Orazov MR, Radzinsky VE, Orekhov RE. The effectiveness of therapy for endometriosis-associated pelvic pain resistant to surgical treatment. Gynecology. 2021; 23 (4): 314–323. DOI: 10.26442/20795696.2021.4.201097
Эффективность терапии эндометриоз-ассоциированной тазовой боли, резистентной к хирургическому лечению
Orazov MR, Radzinsky VE, Orekhov RE. The effectiveness of therapy for endometriosis-associated pelvic pain resistant to surgical treatment. Gynecology. 2021; 23 (4): 314–323. DOI: 10.26442/20795696.2021.4.201097
Цель. Оценить эффективность и безопасность терапии диеногестом в течение 24 нед у пациенток с эндометриоз-ассоциированной тазовой болью, резистентной к хирургическому лечению. Материалы и методы. В исследование включены 126 пациенток в возрасте 33–40 лет с подтвержденным при лапароскопии и морфологическом исследовании наружным генитальным эндометриозом – НГЭ (Международная классификация болезней 10-го пересмотра – N80.1, 80.2, 80.3, 80.4) и с тазовой болью, возникшей через 3–6 мес после хирургического лечения НГЭ (Международная классификация болезней 10-го пересмотра – N94.8 «Болевые и другие состояния, связанные с женскими половыми органами и менструальным циклом»). Участницы стратифицированы на 3 группы в зависимости от степени выраженности болевого синдрома по вербальной рейтинговой шкале (Verbal Analog Scale – VAS). В 1-ю группу включены пациентки с оценкой боли по VAS 10–40 мм, во 2-ю – 41–70 мм, в 3-ю – более 71 мм. Пациенткам всех 3 групп назначен препарат диеногест (Зафрилла®, Гедеон Рихтер, по 2 мг/сут) курсом 24 нед (согласно действующей инструкции к препарату). Наблюдение и оценку результатов лечения проводили в течение 6 мес. Дизайн исследования: проспективное, обсервационное, сравнительное исследование. Результаты. По всем шкалам (Biberoglu & Behrman Scale, Numeral Rating Scale, VAS) в каждой из групп через 3 и 6 мес после начала терапии отмечено стабильное статистически значимое снижение выраженности болевого синдрома (p<0,01). В результате лечения показатели сексуальной функции, оцененной по шкале опросника Female Sexual Function Index, во всех 3 группах статистически значимо улучшились (p<0,01). Согласно опроснику качества жизни при эндометриозе (Endometriosis Health Profile), анализируемые показатели статистически значимо улучшились у всех участниц исследования (p<0,01). Заключение. Диеногест – эффективный и безопасный метод терапии эндометриоз-ассоциированной тазовой боли, резистентной к хирургическому лечению. Прием диеногеста в течение 24 нед обеспечивает эффективное купирование болевого синдрома, позволяет облегчить симптомы заболевания, а также улучшить качество жизни и сексуальное функционирование.
Ключевые слова: эндометриоз, тазовая боль, диеногест, качество жизни
________________________________________________
Aim. To assess the efficacy and safety of 24-week therapy with dienogest in patients with endometriosis-associated pelvic pain resistant to surgical treatment. Materials and methods. The study included 126 patients aged 33–40 years with external genital endometriosis (EGE) confirmed by laparoscopy and morphological examination (International classification of diseases, 10th revision [ICD-10] – N80.1, 80.2, 80.3, 80.4) and with pelvic pain that occurred in 3–6 months after surgical treatment of EGE (ICD-10 – N94.8 "Pain and other conditions associated with female genital organs and menstrual cycle"). The participants were stratified into 3 groups by pain syndrome severity according to the Verbal Analog Scale (VAS). The group-1 included patients with 10–40 mm, the group-2 – with 41–70 mm, and the group-3 – with more than 71 mm pain score according to VAS. Patients of all 3 groups were prescribed the denogest (Zafrilla®, Gedeon Richter, 2 mg/day) for 24 weeks (according to the current pack insert). Follow-up and assessment of treatment outcomes were carried out over 6 months. Study design: prospective, observational, comparative study. Results. In 3 and 6 months after the start of therapy, there was a stable statistically significant decrease in pain syndrome severity by all scales (Biberoglu & Behrman Scale, Numeral Rating Scale, VAS) in each of the groups (p<0.01). In all 3 groups, treatment led to an improvement in sexual function, assessed with the Female Sexual Function Index scale, in 3 and 6 months after the start of therapy (p<0.01). According to the quality of life in endometriosis (Endometriosis Health Profile) questionnaire, the analyzed indicators significantly improved in all study participants (p<0.01). Conclusion. Dienogest is an effective and safe method for the treatment of endometriosis-associated pelvic pain resistant to surgical treatment. Treatment with dienogest for 24 weeks effectively relieves pain, improves symptoms, and improves quality of life and sexual functioning.
