Combined hormonal contraceptive containing estetrol and drospirenone: pharmacokinetics and opportunities for clinical use
Nazarova N.M., Prilepskaya V.N.
A new combined hormonal contraceptive (CHC) containing estetrol 15 mg and drospirenone 3 mg (E4/DRSP) is now registered in Russia and in a number of countries around the world. Estetrol (E4) is a third-generation native fetal estrogen produced by fetal liver cells during pregnancy. Drospirenone is the first synthetic progestin derived from 17-α-spirolactone. E4 differs from other estrogens (17-β-estradiol or ethinyl estradiol) by its highly selective action on various tissues, as well as by its antiproliferative properties.
This article presents studies on the pharmacokinetics of CHC containing E4/DRSP and the possibility of its clinical use taking into account the characteristics of the components. E4/DRSP has been shown to have minimal effect on hemostasis parameters, lipid profile, and antiproliferative properties.
Conclusion: The pharmacokinetic features of E4/DRSP make it possible to consider it as the first-line drug for young women who plan to use hormonal contraception for the first time with undesirable side effects (prolonged spotting/bleeding, pain in the mammary glands, tendency to swelling) while using other combined oral contraceptives.
Authors’ contributions: Nazarova N.M. – review of literature, analysis and translation of articles, formulation of the subject of the article, writing the article; Prilepskaya V.N. – writing the article, editing the text of the article.
Conflicts of interest: The authors declare no possible conflicts of interest.
Funding: The study was conducted without sponsorship.
For citation: Nazarova N.M., Prilepskaya V.N. Combined hormonal contraceptive containing estetrol and drospirenone: pharmacokinetics and opportunities for clinical use.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2024; (4): 156-161 (in Russian)
https://dx.doi.org/10.18565/aig.2024.103
Keywords
estetrol
drospirenone
combined hormonal contraceptive
References
- МакВэй Э., Джиллбоуд Дж., Хамбэг Р. Репродуктивная медицина и планирование семьи: Практическое руководство. Прилепская В.Н., Сухих Г.Т., ред.; пер. с англ. М.: МЕДпресс-информ; 2016. 368 c. [McVeigh E., Guillebaud J., Homburg R. Oxford handbook of reproductive medicine and family planning. Second edition. Oxford University Press; 2013].
- Прилепская В.Н., ред. Руководство по контрацепции. 4-е изд. М.: МЕДпресс-информ; 2017. [Prilepskaya V.N., ed. Guide to contraception. 4th ed. Moscow: MEDpress-inform; 2017. (in Russian)].
- Frost J.J., Darroch J.E., Remez L. Improving contraceptive use in the United States. Issues Brief (Alan Guttmacher Inst). 2008; (1): 1-8.
- Douxfils J,, Klipping C,, Duijkers I,, Kinet V,, Mawet M,, Maillard C. et al. Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception. 2020; 102(6): 396-402. https://dx.doi.org/10.1016/j.contraception.2020.08.015.
- Stegeman B.H., de Bastos M., Rosendaal F.R., Vlieg A.V., Helmerhorst F.M. et al. Different combined oral contraceptives and the risk of venous thrombosis: Systematic review and network meta-analysis. BMJ. 2013; 347: f5298. https://dx.doi.org/10.1136/bmj.f5298.
- Kaunitz A.M., Achilles S.L., Zatik J., Weyers S., Piltonen T., Suturina L. et al. Pooled analysis of two phase 3 trials evaluating the effects of a novel combined oral contraceptive containing estetrol/drospirenone on bleeding patterns in healthy women. Contraception. 2022; 116: 29-36. https://dx.doi.org/10.1016/j.contraception.2022.07.010.
- Fruzzetti F., Fidecicchi T., Montt Guevara M.M., Simoncini T. Estetrol: a new choice for contraception. J. Clin. Med. 2021; 10(23): 5625. https://dx.doi.org/10.3390/jcm10235625.
- Gemzell-Danielsson K., Apter D., Zatik J., Weyers S., Piltonen T., Suturina L. et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022; 129(1): 63-71. https://dx.doi.org/10.1111/1471-0528.16840.
