Совершенная молекула для гормональной контрацепции: преференции эстетрола

Горбунова Е.А., Аполихина И.А. Совершенная молекула для гормональной контрацепции: преференции эстетрола. Гинекология. 2024;26(4):304–310. DOI: 10.26442/20795696.2024.4.203070

© ООО «КОНСИЛИУМ МЕДИКУМ», 2024 г.

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Gorbunova EA, Apolikhina IA. The perfect molecule for hormonal contraception: Estetrol benefits. A review. Gynecology. 2024;26(4):304–310. DOI: 10.26442/20795696.2024.4.203070

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Аннотация

Статья посвящена исследованию применения эстетрола (Е4) в составе комбинированных оральных контрацептивов (КОК) и его различным эффектам в организме. Несмотря на быстрое восстановление фертильности после отмены КОК, их популярность снижается из-за негативных побочных эффектов, таких как прибавка массы тела, изменение настроения, плохой контроль менструального цикла, масталгия. В ответ на это изучается потенциал естественного фетального эстрогена Е4, который отличается высокой биодоступностью и низким риском метаболических последствий. Анализируемые данные указывают на то, что Е4 может снижать риск развития рака молочной железы, так как его действие приводит к меньшей пролиферации клеток молочной железы по сравнению с другими эстрогенами. На фоне приема Е4 минимизирован риск венозной тромбоэмболии и наблюдается меньшее воздействие на печеночные ферменты, что сказывается на качестве сексуальной жизни и открывает возможность назначать КОК с Е4 женщинам, получающим постоянно другие лекарственные препараты – статины, антиретровирусные, противосудорожные. Статья подчеркивает многообещающие результаты клинических исследований, подтверждающих эффективность КОК на основе Е4, показывающих высокий уровень удовлетворенности женщин. Клиническое применение КОК с Е4 может улучшить качество жизни, устраняя негативные последствия, связанные с сексуальной функцией, и обеспечивая высокий контроль над менструальным циклом. Необходимы дальнейшие исследования влияния КОК с Е4 на психоэмоциональное состояние и качество сексуальной жизни женщин, а также возможных лечебных эффектов от КОК с Е4, что позволит индивидуализировать подход к контрацепции и обеспечивать женщинам более безопасные и эффективные ее варианты.

Ключевые слова: эстетрол, либидо, половое влечение, этинилэстрадиол, комбинированные гормональные контрацептивы, гормональная контрацепция, эстрадиола валерат, эстрадиол, рак молочной железы, эндометриоз

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The article addresses studies of estetrol (E4) use as part of combined oral contraceptives (COCs) and its various effects on the body. Despite the rapid recovery of fertility after discontinuation of COCs, their popularity is declining due to adverse side effects such as weight gain, mood changes, poor menstrual control, and mastalgia. Therefore, the potential of the natural fetal estrogen E4, with high bioavailability and low risk of metabolic sequelae, is being studied. The data analyzed suggest that E4 may reduce the risk of breast cancer, as it induces less breast cell proliferation compared to other estrogens. During E4 therapy, the risk of venous thromboembolism is minimized, and there is less impact on hepatic enzymes, which improves the quality of sexual life and opens up the opportunities of prescribing COCs with E4 to women who are continuously receiving other drugs – statins, antiretroviral agents, or anticonvulsants. The article highlights promising results from clinical studies that confirm the efficacy of E4-based COCs, showing high levels of patient satisfaction. Clinical use of COCs with E4 can improve quality of life by eliminating the adverse effects associated with sexual function and providing high control over the menstrual cycle. Further research is needed on the impact of COCs with E4 on the psycho-emotional state and quality of women's sexual life, as well as the possible therapeutic effects of E4-based COCs, which will individualize the approach to contraception and provide women with safer and more effective options.

