Treatment of endometriosis-associated pain: an individualized approach

Radzinsky V.E., Orazov M.R., Orekhov R.E.

Peoples’ Friendship University of Russia (RUDN University), Ministry of Education and Higher Science of the Russian Federation, Moscow, Russia
Objective: To conduct a systematic analysis of the data available in the modern literature on the efficacy, safety and pharmacodynamics of combined oral contraceptives (COCs), to evaluate the results of prospective clinical studies in the treatment of endometriosis-associated pain.
Main points: Despite the fact that endometriosis continues to be one of the most common gynecological diseases, there are still considerable discussions in the scientific world regarding its diagnosis and treatment. Chronic pelvic pain, dysmenorrhea, dyspareunia, dyschezia and infertility are the key symptoms of the disease and seriously affect the quality of life. The combination of surgical and medical methods of treatment before and/or after surgery is one of the most common approaches to the management of endometriosis. Although COCs have been approved by a variety of clinical protocols and they are widely used to relieve pain in endometriosis, clinical studies confirming their effectiveness are few.
Conclusion: According to the results of numerous studies, one of the most effective drugs for the treatment of endometriosis is a COC, Siluette. This oral contraceptive contains 30 mcg of ethinyl estradiol and 2 mg of dienogest and affects pathogenetic mechanisms of the disease. Due to dienogest, there is a high antiproliferative activity, activation of apoptosis, subsequent pseudodecidualization and suppression of neoangiogenesis which give the molecule non-contraceptive advantages. Therefore, the pain syndrome is significantly reduced, sexual function is restored and the quality of life is improved.


chronic pelvic pain
combined oral contraceptives (COCs)


