Modern principles of medical treatment for endometriosis at an early reproductive age

Khashchenko E.P., Sivirinova A.S., Uvarova E.V.

1) Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of the Russian Federation, Moscow, Russian Federation 2) M.V. Lomonosov Moscow State University, Moscow, Russian Federation 3) I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russian Federation
It is generally accepted that the priority in the choice of treatment belongs to drug therapy, since an adequately and timely selected regimen can prevent the need for surgery. To date, there is no universal approach to medical treatment for endometriosis. However, given that drugs control, but do not cure the disease, long-term pharmacological treatment may be required until pregnancy or, sometimes, physiological menopause occurs. This review presents the current state of the problem of medical treatment for endometriosis and the available clinical guidelines on this topic, including in the treatment of early reproductive-aged patients. It summarizes currently available information on approaches to treating endometriosis. The review discusses the drug groups that show the highest efficacy in treating endometriosis and dysmenorrhea associated with endometriosis (gestagens, combined oral contraceptives, gonadotropin-releasing hormone agonists), as well as the promising drugs that go through clinical trials (selective progesterone and estrogen receptor modulators, metformin, statins, cabergoline, etc.). Particular attention is paid to the mechanisms of anti-endometrioid action of gestagens, which is associated not only with the induction of endometrial decidualization, but also with anti-inflammatory and immunomodulatory effects, the decrease in the transcription of neuro- and angiogenic factors, and the suppression of the proliferative activity of foci and trophism to the latter, by inhibiting the growth of blood vessels and nerves.
Conclusion: The available treatment regimens for endometriosis combine symptomatic and pathogenic effects that determine the long-term efficacy, safety profile, and rationale, starting from the diagnosis at an early reproductive age.

Keywords

endometriosis
adolescent females
hormonal therapy
gestagens
dienogest
dydrogesterone
combined oral contraceptives
medical rehabilitation