Keywords: estetrol, libido, sexual desire, ethinyl estradiol, combined hormonal contraceptives, hormonal contraception, estradiol valerate, estradiol, breast cancer, endometriosis

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23. Gallez A, Dias Da Silva I, Wuidar V, et al. Estetrol and mammary gland: Friends or foes? J Mammary Gland Biol Neoplasia. 2021;26(3):297-308. DOI:10.1007/s10911-021-09497-0
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1. Girum T, Wasie A. Return off ertility after discontinuation of contraception: asystematic review and meta-analysis. Contracept Reprod Med. 2018;3:9. DOI:10.1186/s40834-018-0064-y
2. United Nations. Contraceptive Use by Method 2019: Data Booklet (ST/E-SA/SER.A/435). New York: United Nations, Department of Eco-nomicand Social Affairs, Population Division, 2019.
3. Moreau C, Cleland K, Trussell J. Contraceptive discontinuation attributed to method dissatisfactionin the United States. Contraception. 2007;76(4):267-72. DOI:10.1016/j.contraception.2007.06.008
4. Küçük M, Aksu H, Sezer SD. Misconceptions about the side effects of combined oral contraceptive pills. Gynecol Endocrinol. 2012;28(4):282-5. DOI:10.3109/09513590.2011.613502
5. Rosenberg M. Weight change with oral contraceptive use and during the menstrual cycle. Results of daily measurements. Contraception. 1998;58(6):345-9.
DOI:10.1016/s0010-7824(98)00127-9
6. Fruzzetti F, Fidecicchi T, Gambacciani M. Oestrogens in oral contraception: considerations for tailoring prescription to women's needs. Eur J Contracept Reprod Health Care. 2024;29(3):93-102. DOI:10.1080/13625187.2024.2334350
7. Schwers J, Eriksson G, Diczfalusy E. Metabolism of oestrone and oestradiol in the human foeto-placental unit at midpregnancy. Acta Endocrinol (Copenh). 1965;49(1):65-82. PMID:14277127
8. Stanczyk FZ, Winer SA, Foidart JM, Archer DF. Comparison of estrogenic components used for hormonal contraception. Contraception. 2024;130:110310. DOI:10.1016/j.contraception.2023
9. Lee A, Syed YY. Estetrol/drospirenone: A review in oral contraception. Drugs. 2022;82(10):1117-25. DOI:10.1007/s40265-022-01738-8
10. Gérard C, Arnal JF, Jost M, et al. Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Rev Clin Pharmacol. 2022;15(2):121-37. DOI:10.1080/17512433.2022.2054413
11. Caruso S, Caruso G, Iraci Sareri M, et al. Correlation of sexual desire with sexual hormone binding globulin and free androgen index in women using combined contraceptives. Eur J Contracept Reprod Health Care. 2024;29(3):103-8. DOI:10.1080/13625187.2024.2332302
12. Visser M, Holinka CF, Coelingh Bennink HJT. First human exposure to exogenous single-dose oral estetrol in early postmenopausal women. Climacteric. 2008;11(Suppl. 1):31-40. DOI:10.1080/13697130802056511
13. Kuhl H. Pharmacology of estrogens and progestogens: Influence of different routes of administration. Climacteric. 2005;8(Suppl. 1):3-63. DOI:10.1080/13697130500148875
14. Santen RJ, Yue W, Wang JP. Estrogen metabolites and breast cancer. Steroids. 2015;99(Pt. A):61-6. DOI:10.1016/j.steroids.2014.08.003
15. Jirku H, Kadner S, Levitz M. Pattern of estetrol conjugation in the human. Steroids. 1972;19(4):519-34. PMID:4337649
16. Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and breast cancer: A prospective study of young women. Cancer Epidemiol Biomarkers Prev.
2010;19(10):2496-502. DOI:10.1158/1055-9965.EPI-10-0747
17. Mørch LS, Skovlund CW, Hannaford PC, et al. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med. 2017;377(23):2228-39. DOI:10.1056/NEJMoa1700732
18. Cirillo F, Spinelli A, Talia M, et al. Estetrol/GPER/SERPINB2 transduction signaling inhibits the motility of triple-negative breast cancer cells. J Transl Med. 2024;22(1):450. DOI:10.1186/s12967-024-05269-6
19. Gerard C, Mestdagt M, Tskitishvili E, et al. Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. Oncotarget. 2015;6(19):17621-36. DOI:10.18632/oncotarget.4184
20. Lippert C, Seeger H, Mueck AO. The effect of endogenous estradiol metabolites on the proliferation of human breast cancer cells. Life Sci. 2003;72(8):877-83.
DOI:10.1016/s0024-3205(02)02305-6
