A novel estetrol-containing combined oral contraceptive: European expert panel review

Česká verzia

Authors: Kristina Gemzell-Danielsson ¹; Angelo Cagnacci ²; Nathalie Chabbert-Buffet ³; Jonathan Douxfils ⁴; Jean-Michel Foidart ⁵; Ali Kubba ⁶; Luis Ignacio Lete Lasa ⁷; Diana Mansour ⁸; Joseph Neulen ⁹; Jaoquim Neves ¹⁰; Fátima Palma ¹¹; Thomas Römer ¹²; Robert Spaczy Ski ¹³; Vera Tóth ¹⁴
Authors place of work: Department of Women’s and Children’s Health, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden ¹; IRCCS-Policlinic Hospital San Martino, Obstetrics and Gynecology Unit, University of Genoa, DINOGMI, Genoa, Italy ²; Service de gynécologie obstétrique, médecine de la reproduction, APHP Sorbonne Université, Site Tenon, Paris, France ³; Department of Pharmacy, Namur Thrombosis and Hemostasis Center, Namur Research Institute for LIfe Sciences, University of Namur, Namur, Belgium, Qualiblood s. a., Namur, Belgium ⁴; Estetra SRL, an affiliate company of Mithra Pharmaceuticals, University of Liège, Liège, Belgium ⁵; Department of Obstetrics And Gynaecology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK ⁶; Obstetrics and Gynecology Clinical Management Unit, Araba University Hospital, Vitoria, Spain ⁷; Department of Obstetrics And Gynaecology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK ⁸; Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, RWTH Aachen, Aachen, Germany ⁹; Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal ¹⁰; Department of Obstetrics, Maternidade Alfredo da Costa, Centro Hospitalar Universiário Lisboa Central, Lisbon, Portugal ¹¹; Department of Obstetrics and Gynecology, Academic Hospital of Obstetrics and Gynecology, University of Cologne, Cologne, Germany ¹²; Klinika Niepłodności I Endokrynologii Rozrodu Uniwersytet Medyczny im. Karola Marcinkowskiego ul, Polna, Poznań, Poland ¹³; Medical Information Scientifi c Service, Gedeon Richter Plc, Budapest, Hungary ¹⁴
Published in the journal: Ceska Gynekol 2022; 87(6): 440-452
Category: Review Article
doi: https://doi.org/10.1080/ 13625187.2022.2093850

Summary

Purpose: Despite considerable advances in recently developed combined oral contraceptives (COCs), resulting in lower rates of adverse events while maintaining contraceptive efficacy, there is interest in further innovation. Materials and Methods: Estetrol (E4), a native oestrogen, and progestin drospirenone (DRSP) were combined in a new COC. A European expert panel reviewed the pharmacology, efficacy, and safety and tolerability of this combination. Their findings are presented as a narrative review. Results: E4 15mg/DRSP 3 mg in a 24/4 regimen provided effective contraception with good cycle control, characterised by a predictable regular bleeding pattern and minimal unscheduled bleeding, together with a good safety profile. The combination was associated with high user satisfaction, wellbeing, and minimal changes in body weight. The effects on endocrine and metabolic parameters were limited, and the combination was found to have a limited impact on liver function and lipid and carbohydrate metabolism. Moreover, its effect on several haemostatic parameters was lower than that of comparators containing ethinyl oestradiol (EE) 20 mg/DRSP 3 mg and EE 30 mg/levonorgestrel 150 mg. Conclusion: E4 15 mg/DRSP 3 mg provides safe and effective contraception, with high user satisfaction and predictable bleeding. Further research will evaluate the long-term safety of the COC.

Keywords:

efficacy – drospirenone – estetrol – satisfaction – combined oral contraceptive – contraceptive – bleeding pattern – safety profile

Article was adopted from: Eur J Contracept Reprod Health Care 2022; 27(5): 373–383. doi: 10.1080/13625187.2022.2093850

Zdroje

1. Szarewski A, Mansour D, Shulman LP. 50 years of “the Pill”: celebrating a golden anniversary. J Fam Plann Reprod Health Care. 2010; 36 (4): 231–238.

2. FSRH. Faculty of Sexual & Reproductive Healthcare Clinical Effectiveness Unit. FSRH Clinical Guideline. Combined Hormonal Contraception. London, UK: FSRH; January 2019; [amended November 2020. cited 2021 May 12]. Available from: https: //www.fsrh.org/documents/combined-hormonalcontraception/.

3. European Medicines Agency (EMA). Assessment report for combined hormonal contraceptives containing medicinal products – Procedure number: EMEA/H/A-31/1356. 2014; [cited 2022 April 27]. Available from: https: //www.ema.europa.eu/en/documents/referral/combined-hormonal-contraceptivesarticle-31-referral-prac-assessment-report_en.pdf.

4. Fruzzetti F, Tremollieres F, Bitzer J. An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol. 2012; 28 (5): 400–408.

5. Pintiaux A, Gaspard U, Nisolle M. [Zoely, a combined oral contraceptive, monophasic pill containing estradiol and nomegestrol acetate]. Rev Med Liege. 2012; 67 (3): 152–156.

6. Lete I, Chabbert-Buffet N, Jamin C, et al. Haemostatic and metabolic impact of estradiol pills and drospirenone-containing ethinylestradiol pills vs. levonorgestrel-containing ethinylestradiol pills: a literature review. Eur J Contracept Reprod Health Care. 2015; 20 (5): 329–343.