References

  1. Parker M.A, Sneddon A.E., Arbon P. The menstrual disorder of teenagers (MDOT) study: Determining typical menstrual patterns and menstrual disturbance in a large population-based study of Australian teenagers. 2010; 117(2): 185-92. https://dx.doi.org/10.1111/j.1471-0528.2009.02407.x.
  2. Committee on Professional Liability, American College of Obstetricians and Gynecologists. ACOG Committee Opinion #309: Coping with the stress of medical professional liability litigation. Gynecol. 2005; 105(2): 453-4. https://dx.doi.org/10.1097/00006250-200502000-00066.
  3. Harlow S.D., Gass M., Hall J.E., Lobo R., Maki P., Rebar R.W. et al. Executive summary of the Stages of Reproductive Aging Workshop + 10: addressing the unfinished agenda of staging reproductive aging. Menopause. 2012; 19(4): 387-95. https://dx.doi.org/10.1097/gme.0b013e31824d8f40.
  4. Management of women with endometriosis. Guideline of the European Society of Human Reproduction and Embryology. September 2013.
  5. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Steril. 2014; 101(4): 927-35. https://dx.doi.org/10.1016/ j.fertnstert.2014.02.012.
  6. Министерство здравоохранения Российской Федерации. Клинические рекомендации. Эндометриоз. М.; 2020. [Ministry of Health of the Russian Federation. Clinical Guidelines. M.; 2020. (in Russian)].
  7. Tosti C., Biscione A., Morgante G., Bifulco G., Luisi S., Petraglia F. Hormonal therapy for endometriosis: from molecular research to bedside. Gynecol. Reprod. Biol. 2017; 209: 61-6. https://dx.doi.org/10.1016/j.ejogrb.2016.05.032.
  8. Bouchard P., Chabbert-Buffet N., Fauser B.C.J.M. Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety. Steril. 2011; 96(5): 1175-89. https://dx.doi.org/10.1016/ j.fertnstert.2011.08.021.
  9. Kaur K., Allahbadia G. An update on pathophysiology and medical management of endometriosis. Reprod. Sci. 2016; 4: 53-73. https://dx.doi.org/10.4236/ arsci.2016.42008.
  10. Yilmaz B., Sucak A., Kilic S., Aksakal O., Aksoy Y., Lortlar N. et al. Metformin regresses endometriotic implants in rats by improving implant levels of superoxide dismutase, vascular endothelial growth factor, tissue inhibitor of metalloproteinase-2, and matrix metalloproteinase-9. Am. J. Obstet. Gynecol. 2010; 202(4): 368.e1-368.e8. https://dx.doi.org/10.1016/j.ajog.2009.10.873.
  11. Jouhari S., Mohammadzadeh A., Soltanghoraee H., Mohammadi Z., Khazali S., Mirzadegan E. et al. Effects of silymarin, cabergoline and letrozole on rat model of endometriosis. Taiwan. J. Obstet. Gynecol. 2018; 57(6): 830-5. https://dx.doi.org/10.1016/j.tjog.2018.10.011.
  12. Kim Y.S., Kim Y.J., Kim M.J., Lee S.J., Kwon H., Lee J.H. Novel medicine for endometriosis and its therapeutic effect in a mouse model. 2020; 8(12): 619. https://dx.doi.org/10.3390/biomedicines8120619.
  13. Zeybek B., Costantine M., Kilic G.S., Borahay M.A. Therapeutic roles of statins in gynecology and obstetrics: the current evidence. Sci. 2018; 25(6): 802-17. https://dx.doi.org/10.1177/1933719117750751.
  14. Dawood Y. Global library of women's medicine's. (ISSN: 1756­2228) 2008. https://dx.doi.org/10.3843/GLOWM.10009.
  15. Vercellini P., Barbara G., Somigliana E., Bianchi S., Abbiati A., Fedele L. Comparison of contraceptive ring and patch for the treatment of symptomatic endometriosis. Steril. 2010; 93(7): 2150-61. https://dx.doi.org/10.1016/ j.fertnstert.2009.01.071.
  16. Chantalat E., Valera M.C., Vaysse C., Noirrit E., Rusidze M., Weyl A. et al. Estrogen receptors and endometriosis. Int. J. Mol. Sci. 2020; 21(8): 2815. https://dx.doi.org/10.3390/ijms21082815.
  17. Dechering K., Boersma C., Mosselman S. Estrogen receptors a and в: two receptors of a Kknd? Member of the nuclear receptor gene. Curr. Med. Chem. 2000; 7(5): 561-76. https://dx.doi.org/10.2174/0929867003375010.
  18. Barkhem T., Carlsson B., Nilsson Y., Enmark E., Gustafsson J., Nilsson S. Differential response of estrogen receptor-а and estrogen receptor-b to partial estrogen agonists/ ntagonists. Pharmacol. 1998; 54(1): 105-12. https://dx.doi.org/10.1124/mol.54.1.105.
  19. Vercellini P., Eskenazi B., Consonni D., Somigliana E., Parazzini F., Abbiati A., Fedele L. Oral contraceptives and risk of endometriosis : a systematic review and meta-analysis. Reprod. Update. 2011; 17(2): 159-70. https://dx.doi.org/10.1093/humupd/dmq042.
  20. Chapron C, Souza C, Borghese B. Oral contraceptives and endometriosis: the past use of oral contraceptives for treating severe primary dysmenorrhea is associated with endometriosis, especially deep infiltrating endometriosis. Reprod. 2011; 26(8): 2028-35. https://dx.doi.org/10.1093/humrep/der156.
  21. Brown J., Crawford T.J., Datta S., Prentice A. Oral contraceptives for pain associated with endometriosis (Review). Cochrane Database Syst. Rev. 2018; (5): CD001019. https://dx.doi.org/10.1002/14651858.CD001019.pub3.
