Drovelis® — a new contraceptive with the only natural selective estetrol E4 (NEST)

9 квітня 2024
474
УДК:  613.888
Спеціальності :
Резюме

The evolution of combined oral contraceptives is due to the need to improve safety and reduce side effects. For contraception, women want to use hormonal drugs that are close in their characteristics to natural ones. Over the last 20 years, the needs of women have changed, so combined oral contraceptives need new innovative solutions. Estetrol (E4) is the first natural estrogen with selective activity, which creates a new direction in endocrine gynecology and contraception. Drovelis® showed a good contraceptive effect and control of the menstrual cycle with a neutral metabolic effect. Estetrol has unique pharmacological features that distinguish it from other estrogens: ethinyl estradiol and estradiol.

References

  • 1. Oelkers W. (2002) Antimineralocorticoid activity of a novel oral contraceptive containing drospirenone, a unique progestogen resembling natural progesterone. Eur. J. Contracept. Reprod. Health Care, 7(Suppl. 3): 19–26.
  • 2. Fruzzetti F., Fidecicchi T., Montt Guevara M.M., Simoncini T. (2021) Estetrol: A New Choice for Contraception. J. Clin. Med., 10: 5625. doi.org/10.3390/jcm10235625.
  • 3. Gérard C., Arnal J.F., Jost M. et al. (2022) Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause. Expert Rev. Clin. Pharmacol., 15: 121–137.
  • 4. Gérard C., Foidart J.M. (2023) Estetrol: from preclinical to Clinical Pharmacology and advances in the understanding of the molecular mechanism of action. Drugs R.D., 23: 77–92.
  • 5. Klipping C., Duijkers I., Mawet M. et al. (2021) Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception, 103(4): 213–221. DOI: 10.1016/j.contraception.2021.01.001.
  • 6. Drovelis assessment report EMA/212533/2021. European Medicines Agency. http://www.ema.europa.eu/en/documents/assessment-report/drovelis-epar-public-assessment-report_en.pdf.
  • 7. http://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214154s000lbl.pdf.
  • 8. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021676s012lbl.pdf.
  • 9. Stanczyk F.Z., Archer D.F., Bhavnani B.R. (2013) Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception, 87: 706–727.
  • 10. Hammond G.L., Hogeveen K.N., Visser M. et al. (2008) Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric, 11(Suppl. 1): 41–46.
  • 11. Hodgert Jury H., Zacharewski T.R., Hammond G.L. (2000) Interactions between human plasma sex hormone-binding globulin and xenobiotic ligands. J. Steroid Biochem. Mol. Biol., 75: 167–176.
  • 12. Santen R.J., Yue W., Wang J.P. (2015) Estrogen metabolites and breast cancer. Steroids, 99: 61–66.
  • 13. Yager J.D. (2015) Mechanisms of estrogen carcinogenesis: the role of E2/E1-quinone metabolites suggests new approaches to preventive intervention — a review. Steroids, 99: 56–60.
  • 14. Bagot C.N., Marsh M.S., Whitehead M. et al. (2010) The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J. Thromb. Haemost., 8: 1736–1744.
  • 15. Krattenmacher R. (2000) Drospirenone: pharmacology and pharmacokinetics of a unique progestogen. Contraception, 62: 29–38.
  • 16. Muhn P., Fuhrmann U., Fritzemeier K.H. et al. (1995) Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann. N.Y. Acad. Sci., 761: 311–335.
  • 17. Oelkers W. (2004) Drospirenone, a progestogen with antimineralocorticoid properties: a short review. Mol. Cell Endocrinol., 217: 255–261.
  • 18. Rapkin A.J., Sorger S.N., Winer S.A. (2008) Drospirenone/ethinyl estradiol. Drugs Today (Barc), 44: 133–145.
  • 19. Oelkers W., Foidart J.M., Dombrovicz N. et al. (1995) Effects of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism. J. Clin. Endocrinol. Metab., 80: 1816–1821.
  • 20. Foidart J.M., Faustmann T. (2007) Advances in hormone replacement therapy: weight benefits of drospirenone, a 17alpha-spirolactone-derived progestogen. Gynecol. Endocrinol., 23: 692–699.
  • 21. Billon-Galés A., Fontaine C., Douin-Echinard V. et al. (2009) Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17-beta estradiol in low-density lipoprotein receptor-deficient mice. Circulation, 120(25): 2567–2576. DOI: 10.1161/CIRCULATIONAHA.109.898445.
  • 22. Duijkers I.J., Klipping C., Zimmerman Y. et al. (2015) Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study. Eur. J. Contracept. Reprod. Health Care, 20(6): 476–489. DOI: 10.3109/13625187.2015.1074675.
  • 23. Apter D., Zimmerman Y., Beekman L. et al. (2017) Estetrol combined with drospirenone: an oral contraceptive with high acceptability, user satisfaction, well-being and favourable body weight control. Eur. J. Contracept. Reprod. Health Care, 22: 260–267.
  • 24. Apter D., Zimmerman Y., Beekman L. et al. (2016) Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA) Contraception, 94: 366–373.
  • 25. Douxfils J., Klipping C., Duijkers I. et al. (2020) Evaluation of the effect of a new oral contraceptive containing estetrol and drospirenone on hemostasis parameters. Contraception, 102: 396–402. DOI: 10.1016/j.contraception.2020.08.015.
