.)]
  • laesus-de-liro.livejournal.com [интернет]. Клиническая феноменология болевого синдрома при эндометриозе [доступ от 04.01.2018]. Доступ по ссылке: https://laesus-de-liro.livejournal.com/358888.html. [laesus-de-liro.livejournal.com [Internet]. Clinical phenomenology of pain with endometriosis [cited 2018 Jan 04]. Available from: https://laesus-de-liro.livejournal.com/358888.html. (In Russ.)]
  • Кузнецова И.В. Эндометриоз и тазовая боль // Эффек тивная фармакология. — 2014. — № 35. — С. 18–27. [Kuznetsova IV. Endometriosis and pelvic pain. Effektivnaya farmakologiya. 2014;(35):18-27. (In Russ.)]
  • Прилепская В.Н., Острейкова Л.И. Диеногест: фармакологические, клинические и лечебные аспекты. — М., 2005. [Prilepskaya VN, Ostreykova LI. Dienogest: pharmacological, clinical and therapeutic aspects. Moscow; 2005. (In Russ.)]
  • Olivares C, Bilotas M, Buquet R, et al. Effects of a selective cyclooxygenase-2 inhibitor on endometrial epithelial cells from patients with endometriosis. Hum Reprod. 2008;23(12):2701-2708. doi: 10.1093/humrep/den315.
  • Trelle S, Reichenbach S, Wandel S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086. doi: 10.1136/bmj.c7086.
  • rlsnet.ru [интернет]. Визанна [доступ от 11.02.2018]. Доступ по ссылке: https://www.rlsnet.ru/tn_index_id_48089.htm#pobochnye-dejstviya. [rlsnet.ru [Internet]. Visanne [cited 2018 Feb 11]. Available from: https://www.rlsnet.ru/tn_index_id_48089.htm#pobochnye-dejstviy. (In Russ.)]

Supplementary files

Supplementary Files Action
1. Fig. 1. Change of pain syndrome during the treatment (is according to the VAS) View (51KB) Indexing metadata
2. Fig. 2. The dynamics of change of irritability in groups during the treatment View (35KB) Indexing metadata

Views

Abstract - 26

PDF (Russian) - 14

PlumX


Copyright (c) 2018 Samoshkin N.G., Yarmolinskaya M.I., Polyakova V.O.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.