Key words: endometriosis, pelvic pain, dienogest, quality of life
1. Royal College of Obstetricians and Gynaecologists. Chronic Pelvic Pain, Initial Management (Green-top 41). Royal College of Obstetricians and Gynaecologists, 2012.
2. Vincent K, Evans E. An update on the management of chronic pelvic pain in women. Anaesthesia. 2021;76(Suppl.4):96-107. DOI:10.1111/anae.15421; PMID: 33682093
3. Steege JF, Siedhoff MT. Chronic pelvic pain. Obstet Gynecol. 2014;124(3):616-9.
4. Moore J, Kennedy S. Causes of chronic pelvic pain. Baillières Best Pract Res Clin Obstet Gynaecol. 2000;14(3):389-402.
5. Tirlapur SA, Kuhrt K, Chaliha C, et al. The ’evil twin syndrome’ in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. 2013;11:233-7.
6. Оразов М.Р., Радзинский В.Е., Михалева Л.М., и др. Диспареуния как визитная карточка инфильтративных форм эндометриоза. Трудный пациент. 2021;1 [Orazov MR, Radzinskii VE, Mikhaleva LM, et al. Dispareuniia kak vizitnaia kartochka infil'trativnykh form endometrioza. Trudnyi patsient. 2021;1 (in Russian)].
7. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441-61. DOI:10.1093/humupd/dmp007
8. Sinaii N, Plumb K, Cotton L, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril. 2008;89:538-45.
9. Koninckx PR, Meuleman C, Demeyere S, et al. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55:759-65.
10. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511-9.
11. Оразов М.Р., Радзинский В.Е., Хамошина М.Б., и др. Эффективность лечения тазовой боли, обусловленной наружным генитальным эндометриозом. Трудный пациент. 2017;8-9 [Orazov MR, Radzinskii VE, Khamoshina MB, et al. Effektivnost' lecheniia tazovoi boli, obuslovlennoi naruzhnym genital'nym endometriozom. Trudnyi patsient. 2017;8-9 (in Russian)].
12. Brown J, Crawford TJ, Allen C, et al. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;1:CD004753.
13. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod. 2014;29:400-12.
14. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2010:CD008475.
15. Practice Committee of American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2008;90:S260-9.
16. Brown J, Kives S, Akhtar M. Progestagens and antiprogestagens for pain associated with endometriosis. Cochrane Database Syst Rev. 2012:CD002122.
17. Grandi G, Mueller M, Bersinger NA, et al. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res. 2016;65:183-92.
18. Harada T, Taniguchi F. Dienogest: A new therapeutic agent for the treatment of endometriosis. Womens Health (Lond). 2010;6:27-35.
19. Horie S, Harada T, Mitsunari M, et al. Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril. 2005;83:1530-5.
20. Katsuki Y, Takano Y, Futamura Y, et al. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol. 1998;138:216-26.
21. Mita S, Shimizu Y, Notsu T, et al. Dienogest inhibits Toll-like receptor 4 expression induced by costimulation of lipopolysaccharide and high-mobility group box 1 in endometrial epithelial cells. Fertil Steril. 2011;96:1485-9.
22. Nirgianakis K, Grandi G, McKinnon B, et al. Dienogest mediates midkine suppression in endometriosis. Hum Reprod. 2016;31:1981-6.
23. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175-84.
24. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis–a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91:675-81.
25. Kohler G, Faustmann TA, Gerlinger C, et al. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010;108:21-5.
26. Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: A 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2010;151:193-8.
27. Strowitzki T, Marr J, Gerlinger C, et al. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: A 24-week, randomized, multicentre, open-label trial. Hum Reprod. 2010;25:633-41.