  • 26. Douxfils J., Morimont L., Delvigne A.S. et al. (2020) Validation and standardization of the ETP-based activated protein C resistance test for the clinical investigation of steroid contraceptives in women: an unmet clinical and regulatory need. Clin. Chem. Lab. Med., 58: 294–305.
  • 27. Gemzell-Danielsson K., Apter D., Zatik J. et al. Estetrol-Drospirenone combination oral contraceptive: a clinical study of contraceptive efficacy, bleeding pattern, and safety in Europe. BJOG 2021.
  • 28. Gemzell-Danielsson K., Cagnacci A., Chabbert-Buffet N. et al. (2022) A novel estetrol-containing combined oral contraceptive: European expert panel review. Eur. J. Contracept. Reprod. Health Care, 27: 373–383.
  • 29. Lidegaard Ø., Milsom I., Geirsson R.T., Skjeldestad F.E. (2012) Hormonal contraception and venous thromboembolism. Acta Obstet. Gynecol. Scand., 91: 769–778.
  • 30. Billon-Galés A., Fontaine C., Douin-Echinard V. et al. (2009) Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17-beta estradiol in low-density lipoprotein receptor-deficient mice. Circulation, 120(25): 2567–2576. DOI: 10.1161/CIRCULATIONAHA.109.898445.
  • 31. Brouchet L., Krust A., Dupont S. et al. (2001) Estradiol accelerates reendothelialization in mouse carotid artery through estrogen receptor-alpha but not estrogen receptor-beta. Circulation, 103(3): 423–428. DOI: 10.1161/01.cir.103.3.423.
  • 32. Darblade B., Pendaries C., Krust A. et al. (2002) Estradiol alters nitric oxide production in the mouse aorta through the alpha-, but not beta-, estrogen receptor. Circ. Res., 90(4): 413–419. DOI: 10.1161/hh0402.105096.
  • 33. Tarhouni K., Freidja M.L., Guihot A.L. et al. (2014) Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries. Am. J. Physiol. Heart Circ. Physiol., 307(4): 504–14. DOI: 10.1152/ajpheart.00986.2013.
  • 34. Montt-Guevara M.M., Giretti M.S., Russo E. et al. (2015) Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells. Front. Endocrinol. (Lausanne), 6: 111. DOI: 10.3389/fendo.2015.00111.
  • 35. Hilgers R.H., Oparil S., Wouters W., Coelingh Bennink H.J. (2012) Vasorelaxing effects of estetrol in rat arteries. J. Endocrinol., 215(1): 97–106. DOI: 10.1530/JOE-12-0009.
  • 36. Palacios S., Colli E., Regidor P.A. (2021) Metabolic and laboratory effects of a progestin-only pill containing drospirenone 4 mg in comparison to desogestrel 75 µg: a double-blind, double-dummy, prospective, randomised study. Eur. J. Contracept. Reprod. Health Care, 26: 454–461.
  • 37. Palacios S., Colli E., Regidor P.A. (2019) Multicenter, phase III trials on the contraceptive efficacy, tolerability and safety of a new drospirenone-only pill. Acta Obstet.Gynecol. Scand., 98: 1549–1557.
  • 38. Palacios S., Colli E., Regidor P.A. (2020) Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4 mg drospirenone alone in a 24/4 regime. BMC Women’s Health 20, 218. doi.org/10.1186/s12905-020-01080-9.
  • 39. Mawet M., Maillard C., Klipping C. et al. (2015) Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod. Health Care, 20(6): 463–475. DOI: 10.3109/13625187.2015.1068934.
  • 40. Klipping C., Duijkers I., Mawet M. et al. (2021) Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception, 103(4): 213–221. DOI: 10.1016/j.contraception.2021.01.001.
  • 41. Mawet M., Maillard C., Klipping C. et al. (2015) Unique effects on hepatic function, lipid metabolism, bone and growth endocrine parameters of estetrol in combined oral contraceptives. Eur. J. Contracept. Reprod Health Care, 20(6): 463–475. DOI: 10.3109/13625187.2015.1068934.
  • 42. DeCherney A.H. (2000) Hormone receptors and sexuality in the human female. J Womens Health Gend Based. Med., 9 Suppl. 1: S9–S13.
  • 43. van Lunsen R.H.W., Zimmerman Y., Coelingh Bennink H.J.T. et al. (2018) Maintaining physiologic testosterone levels during combined oral contraceptives by adding dehydroepiandrosterone: II. Effects on sexual function. A phase II randomized, doubleblind, placebo-controlled study. Contraception, 98(1): 56–62.
  • 44. Armanini D., Andrisani A., Bordin L., Sabbadin C. (2016) Spironolactone in the treatment of polycystic ovary syndrome. Expert Opin. Pharmacother., 17(13): 1713–1715.
  • 45. Estetra S.P.R.L. MIT-Es0001-C301 A Multicenter, Open-label, Single-Arm Study to Evaluate the Contraceptive Efficacy and Safety of a Combined Oral Contraceptive Containing 15 mg Estetrol and 3 mg Drospirenone (E4 FREEDOM Study).
  • 46. Estetra S.P.R.L. MIT-Es0001-C302 A multicenter, open-label, single-arm study to evaluate the contraceptive efficacy and safety of a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone.
  • 47. Creinin M.D., Westhoff C.L., Bouchard C. et al. (2021) Estetrol-drospirenone combination oral contraceptive: North American phase 3 efficacy and safety results. Contraception., 104(3): 222-8. DOI: 10.1016/j.contraception.2021.05.002.