  1. Оразов М.Р., Радзинский В.Е., Хамошина М.Б., Духин А.О., Токтар Л.Р., Орехов Р.Е., Читанава Ю.С. Эффективность комплексной терапии тазовой боли, ассоциированной с аденомиозом. Трудный пациент. 2020; 18(4): 34-40. [Orazov M.R., Radzinskiy V.E., Khamoshina M.B., Dukhin A.O., Toktar L.R., Orekhov R.E., Chitanava Yu.S. Effectiveness of Complex Therapy of Pelvic Pain Associated with Adenomyosis. Difficult Patient. 2020; 18(4): 34-40. (in Russian)].
  2. Vercellini P., Buggio L., Borghi A., Monti E., Gattei U., Frattaruolo M.P. Medical treatment in the management of deep endometriosis infiltrating the proximal rectum and sigmoid colon: a comprehensive literature review. Acta Obstet Gynecol Scand. 2018; 97(8): 942-55.
  3. Zondervan K.T., Becker C.M., Koga K., Missmer S.A., Taylor R.N., Viganò P. Endometriosis Nat Rev Dis Prim. 2018; 4(1): 9.
  4. Чернуха Г.Е., Марченко Л.А., Гусев Д.В. Поиск оптимальных решений и пересмотр тактики ведения пациенток с эндометриозом. Акушерство и гинекология. 2020; 8: 12-20. [Chernukha G.E., Marchenko L.A., Gusev D.V. Searching for optimal decisions and revising management tactics for patients with endometriosis. Obstetrics and Gynecology. 2020; 8: 12-20. (in Russian)].
  5. Buggio L., Barbara G., Facchin F., Frattaruolo M.P., Aimi G., Berlanda N. Self-management and psychological-sexological interventions in patients with endometriosis: strategies, outcomes, and integration into clinical care. Int J Womens Health. 2017; 9: 281-93.
  6. American College of Obstetricians and Gynecologists (ACOG). Practice Bulletin no. 114: Management of endometriosis. Obstet Gynecol. 2010; 116(1): 223-36.
  7. Овакимян А.С., Кречетова Л.В., Вторушина В.В., Ванько Л.В., Козаченко И.Ф., Адамян Л.В. Содержание ИЛ-1β, ИЛ-8 и субстанции Р в плазме крови и перитонеальной жидкости пациенток с различными формами наружного генитального эндометриоза и хронической тазовой болью. Акушерство и гинекология. 2015; 3: 79-86. [Ovakimyan A.S., Krechetova L.V., Vtorushina V.V., Vanko L.V., Kozachenko I.F., Yarotskaya E.L., Adamyan L.V. Plasma and peritoneal fluid IL-1β, IL-8, and substance P levels in patients with different forms of external genital endometriosis and chronic pelvic pain. Obstetrics and Gynecology. 2015; 3: 79-86. (in Russian)].
  8. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014; 101(4): 927-35.
  9. Aredo J.V., Heyrana K.J., Karp B.I., Shah J.P., Stratton P. Relating chronic pelvic pain and endometriosis to signs of sensitization and myofascial pain and dysfunction. Semin Reprod Med. 2017; 35(1): 88-97.
  10. Yosef A., Allaire C., Williams C., Ahmed A.G., Al-Hussaini T., Abdellah M.S. et al. Multifactorial contributors to the severity of chronic pelvic pain in women. Am J Obstet Gynecol. 2016; 215(6): 760.e1-760.e14.
  11. Mowers E.L., Lim C.S., Skinner B., Mahnert N., Kamdar N., Morgan D.M. et al. Prevalence of endometriosis during abdominal or laparoscopic hysterectomy for chronic pelvic pain. Obstet Gynecol. 2016; 127(6): 1045-53.
  12. Balasch J., Creus M., Fabregues F., Carmona F., Ordi J., Martinez-Roman S. et al. Visible and non-visible endometriosis at laparoscopy in fertile and infertile women and in patients with chronic pelvic pain: a prospective study. Hum Reprod. 1996; 11(2): 387-91.
  13. Радзинский В.Е., Раевская О.А., Маклецова С.А. КОК и эндометриоз: где правда? StatusPraesens. Гинекология, акушерство, бесплодный брак. 2017; 4: 63-9. [Radzinsky V.E., Raevskaya O.A., Makletsova S.A. KOK and endometriosis: where is it? StatusPraesens. Gynecology, obstetrics, infertile marriage. 2017; 4: 63-9. (in Russian)].
  14. Stratton P., Berkley K.J. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update. 2011; 17(3): 327-46.
  15. Vercellini P., Fedele L., Aimi G., Pietropaolo G., Consonni D., Crosignani P.G. Association between endometriosis stage, lesion type, patient characteristics and severity of pelvic pain symptoms: a multivariate analysis of over 1000 patients. Hum Reprod. 2007; 22(1): 266-71.
  16. Hirsch M., Begum M.R., Paniz É., Barker C., Davis C.J., Duffy J. Diagnosis and management of endometriosis: a systematic review of international and national guidelines. BJOG. 2018; 125(5): 556-64.
  17. Министерство здравоохранения Российcкой Федерации. Клинические рекомендации «Эндометриоз». М.; 2020. ID:КР259/1. [Ministry of Health of the Russian Federation. Clinical Guidelines “Endometriosis”. М.; 2020. ID:KP259/1 (in Russian)].
  18. Chapron C., Souza C., Borghese B., Lafay-Pillet M.C., Santulli P., Bijaoui G., Goffinet F., de Ziegler D. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Hum Reprod. 2011; 26(8): 2028-35. doi: 10.1093/humrep/der156.
  19. Dunselman G.A., Vermeulen N., Becker C., Calhaz-Jorge C., D'Hooghe T., De Bie B., Heikinheimo O. et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014; 29(3): 400-12.