  22. Jensen J.T., Schlaff W., Gordon K. The use of combined hormonal contraceptives for the treatment of endometriosis-related pain: a systematic review of the evidence. Steril. 2018; 110(1): 137-52.e1. https://dx.doi.org/10.1016/ j.fertnstert.2018.03.012.
  23. de Bastos M., Stegeman B.H., Rosendaal F.R., Van Hylckama Vlieg A., Helmerhorst F.M., Stijnen T, Dekkers O.M. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst. Rev. 2014; (3): CD010813. https://dx.doi.org/10.1002/14651858.CD010813.pub2.
  24. Gialeraki A., Valsami S., Pittaras T., Panayiotakopoulos G., Politou M. Oral contraceptives and HRT Risk of thrombosis. Appl. Thromb. 2018; 24(2): 217-25. https://dx.doi.org/10.1177/1076029616683802.
  25. Leyland N., Casper R., Laberge P, Singh S.S., Endometriosis: diagnosis and management. J. Obstet. Gynaecol. Can. 2010; 32(7, Suppl. 2): S1-32.
  26. Collinet P., Fritel X., Revel-Delhom C., Ballester M., Bolze P.A. et al. Management of endometriosis: CNGOF/HAS clinical practice guidelines - Short version. J. Gynecol. Obstet. Hum. Reprod. 2018; 47(7): 265-74. https://dx.doi.org/10.1016/j.jogoh.2018.06.003.
  27. Endometriosis: diagnosis and management. NICE Guideline No. 73. 2017 September. Available at: https://www.ncbi.nlm.nih.gov/books/ NBK11822/ Accessed 01.12.2021.
  28. Kistner R. W The use of newer progestins in the treayment of endometriosis. J. Obstet. Gynecol. 1958; 75(2): 264-78. https://dx.doi.org/10.1016/ 0002-9378(58)90384-3.
  29. Vercellini P, Buggio L., Berlanda N., Barbara G. Estrogen-progestins and progestins for the management of endometriosis. Steril. 2016; 106(7): 1552-71.e2. https://dx.doi.org/10.1016/j.fertnstert.2016.10.022.
  30. Horie S., Harada T., Mitsunari M., Taniguchi F. Progesterone and progestational compounds attenuate tumor necrosis factor alpha — induced interleukin-8 production via nuclear factor kappaB inactivation in endometriotic stromal cells. Steril. 2005; 83(5): 1530-5. https://dx.doi.org/10.1016/j.fertnstert.2004.11.042.
  31. Buggio L., Somigliana E., Barbara G., Frattaruolo M.P, Vercellini P. Oral and depot progestin therapy for endometriosis: towards a personalized medicine. Expert Opin. Pharmacother. 2017; 18(15): 1569-81. https://dx.doi.org/10.1080/2017.1381086.
  32. Sasagawa S., Shimizu Y., Nagaoka T., Tokado H., Imada K., Mizuguchi K. Dienogest, a selective progestin, reduces plasma estradiol level through induction of apoptosis of granulosa cells in the ovarian dominant follicle without follicle­stimulating hormone suppression in monkeys. Endocrinol. Invest. 2008; 31(7): 636-41. https://dx.doi.org/10.1007/BF03345616.
  33. Fechner S., Husen B., Thole H., Schmidt M., Gashaw I., Kimmig R. et al. Expression and regulation of estrogen-converting enzymes in ectopic human endometrial tissue. Fertil. Steril. 2007; 88(4, Suppl.): 1029-38. https://dx.doi.org/10.1016/j.fertnstert.2006.11.153.
  34. Beranic N., Rizner T.L. Effects of progestins on local estradiol biosynthesis and action in the Z-12 endometriotic epithelial cell line. Steroid Biochem. Mol. Biol. 2012; 132(3-5): 303-10. https://dx.doi.org/10.1016/j.jsbmb.2012.07.004.
  35. Mori T., Ito F, Matsushima H., Takaoka O., Koshiba A., Tanaka Y. et al. Dienogest reduces HSD17P1 expression and activity in endometriosis. J. Endocrinol. 2015; 225(2): 69-76. https://dx.doi.org/10.1530/JOE-15-0052.
  36. Katayama H., Katayama T., Uematsu K., Hiratsuka M., Kiyomura M., Shimizu Y. et al. Effect of dienogest administration on angiogenesis and hemodynamics in a rat endometrial autograft model. Hum. Reprod. 2010; 25(11): 2851-8. https://dx.doi.org/10.1093/humrep/deq241.
  37. Hardy D.B., Janowski B.A., Corey D.R., Mendelson C.R. Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-кВ activation of cyclooxygenase 2 expression. Endocrinol. 2006; 20(11): 2724-33. https://dx.doi.org/10.1210/me.2006-0112.
  38. Grandi G., Mueller M., Bersinger N.A., Cagnacci A., Volpe A., McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm. Res. 2016; 65(3): 183-92. https://dx.doi.org/10.1007/s00011-015-0909-7.
  39. Moehner S., Becker K., Lange J.A., von Stockum S., Serrani M., Heinemann K. Long-term treatment of endometriosis with dienogest: Real-world results from the VIPOS study. Endometrios. Pelvic Pain Dis. 2021; 13(2): 104-10. https://dx.doi.org/10.1177/2284026521993688.
  40. Romer Т. Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. Gynecol. Obstet. 2018; 298(4): 747-53. https://dx.doi.org/10.1007/s00404-018-4864-8.
  41. Momoeda M., Harada T., Terakawa N., Aso T., Fukunaga M., Hagino H., Taketani Y. Long-term use of dienogest for the treatment of endometriosis. Obstet. Gynaecol. Res. 2009; 35(6): 1069-76. https://dx.doi.org/10.1111/ j.1447-0756.2009.01076.x.