28. Strowitzki T, Marr J, Gerlinger C, et al. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet. 2012;117:22-33.
29. Оразов М.Р., Чайка А.В., Носенко Е.Н. Диеногест в лечении хронической тазовой боли при аденомиозе. Медико-социальные проблемы семьи. 2013;18(3). Режим доступа: http://www.mif-ua.com/archive/article_print/37185. Ссылка активна на 05.07.2021 [Orazov MR, Chaika AV, Nosenko EN. Dienogest v lechenii khronicheskoi tazovoi boli pri adenomioze. Mediko-sotsial'nye problemy sem'i. 2013;18(3). Available: http://www.mif-ua.com/archive/article_print/37185. Accessed: 05.07.2021(in Russian)].
30. Liu X, Guo SW. Dysmenorrhea: risk factors in women with endometriosis. Women's Health. 2008;4(4):399-411.
31. Strowitzki T, Faustmann A, Christoph G, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2010;151:193-8.
32. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis – a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91:675-81.
33. Katsuki Y, Takano Y, Futamura Y, et al. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol. 1998;138:216-26.
34. Okada H, Nakajima T, Yoshimura T, et al. The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod. 2001;7:341-7.
35. Horie P, Harada T, Mitsunari M, et al. Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril. 2005;83:1530-5.
36. Chauvet P, Guiguet-Auclair C, Comptour A, et al. Feelings and expectations in endometriosis: Analysis of open comments from a cohort of endometriosis patients. J Gynecol Obstet Hum Reprod. 2018;47(7):281-7.
37. Shum LK, Bedaiwy MA, Allaire C, et al. Deep Dyspareunia and Sexual Quality of Life in Women With Endometriosis. Sex Med. 2018;6(3):224-33.
38. Yarmolinskaya M, Makarova I, Veremiova R, et al. A noninterventional study with dienogest 2 mg to assess the quality of life in patients with endometriosis (DIVA study). Presented at: 2nd Congress of the Society of Endometriosis and Uterine Disorders; May 12-14, 2016; Barcelona, Spain. Abstract 1576.
39. Iglesias-Rios L, Harlow SD, Reed BD. Depression and Posttraumatic Stress Disorder Among Women with Vulvodynia: Evidence from the Population-Based Woman to Woman Health Study. J Women's Health. 2015;24:557.
________________________________________________
1. Royal College of Obstetricians and Gynaecologists. Chronic Pelvic Pain, Initial Management (Green-top 41). Royal College of Obstetricians and Gynaecologists, 2012.
2. Vincent K, Evans E. An update on the management of chronic pelvic pain in women. Anaesthesia. 2021;76(Suppl.4):96-107. DOI:10.1111/anae.15421; PMID: 33682093
3. Steege JF, Siedhoff MT. Chronic pelvic pain. Obstet Gynecol. 2014;124(3):616-9.
4. Moore J, Kennedy S. Causes of chronic pelvic pain. Baillières Best Pract Res Clin Obstet Gynaecol. 2000;14(3):389-402.
5. Tirlapur SA, Kuhrt K, Chaliha C, et al. The ’evil twin syndrome’ in chronic pelvic pain: a systematic review of prevalence studies of bladder pain syndrome and endometriosis. Int J Surg. 2013;11:233-7.
6. Orazov MR, Radzinskii VE, Mikhaleva LM, et al. Dispareuniia kak vizitnaia kartochka infil'trativnykh form endometrioza. Trudnyi patsient. 2021;1 (in Russian).
7. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441-61. DOI:10.1093/humupd/dmp007
8. Sinaii N, Plumb K, Cotton L, et al. Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril. 2008;89:538-45.
9. Koninckx PR, Meuleman C, Demeyere S, et al. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55:759-65.
10. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511-9.
11. Orazov MR, Radzinskii VE, Khamoshina MB, et al. Effektivnost' lecheniia tazovoi boli, obuslovlennoi naruzhnym genital'nym endometriozom. Trudnyi patsient. 2017;8-9 (in Russian).
12. Brown J, Crawford TJ, Allen C, et al. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;1:CD004753.
13. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: Management of women with endometriosis. Hum Reprod. 2014;29:400-12.
14. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2010:CD008475.
15. Practice Committee of American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2008;90:S260-9.
16. Brown J, Kives S, Akhtar M. Progestagens and antiprogestagens for pain associated with endometriosis. Cochrane Database Syst Rev. 2012:CD002122.
17. Grandi G, Mueller M, Bersinger NA, et al. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res. 2016;65:183-92.
18. Harada T, Taniguchi F. Dienogest: A new therapeutic agent for the treatment of endometriosis. Womens Health (Lond). 2010;6:27-35.
19. Horie S, Harada T, Mitsunari M, et al. Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril. 2005;83:1530-5.
20. Katsuki Y, Takano Y, Futamura Y, et al. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol. 1998;138:216-26.
21. Mita S, Shimizu Y, Notsu T, et al. Dienogest inhibits Toll-like receptor 4 expression induced by costimulation of lipopolysaccharide and high-mobility group box 1 in endometrial epithelial cells. Fertil Steril. 2011;96:1485-9.
22. Nirgianakis K, Grandi G, McKinnon B, et al. Dienogest mediates midkine suppression in endometriosis. Hum Reprod. 2016;31:1981-6.
23. Schindler AE. Dienogest in long-term treatment of endometriosis. Int J Womens Health. 2011;3:175-84.
24. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis–a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91:675-81.
25. Kohler G, Faustmann TA, Gerlinger C, et al. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010;108:21-5.
26. Strowitzki T, Faustmann T, Gerlinger C, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: A 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2010;151:193-8.
27. Strowitzki T, Marr J, Gerlinger C, et al. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: A 24-week, randomized, multicentre, open-label trial. Hum Reprod. 2010;25:633-41.
28. Strowitzki T, Marr J, Gerlinger C, et al. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet. 2012;117:22-33.
29. Orazov MR, Chaika AV, Nosenko EN. Dienogest v lechenii khronicheskoi tazovoi boli pri adenomioze. Mediko-sotsial'nye problemy sem'i. 2013;18(3). Available: http://www.mif-ua.com/archive/article_print/37185. Accessed: 05.07.2021(in Russian).
30. Liu X, Guo SW. Dysmenorrhea: risk factors in women with endometriosis. Women's Health. 2008;4(4):399-411.
31. Strowitzki T, Faustmann A, Christoph G, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2010;151:193-8.
32. Harada T, Momoeda M, Taketani Y, et al. Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis – a randomized, double-blind, multicenter, controlled trial. Fertil Steril. 2009;91:675-81.
33. Katsuki Y, Takano Y, Futamura Y, et al. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol. 1998;138:216-26.
34. Okada H, Nakajima T, Yoshimura T, et al. The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod. 2001;7:341-7.
35. Horie P, Harada T, Mitsunari M, et al. Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril. 2005;83:1530-5.
36. Chauvet P, Guiguet-Auclair C, Comptour A, et al. Feelings and expectations in endometriosis: Analysis of open comments from a cohort of endometriosis patients. J Gynecol Obstet Hum Reprod. 2018;47(7):281-7.
37. Shum LK, Bedaiwy MA, Allaire C, et al. Deep Dyspareunia and Sexual Quality of Life in Women With Endometriosis. Sex Med. 2018;6(3):224-33.
38. Yarmolinskaya M, Makarova I, Veremiova R, et al. A noninterventional study with dienogest 2 mg to assess the quality of life in patients with endometriosis (DIVA study). Presented at: 2nd Congress of the Society of Endometriosis and Uterine Disorders; May 12-14, 2016; Barcelona, Spain. Abstract 1576.
39. Iglesias-Rios L, Harlow SD, Reed BD. Depression and Posttraumatic Stress Disorder Among Women with Vulvodynia: Evidence from the Population-Based Woman to Woman Health Study. J Women's Health. 2015;24:557.
Авторы
М.Р. Оразов*, В.Е. Радзинский, Р.Е. Орехов
ФГАОУ ВО «Российский университет дружбы народов», Москва, Россия
*omekan@mail.ru
________________________________________________
Mekan R. Orazov*, Viktor E. Radzinsky, Roman E. Orekhov
People’s Friendship University of Russia (RUDN University), Moscow, Russia
*omekan@mail.ru