- Lee A., Syed Y.Y. Estetrol/Drospirenone: a review in oral contraception. Drugs. 2022; 82(10): 1117-25. https://dx.doi.org/10.1007/s40265-022-01738-8.
- Mayne Pharma. NEXTSTELLIS (estetrol/drospirenone) tablets: US prescribing information. 2021. Available at: https://dailymed.nlm.nih. gov/ Accessed: 09.06.2022.
- Hagen A.A., Barr M., Diczfalusy E. Metabolism of 17-Beta-oestradiol-4-14-C in early infancy. Acta Endocrinol. (Copenh). 1965; 49: 207-20.
- Arnal J.F., Lenfant F., Metivier R., Flouriot G., Henrion D., Adlanmerini M. et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol. Rev. 2017; 97(3): 1045-87. https://dx.doi.org/10.1152/physrev.00024.2016.
- Юрова М.В., Межевитинова Е.А., Якушевская О.В., Родионов В.В. Прилепская В.Н., Павлович С.В. Влияние гормональной контрацепции на риск развития рака молочной железы. Современная Онкология. 2023; 25(2): 199-207. [Iurova M.V., Mezhevitinova E.A., Yakushevskaya O.V., Rodionov V.V., Prilepskaya V.N., Pavlovich S.V. The effect of hormonal contraception on the risk of breast cancer: A review. Journal of Modern Oncology. 2023; 25(2): 199-207. (in Russian)]. https://dx.doi.org/10.26442/18151434.2023.2.202287.
- Gemzell-Danielsson K., Apter D., Zatik J., Weyers S., Piltonen T., Suturina L. et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern and safety in Europe and Russia. BJOG. 2022; 129(1): 63-71. https://dx.doi.org/10.1111/1471-0528.16840.
- Creinin M.D., Westhoff C.L., Bouchard C., Chen M.J., Jensen J.T., Kaunitz A.M. et al. Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception. 2021; 104(3): 222-8. https://dx.doi.org/10.1016/j.contraception.2021.05.002.
- Сухих Г.Т., Прилепская В.Н., ред. Национальные медицинские критерии приемлемости методов контрацепции. Изд. перераб. и доп. М.; 2023. [Sukhikh G.T., Prilepskaya V.N., ed. National medical acceptance criteria for contraceptive methods. Ed. reworked and add. Moscow; 2023. (in Russian)].
- Mawet M., Maillard C., Klipping C., Zimmerman Y., Foidart J.M., Coelingh Bennink H.J. 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. https://dx.doi.org/10.3109/13625187.2015.1068934.
- Klipping C., Duijkers I., Mawet M., Maillard C., Bastidas A., Jost M. et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021; 103(4): 213-21. https://dx.doi.org/10.1016/j.contraception.2021.01.001.
- Хамадьянова А.У., Тухтабоев А.Х., Шафиева В.А., Колодяжная Е.А., Мансурова Ю.Р., Муратова А.А., Андреева А.А., Музафарова Ю.А. Эстетрол: новый эстрогенный компонент в составе комбинированных оральных контрацептивов. Гинекология. 2022; 24(6): 459-64. [Khamadyanova A.U., Tuhtaboev A.H., Shafieva V.A., Kolodyazhnaya E.A., Mansurova Ju.R., Muratova A.A., Andreeva A.A., Muzafarova Ju.A. Estetrol: a new estrogen component in combined oral contraceptives: A review. Gynecology. 2022; 24(6): 459-64. (in Russian)]. https://dx.doi.org/10.26442/20795696.2022.6.201749
- Douxfils J., Gaspard U., Taziaux M., Jost M., Bouvy C., Lobo R.A. et al. Impact of estetrol (E4) on hemostasis, metabolism and bone turnover in postmenopausal women. Climacteric. 2023; 26(1): 55-63. https://dx.doi.org/10.1080/13697137.2022.2139599.
- Visser M., Foidart J.M., Coelingh Bennink H.J. In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric. 2008; 11 Suppl 1: 64-8. https://dx.doi.org/10.1080/13697130802050340.
- Gérard C., Apter D., Chatel G., Nollevaux F., Jost M., Gaspard U. et al. RF34 | PMON202 The Human Metabolic Profile of Estetrol. J. Endocrine Society. 2022; 6(Suppl_1): A714-A715. https://dx.doi.org/10.1210/jendso/bvac150.1472.