  42. Kim S.E., Lim H.H., Lee D.Y., Choi D. The long-term effect of dienogest on bone mineral density after surgical treatment of endometrioma. Sci. 2021; 28(5): 1556-62. https://dx.doi.org/10.1007/s43032-020-00453-7.
  43. Zakhari A., Edwards D., Ryu M., Matelski J., Bougie O., Murji A. Dienogest and the risk of endometriosis recurrence following surgery: A systematic review and meta-analysis. Minim. Invasive Gynecol. 2020; 27(7): 1503-10. https://dx.doi.org/10.1016/j.jmig.2020.05.007.
  44. Peng C., Huang Y., Zhou Y. Dydrogesterone in the treatment of endometriosis: evidence mapping and meta-analysis. Gynecol. Obstet. 2021; 301(4): 231-52. https://dx.doi.org/10.1007/s00404-020-05900-z.
  45. Liang B., Wu L., Xu H., Cheung C.W., Fung W.Y., Wong S.W., Wang C.C. Efficacy, safety and recurrence of new progestins and selective progesterone receptor modulator for the treatment of endometriosis: A comparison study in mice. Biol. Endocrinol. 2018; 16(1): 32. https://dx.doi.org/10.1186/ s12958-018-0347-9.
  46. Сухих Г.Т., Адамян Л., Козаченко А.В., Дубровина С.О., Баранов И.И., Радзинский В., Артымук Н., Столярова У.В., Макаренко Т.А., Оразов М.Р., Беженарь В.Ф., Чернуха Г.Е., Чупрынин В.Д., Енькова Е.В., Коротких И.Н., Глухов Е.Ю., Мазитова М.И., Карахалис Л.Ю., Цхай В.Б., Качалина О.В. и др. Дидрогестерон для лечения подтвержденного эндометриоза: ключевые результаты наблюдательного открытого многоцентрового исследования в условиях реальной клинической практики (исследование ОРХИДЕЯ). Акушерство и гинекология: новости, мнения, обучение. 2020; 8(4): 79-81. [Sukhikh G.T., Adamyan L.V., Kozachenko A.V., Dubrovina S.O., Baranov I.I. et al. Dydrogesterone for the treatment of confirmed endometriosis: key findings from an observational, open-label, multicenter, real-life clinical trial (ORCHID study). Obstetrics and Gynecology: News, Opinions, Training. 2020; 8(4): 79-81. (in Russian)]. https://dx.doi.org/10.24411/2303-9698-2020-14006.
  47. Vlahos N., Vlachos A., Triantafyllidou O., Vitoratos N., Creatsas G. Continuous versus cyclic use of oral contraceptives after surgery for symptomatic endometriosis: A prospective cohort study. Steril. 2013; 100(5): 1337-42. https://dx.doi.org/10.1016/j.fertnstert.2013.07.008.
  48. Barbieri R.L. Hormone treatment of endometriosis: The estrogen threshold hypothesis. J. Obstet. Gynecol. 1992; 166(2): 740-5. https://dx.doi.org/10.1016/0002-9378(92)91706-G.
  49. Selak V., Farquhar C., Prentice A., Singla A. Danazol for pelvic pain associated with endometriosis. Cochrane Database Syst. Rev. 2007; 4: CD000068. https://dx.doi.org/10.1002/14651858.CD000068.pub2.
  50. Hung S.W., Zhang R., Tan Z., Chung J.P.W., Zhang T., Wang C.C. Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review. Res. Rev. 2021; 41(4): 2489-564. https://dx.doi.org/10.1002/med.21802.
  51. Радзинский В.Е., Оразов М.Р., Орехов Р.Е. Индивидуализированный под­ход в терапии боли, ассоциированной с эндометриозом. Акушерство и гинекология. 2021; 10: 31-7. [Radzinsky V.E., Orazov M.R., Orekhov R.E. An individualized approach to the treatment of pain associated with endometriosis. Akusherstvo i ginekologiya/Obstetrics and Gynecology. 2021; 10: 31-7. (in Russian)]. https://dx.doi.org/10.18565/aig.2021.10.31-37.
  52. Vannuccini S., Clemenza S., Rossi M., Petraglia F. Hormonal treatments for endometriosis: The endocrine background. Endocr. Metab. Disord. 2021 Aug 17. https://dx.doi.org/10.1007/s11154-021-09666-w.
  53. 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 solutions and revising the tactics of managing patients with endometriosis. Akusherstvo i ginekologiya/Obstetrics and Gynecology. 2020; 8: 12-20. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.8.12-20.
  54. Флорова М.С., Ярмолинская М.И., Потин В.В. Перспективы исполь­зования метформина в терапии эндометриоза. Журнал акушерства и женских болезней. 2017; 66(2): 67-76. [Florova M.S., Yarmolinskaya M.I., Potin V.V. Prospects of metformin in the treatment of endometriosis. Journal of obstetrics and women's diseases. 2017; 66(2): 67-76. (in Russian)]. https://dx.doi.org/10.17816/JOWD66267-76.
  55. Ярмолинская М.И., Петросян М.А., Флорова М.С., Молотков А.С., Денисова А.С., Суслова Е.В., Тхазаплижева С.Ш. Сравнительная оцен­ка эффективности перспективных препаратов для таргетной терапии эндометриоза на основании экспериментальной модели заболевания. Гинекология. 2018; 20(5): 46-51. [Yarmolinskaya M.I., Petrosyan M.A., Florova M.S., Molotkov A.S. et al. Comparative evaluation of the effectiveness of promising drugs for targeted therapy of endometriosis based on an experimental model of the disease. 2018; 20(5): 46-51. (in Russian)].