  20. Meresman G.F., Augé L., Barañao R.I., Lombardi E., Tesone M., Sueldo C. Oral contraceptives suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis. Fertil Steril. 2002; 77(6): 1141-7.
  21. Reis F.M., Petraglia F., Taylor R.N. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update. 2013; 19(4): 406-18.
  22. Gebel H.M., Braun D.P., Tambur A., Frame D., Rana N., Dmowski W.P. Spontaneous apoptosis of endometrial tissue is impaired in women with endometriosis. Fertil Steril. 1998; 69(6): 1042-7.
  23. Izawa M., Harada T., Deura I., Taniguchi F., Iwabe T., Terakawa N. Drug-induced apoptosis was markedly attenuated in endometriotic stromal cells. Hum Reprod. 2006; 21(3): 600-4.
  24. Nasu K., Nishida M., Kawano Y., Tsuno A., Abe W., Yuge A. et al. Aberrant expression of apoptosis-related molecules in endometriosis: a possible mechanism underlying the pathogenesis of endometriosis. Reprod Sci. 2011; 18(3): 206-18.
  25. Zeitoun K., Takayama K., Sasano H., Suzuki T., Moghrabi N., Andersson S. et al. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. J Clin Endocrinol Metab. 1998; 83(12): 4474-80.
  26. Kitawaki J., Noguchi T., Amatsu T., Maeda K., Tsukamoto K., Yamamoto T. et al. Expression of aromatase cytochrome P450 protein and messenger ribonucleic acid in human endometriotic and adenomyotic tissues but not in normal endometrium. Biol Reprod. 1997; 57(3): 514-9.
  27. Bono Y., Kyo S., Kiyono T., Mizumoto Y., Nakamura M., Maida Y. et al. Concurrent estrogen action was essential for maximal progestin effect in oral contraceptives. Fertil Steril. 2014; 101(5): 1337-43.
  28. Somigliana E., Vercellini P., Vigano P., Abbiati A., Benaglia L., Fedele L. Endometriosis and estroprogestins: the chicken or the egg causality dilemma. Fertil Steril. 2011; 95(1): 431-3.
  29. Maia HJ, Casoy J. Non-contraceptive health benefits of oral contraceptives. Eur J Contracept Reprod Health Care 2008;13:17–24
  30. Tarjanne S., Ng C.H.M., Manconi F., Arola J., Mentula M., Maneck B. et al. Use of hormonal therapy is associated with reduced nerve fiber density in deep infiltrating, rectovaginal endometriosis. Acta Obstet Gynecol Scand. 2015; 94(7): 693-700.
  31. Laschke M.W., Menger M.D. Anti-angiogenic treatment strategies for the therapy of endometriosis. Hum Reprod Update. 2012; 18(6): 682-702. 10.1093/humupd/dms026.
  32. Harada T., Momoeda M., Taketani Y., Hoshiai H., Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008; 90(5): 1583-8.
  33. Vercellini P., Barbara G., Somigliana E., Bianchi S., Abbiati A., Fedele L. Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis. Fertil Steril. 2010; 93(7): 2150-61.
  34. Vercellini P., de Giorgi O., Mosconi P., Stellato G., Vicentini S., Crosignani P.G. Cyproterone acetate versus a continuous monophasic oral contraceptive in the treatment of recurrent pelvic pain after conservative surgery for symptomatic endometriosis. Fertil Steril. 2002; 77(1): 52-61.
  35. Vercellini P., Pietropaolo G., de Giorgi O., Pasin R., Chiodini A., Crosignani P.G. Treatment of symptomatic rectovaginal endometriosis with an estrogenprogestogen combination versus low-dose norethindrone acetate. Fertil Steril. 2005; 84(5):1375-87.
  36. Ferrari S., Persico P., DI Puppo F., Vigano P., Tandoi I., Garavaglia E. et al. Continuous low-dose oral contraceptive in the treatment of colorectal endometriosis evaluated by rectal endoscopic ultrasonography. Acta Obstet Gynecol Scand. 2012; 91(6): 699-703.
  37. Tanaka Y., Mori T., Ito F., Koshiba A., Kusuki I., Kitawaki J. Effects of lowdose combined drospirenone-ethinylestradiol on perimenstrual symptoms experienced by women with endometriosis. Int J Gynaecol Obstet. 2016; 135(2):135-9.
  38. Taniguchi F., Enatsu A., Ota I., Toda T., Arata K., Harada T. Effects of low dose oral contraceptive pill containing drospirenone/ethinylestradiol in patients with endometrioma. Eur J Obstet Gynecol Reprod Biol. 2015; 191:116-20.
  39. Vercellini P., Frontino G., de Giorgi O., Pietropaolo G., Pasin R., Crosignani P.G. Continuous use of an oral contraceptive for endometriosis-associated recurrent dysmenorrhea that does not respond to a cyclic pill regimen. Fertil Steril. 2003; 80(3): 560-3. doi: 10.1016/s0015-0282(03)00794-5.
  40. Harada T., Kosaka S., Elliesen J., Yasuda M., Ito M., Momoeda M. Ethinylestradiol 20 mg/drospirenone 3 mg in a flexible extended regimen for the management of endometriosis-associated pelvic pain: a randomized controlled trial. Fertil Steril. 2017; 108(5): 798-805.
  41. Caruso S., Iraci M., Cianci S., Fava V., Casella E., Cianci A. Comparative, openlabel prospective study on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain on 2 mg dienogest/30 mg ethinyl estradiol continuous or 21/7 regimen oral contraceptive. J Endocrinol Invest. 2016; 39(8): 923-31.
  42. Grandi G., Xholli A., Napolitano A., Palma F., Cagnacci A. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study. Reprod Sci. 2015; 22(5): 626-32.