21. Yue W, Verhoeven C, Bernnink HC, et al. Pro-apoptotic effects of estetrol on long-term estrogen-deprived breast cancer cells and at low doses on hormone-sensitive cells. Breast Cancer Basic Clin Res. 2019;13:1178223419844198. DOI:10.1177/1178223419844198
22. Gallez A, Blacher S, Maquoi E, et al. Estetrol combined to progestogen for menopause or contraception indication is neutral on breast cancer. Cancers (Basel). 2021;13(10):2486. DOI:10.3390/cancers13102486
23. Gallez A, Dias Da Silva I, Wuidar V, et al. Estetrol and mammary gland: Friends or foes? J Mammary Gland Biol Neoplasia. 2021;26(3):297-308. DOI:10.1007/s10911-021-09497-0
24. Abderrahman B, Maximov PY, Curpan RF, et al. Pharmacology and molecular mechanisms of clinically relevant estrogen estetrol and estrogen mimic BMI-135 for the treatment of endocrine-resistant breast cancer. Mol Pharmacol. 2020;98(4):364-81. DOI:10.1124/molpharm.120.000054
25. Singer CF, Bennink HJTC, Natter C, et al. Antiestrogenic effects of the fetal estrogen estetrol in women with estrogen-receptor positive early breast cancer. Carcinogenesis. 2014;35(11):2447-51. DOI:10.1093/carcin/bgu144
26. Zabala AS, Conforti RA, Delsouc MB, et al. Estetrol inhibits endometriosis development in an in vivo murine model. Biomolecules. 2024;14(5):580. DOI:10.3390/biom14050580
27. Tanis BC, Rosendaal FR. Venous and arterial thrombosis during oral contraceptive use: Risks and risk factors. Semin Vasc Med. 2003;3(1):69-84. DOI:10.1055/s-2003-38334
28. Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021;104(3):222-8. DOI:10.1016/j.contraception.2021.05.002
29. Creinin MD, Cagnacci A, Spaczyński RZ, et al. Experts' view on the role of oestrogens in combined oral contraceptives: Emphasis on oestetrol (E4). Front Glob Womens Health. 2024;5:1395863. DOI:10.3389/fgwh.2024.1395863
30. Apolikhina IA, Prilepskaya VN, Gorbunova EA, et al. Estetrol – a new stage of combined hormonal contraception. Obstetrics and Gynecology.
2023;3:134-40 (in Russian). DOI:10.18565/aig.2023.72
31. Prilepskaya VN, Iurova MV. Estetrol: a new word in modern hormonal contraception. A review. Gynecology. 2024;26(2):108-18 (in Russian). DOI:10.26442/20795696.2024.2.202621
32. Douxfils J, Klipping C, Duijkers I, et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020;102(6):396-402. DOI:10.1016/j.contraception.2020.08.015
33. Foidart JM, Gaspard U, Pequeux C, et al. Unique vascular benefits of estetrol, a native fetal estrogen with specific actions in tissues (NEST). In: Brinton R, Genazzani A, Simoncini T, Stevenson J, eds. Sex steroids’ effects on brain, heart and vessels. Vol. 6: Frontiers in gynecological endocrinology. Cham: Springer International Publishing, 2019. P. 169-95. DOI:10.1007/978-3-030-11355-1_12
34. Visser M, Coelingh Bennink HJ. Clinical applications for estetrol. J Steroid Biochem Mol Biol. 2009;114(1-2):85-9. DOI:10.1016/ j.jsbmb.2008.12.013
35. Mawet M, Maillard C, Klipping C, et al. Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur J Contracept Reprod Health Care. 2015;20(6):463-75. DOI:10.3109/13625187.2015.1068934
36. Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ. Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric. 2008;11(Suppl. 1):41-6. DOI:10.1080/13697130701851814
37. Klipping C, Duijkers I, Mawet M, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021;103(4):213-21. DOI:10.1016/j.contraception.2021.01.001
38. Coelingh Bennink HJT, Holinka CF, Diczfalusy E. Estetrol review: Profile and potential clinical applications. Climacteric. 2008;11(Suppl. 1):47-58. DOI:10.1080/13697130802073425
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Авторы

Е.А. Горбунова¹, И.А. Аполихина*^1,2

¹ФГБУ «Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова» Минздрава России, Москва, Россия;
²ФГАОУ ВО «Первый Московский государственный медицинский университет им. И.М. Сеченова» Минздрава России (Сеченовский Университет), Москва, Россия
*i_apolikhina@oparina4.ru

________________________________________________

Elena A. Gorbunova¹, Inna A. Apolikhina*^1,2

¹Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia;
²Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
*i_apolikhina@oparina4.ru

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