Received 02.12.2021

Accepted 12.01.2022 

About the Authors

Elena P. Khashchenko, PhD, Senior Researcher of 2nd Gynecological (child and adolescent) Department, Academician V.I. Kulakov National edical Research Genter for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, khashchenko_elena@mail.ru, https://orcid.org/0000-0002-3195-307X, 117997, Russia, Moscow, Ac. Oparina str., 4.
Anastasia S. Sivirinova, student, Faculty of Fundamental Medicine, MV. Lomonosov Moscow State University, sivirinovaa@gmail.com, https://orcid.org/0000-0002-1334-2638, 119991, Russia, Moscow, Leninskye Gory, 1.
Elena V. Uvarova, Dr. Med. Sci., Professor, Corresponding Member of the RAS, Head of 2nd Gynecological (child and adolescent) Department, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, elena-uvarova@yandex.ru, https://orcid.org/0000-0002-3105-5640, 117997, Russia, Moscow, Ac. Oparina str., 4.

Authors' contributions: Khashchenko E.P., Sivirinova A.S. (the authors’ equal contribution) - concept of the investigation, search for literature sources, writing and editing the text; Uvarova E.V. - final editing of the text.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The investigation has been sponsored by the Russian Foundation for Basic Research, Project No. 19-013-00397 “Affective states in adolescent and early reproductive-aged female patients with chronic pelvic pain in the presence of gynecological diseases”, the Ministry of Health state assignment 18-A21 “The role of energy metabolism and immune defense disorders in the development of various types of endometriosis and in that of personalized therapy and prognosis of its efficiency in the early reproductive period (from menarche to age 18 years)”.
For citation: Khashchenko E.P., Sivirinova A.S., Uvarova E.V. Modern principles of medical treatmentfor endometriosis at an early reproductive age.
Akusherstvo i Ginekologiya/ Obstetrics and Gynecology. 2022; 1: (in Russian)
https://dx.doi.org/10.18565/aig.2022.1.

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