  43. Morotti M., Remorgida V., Venturini P.L., Ferrero S. Progestogen-only contraceptive pill compared with combined oral contraceptive in the treatment of pain symptoms caused by endometriosis in patients with migraine without aura. Eur J Obstet Gynecol Reprod Biol. 2014; 179: 63-8.
  44. Di Francesco A., Pizzigallo D. Use of micronized palmitoylethanolamide and trans-polydatin in chronic pelvic pain associated with endometriosis. An open-label study. Giorn It Ost Gin. 2014; 36(2): 353-8.
  45. Zupi E., Marconi D., Sbracia M., Zullo F., de Vivo B., Exacustos C. et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertil Steril. 2004; 82(5):1303-8. doi: 10.1016/j.fertnstert.2004.03.062.
  46. Seracchioli R., Mabrouk M., Manuzzi L. et al. Post-operative use of oral contraceptive pills for prevention of anatomical relapse or symptom-recurrence after conservative surgery for endometriosis. Hum Reprod. 2009; 24(11): 2729-35.
  47. Seracchioli R., Mabrouk M., Frascà C., Manuzzi L., Savelli L., Venturoli S. Long-term oral contraceptive pills and postoperative pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled trial. Fertil Steril. 2010; 94(2): 464-71.
  48. Takamura M., Koga K., Osuga Y. et al. Post-operative oral contraceptive use reduces the risk of ovarian endometrioma recurrence after laparoscopic excision. Hum Reprod. 2009; 24(12): 3042-8.
  49. Wu L., Wu Q., Liu L. Oral contraceptive pills for endometriosis after conservative surgery: a systematic review and metaanalysis. Gynecol Endocrinol. 2013; 29(10): 883-90.
  50. Muzii L., Di Tucci C., Achilli C. et al. Continuous versus cyclic oral contraceptives after laparoscopic excision of ovarian endometriomas: A systematic review and metaanalysis. Am J Obstet Gynecol. 2016; 214(2): 203-11. doi: 10.1016/j.ajog.2015.08.074.
  51. Zorbas K.A., Economopoulos K.P., Vlahos N.F. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet. 2015; 292(1): 37-43.
  52. Taylor H.S., Giudice L.C., Lessey B.A., Abrao M.S., Kotarski J., Archer D.F. et al. Treatment of endometriosis-associated pain with Elagolix, an oral GnRH antagonist. N Engl J Med. 2017; 377(1): 28-40.
  53. Becker C.M., Gattrell W.T., Gude K., Singh S.S. Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertil Steril. 2017;108(1):125-36.
  54. Lee J.H., Song J.Y., Yi K..W. et al. Efectiveness of Dienogest for Treatment of Recurrent Endometriosis: Multicenter Data Reprod Sci. 2018; 25(10): 1515-22. 1933719118779733.
  55. Techatraisak K., Hestiantoro A., Ruey S. et al. Efectiveness of dienogest in improving quality of life in Asian women with endometriosis (ENVISIOeN): interim results from a prospective cohort study under real-life clinical practice. BMC Womens Health. 2019; 19(1): 68.
  56. Muzii L., Galati G., Di Tucci C. et al. Medical treatment of ovarian endometriomas: a prospective evaluation of the efect of dienogest on ovarian reserve, cyst diameter, and associated pain. Gynecol Endocrinol. 2020; 36(1): 81-3.
  57. Vignali M., Belloni G.M., Pietropaolo G. et al. Efect of Dienogest therapy on the size of the endometrioma. Gynecol Endocrinol. 2020; 36(8): 723-7.
  58. Papíková Z., Hudeček R., Ventruba P., Szypulová M. Efcacy of dienogest treatment of clinical symptoms of rectovaginal endometriosis. Ces Gynekol. 2019; 84(5): 331-6.
  59. Maggiore U.L.R., Ferrero S., Candiani M., Somigliana E., Viganò P., Vercellini P. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol. 2017; 71(5): 790-807.
  60. Angioni S., Nappi L., Pontis A. et al. Dienogest. A possible conservative approach in bladder endometriosis. Results of a pilot study. Gynecol Endocrinol. 2015; 31(5): 406-8.
  61. Leonardo-Pinto J.P., Benetti-Pinto C.L., Cursino K., Yela D.A. Dienogest and deep infltrating endometriosis: The remission of symptoms is not related to endometriosis nodule remission. Eur J Obstet Gynecol Reprod Biol. 2017; 211: 108-11.
  62. Caruso S., Iraci M., Cianci S., Vitale S.G., Fava V., Cianci A. Efects of long-term treatment with Dienogest on the quality of life and sexual function of women afected by endometriosis-associated pelvic pain. J Pain Res. 2019; 12: 2371-8.
  63. Yu Q., Zhang S., Li H. et al. Dienogest for treatment of endometriosis in women: A 28-week, open-label, extension study. J Womens Health (Larchmt). 2019; 28(2): 170-7.
  64. Lee D.Y., Lee J.Y., Seo J.W., Yoon B.K., Choi D.S. Gonadotropinreleasing hormone agonist with add–back treatment is as efective and tolerable as dienogest in preventing pain recurrence after laparoscopic surgery for endometriosis. Arch Gynecol Obstet. 2016; 294(6): 1257-63. .
  65. Seo J.W., Lee D.Y., Kim S.E., Yoon B.K., Choi D.S. Comparison of long-term use of combined oral contraceptive after gonadotropin-releasing hormone agonist plus add-back therapy versus dienogest to prevent recurrence of ovarian endometrioma after surgery. Eur J Obstet Gynecol Reprod Biol. 2019; 236: 53-7.