- Morimont L., Haguet H., Dogné J.M., Gaspard U., Douxfils J. Combined oral contraceptives and venous thromboembolism: review and perspective to mitigate the risk. Front. Endocrinol. (Lausanne). 2021; 12: 769187. https://dx.doi.org/10.3389/fendo.2021.769187.
- Morimont L., Jost M., Gaspard U., Foidart J.M., Dogné J.M., Douxfils J. Low thrombin generation in users of a contraceptive containing estetrol and drospirenone. J. Clin. Endocrinol. Metab. 2022; 108(1): 135-43. https://dx.doi.org/10.1210/clinem/dgac511.
- Kluft C., Zimmerman Y., Mawet M., Klipping C., Duijkers I.J.M., Neuteboom J. et al. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception. 2017; 95(2): 140-7. https://dx.doi.org/10.1016/j.contraception.2016.08.018.
- Chen M.J., Jensen J.T., Kaunitz A.M., Achilles S.L., Zatik J., Weyers S. et al. Tolerability and safety of the estetrol/drospirenone combined oral contraceptive: Pooled analysis of two multicenter, open-label phase 3 trials. Contraception. 2022; 116: 44-50. https://dx.doi.org/10.1016/j.contraception.2022.10.004.
- Gérard C., Blacher S., Communal L., Courtin A., Tskitishvili E., Mestdagt M. et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J. Endocrinol. 2015; 224(1): 85-95. https://dx.doi.org/10.1530/JOE-14-0549.
- Schmidt M., Lenhard H., Hoenig A., Zimmerman Y., Krijgh J., Jansen M. et al. Tumor suppression, dose-limiting toxicity and wellbeing with the fetal estrogen estetrol in patients with advanced breast cancer. J. Cancer Res. Clin. Oncol. 2021; 147(6): 1833-42. https://dx.doi.org/10.1007/s00432-020-03472-8.
- Gallez A., Blacher S., Maquoi E., Konradowski E., Joiret M., Primac I. et al. Estetrol combined to progestogen for menopause or contraception indication is neutral on breast cancer. Cancers (Basel). 2021; 13(10): 2486. https://dx.doi.org/10.3390/cancers13102486.
- Gérard C., Foidart J.M. Estetrol: from preclinical to clinical pharmacology and advances in the understanding of the molecular mechanism of action. Drugs R D. 2023; 23(2): 77-92. https://dx.doi.org/10.1007/s40268-023-00419-5.
- Gallez A., Dias Da Silva I., Wuidar V., Foidart J.M., Péqueux C. Estetrol and mammary gland: friends or foes? J. Mammary Gland Biol. Neoplasia. 2021; 26(3): 297-308. https://dx.doi.org/10.1007/s10911-021-09497-0.
- Archer D.F., Mansour D., Foidart J.M. Bleeding patterns of oral contraceptives with a cyclic dosing regimen: an overview. J. Clin. Med. 2022; 11(15): 4634. https://dx.doi.org/10.3390/jcm11154634.
- Coelingh Bennink H.J., Holinka C.F., Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008; 11 Suppl 1: 47-58. https://dx.doi.org/10.1080/13697130802073425.
- Regidor P.A., Mueller A., Mayr M. Pharmacological and metabolic effects of drospirenone as a progestin-only pill compared to combined formulations with estrogen. Womens Health (Lond). 2023; 19: 17455057221147388. https://dx.doi.org/10.1177/17455057221147388.
- Gérard C., Arnal J.F., Jost M., Douxfils J., Lenfant F., Fontaine C. 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. https://dx.doi.org/10.1080/17512433.2022.2054413.
Received 21.04.2024
Accepted 26.04.2024
About the Authors
Niso M. Nazarova, Dr. Med. Sci., Leading Researcher, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology,Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, +7(495)438-14-03, grab2@yandex.ru
Vera N. Prilepskaya, Dr. Med. Sci., Professor, Head of the Scientific Polyclinic Department, V.I. Kulakov National Medical Research Center for Obstetrics,
Gynecology and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparina str., 4, +7(495)438-69-34, vprilepskaya@mail.ru
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