Received 13.10.2021

Accepted 19.10.2021

About the Authors

Viktor E. Radzinsky, Honored Scientist of the Russian Federation, Corresponding Member of the RAS, Dr. Med. Sci., Professor, Head of the Department of Obstetrics and Gynecology with a course in perinatology of the Medical Institute of the RUDN University, +7(495)321-41-85,,
117198, Russia, Moscow, Miklukho-Maklaya str., 6.
Mekan R. Orazov, Dr. Med. Sci., Professor, Professor of the Department of Obstetrics and Gynecology with a course in perinatology of the Medical Institute of the RUDN University, +7(495)321-41-85, +7(915)237-52-92,, 117198, Russia, Moscow, Miklukho-Maklaya str., 6.
Roman E. Orekhov, assistant at the Department of Obstetrics and Gynecology with a course in perinatology at the RUDN University, +7(495)321-41-85,, 117198, Russia, Moscow, Miklukho-Maklaya str., 6.

Authors’ contributions: Radzinsky V.E. – developing research design, editing the manuscript; Orazov M.R. – analysis and review of literature data, editing the manuscript; Orekhov R.E. – collecting the literature data, analysis and review of the literature data, writing the text and editing the manuscript.
Conflicts of interest: The authors declare that there are no conflicts of interests.
Funding: The article was prepared without sponsorship.
For citation: Radzinsky V.E., Orazov M.R., Orekhov R.E.
Treatment of endometriosis-associated pain: an individualized approach.
Akusherstvo i Ginekologiya / Obstetrics and gynecology. 2021; 10: 31-37 (in Russian)

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.