7. Dinger J, Do Minh T, Heinemann K. Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception. 2016; 94 (4): 328–339.

8. Thomas MP, Potter BV. The structural biology of oestrogen metabolism. J Steroid Biochem Mol Biol. 2013; 137: 27–49.

9. Hagen AA, Barr M, Diczfalusy E. Metabolism of 17-beta-oestradiol-4-14-C in early infancy. Acta Endocrinol. 1965; 49: 207–220.

10. 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 RD, Genazzani AR, Simoncini T, editors. Sex steroids’ effects on brain, heart and vessels. Volume 6: Frontiers in Gynecological Endocrinology. ISGE Series. Switzerland: Springer International Publishing; 2019. p. 169–195.

11. Coelingh Bennink HJ, Holinka CF, Diczfalusy E. Estetrol review: profile and potential clinical applications. Climacteric. 2008; 11 (Suppl 1): 47–58.

12. Abot A, Fontaine C, Buscato M, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014; 6 (10): 1328–1346.

13. Arnal JF, Lenfant F, Metivier R, et al. Membrane and nuclear estrogen receptor alpha actions: from tissue specificity to medical implications. Physiol Rev. 2017; 97 (3): 1045–1087.

14. Guivarc’h E, Buscato M, Guihot AL, et al. Predominant role of nuclear versus membrane estrogen receptor alpha in arterial protection: implications for estrogen receptor alpha modulation in cardiovascular prevention/safety. J Am Heart Assoc. 2018; 7 (13): e008950.

15. Coelingh Bennink HJ, Heegaard AM, Visser M, et al. Oral bioavailability and bone-sparing effects of estetrol in an osteoporosis model. Climacteric. 2008; 11 (Suppl 1): 2–14.

16. Coelingh Bennink HJ, Verhoeven C, Zimmerman Y, et al. Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women. Maturitas. 2016; 91: 93–100.

17. allopregnanolone in intact and ovariectomized rats. J Steroid Biochem Mol Biol. 2014; 143: 285–290.

18. Pluchino N, Drakopoulos P, Casarosa E, et al. Effect of estetrol on Beta-Endorphin level in female rats. Steroids. 2015; 95: 104–110.

19. Valéra M-C, Noirrit-Esclassan E, Dupuis M, et al. Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis. Mol Cell Endocrinol. 2018; 477: 132–139.

20. 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.

21. 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): 463–475.

22. Klipping C, Duijkers I, Mawet M, et al. Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone. Contraception. 2021; 103 (4): 213–221.

23. Voedisch AJ, Fok WK. Oestrogen component of COCs: have we finally found a replacement for ethinyl estradiol? Curr Opin Obstet Gynecol. 2021; 33 (6): 433–439.

24. Fruzzetti F, Fidecicchi T, Montt Guevara MM, et al. Estetrol: a new choice for contraception. J Clin Med. 2021; 10 (23): 5625.

25. Schmidt M, Lenhard H, Hoenig A, 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): 1833–1842.

26. Jozan S, Kreitmann B, Bayard F. Different effects of oestradiol, oestriol, oestetrol and of oestrone on human breast cancer cells (MCF-7) in long term tissue culture. Acta Endocrinol. 1981; 98 (1): 73–80.

27. Coelingh Bennink HJT, Singer C, Simoncini T, et al. Estetrol, a pregnancy-specific human steroid, prevents and suppresses mammary tumor growth in a rat model. Climacteric. 2008; 11 (sup1): 29.

28. Gérard C, Arnal J-F, 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): 121–137.

29. Gerard C, Blacher S, Communal L, et al. Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation. J Endocrinol. 2015; 224 (1): 85–95.

30. Giretti MS, Montt Guevara MM, Cecchi E, et al. Effects of estetrol on migration and invasion in T47-D breast cancer cells through the actin cytoskeleton. Front Endocrinol. 2014; 5: 80. 5:

31. 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. 2019; 13: 1178223419844198.

32. Visser M, Kloosterboer HJ, Bennink HJ. Estetrol prevents and suppresses mammary tumors induced by DMBA in a rat model. Horm Mol Biol Clin Investig. 2012; 9 (1): 95–103.

33. Gallez A, Blacher S, Maquoi E, et al. Estetrol combined to progestogen for menopause or contraception indication is neutral on breast cancer. Cancers. 2021; 13 (10): 2486.

34. Grandi G, Del Savio MC, Lopes da Silva-Filho A, et al. Estetrol (E4): the new estrogenic component of combined oral contraceptives. Expert Rev Clin Pharmacol. 2020; 13 (4): 327–330.

35. Morch LS, Skovlund CW, Hannaford PC, et al. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med. 2017; 377 (23): 2228–2239.

36. Hammond GL, Hogeveen KN, Visser M, et al. Estetrol does not bind sex hormone binding globulin or increase its production by human HepG2 cells. Climacteric. 2008; 11 (Suppl 1): 41–46.

37. Visser M, Foidart JM, Coelingh Bennink HJ. In vitro effects of estetrol on receptor binding, drug targets and human liver cell metabolism. Climacteric. 2008; 11 (Suppl 1): 64–68.

38. Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013; 87 (6): 706–727.

39. Bagot CN, Marsh MS, Whitehead M, et al. The effect of estrone on thrombin generation may explain the different thrombotic risk between oral and transdermal hormone replacement therapy. J Thromb Haemost. 2010; 8 (8): 1736–1744.

40. Gedeon Richter Plc. Drovelis Summary of Product characteristics; [updated 29 April 2022. cited 2022 May 19]. Available from: https: //www.ema.europa.eu/en/documents/productinformation/drovelis-epar-product-information_en.pdf.

41. Muhn P, Fuhrmann U, Fritzemeier KH, et al. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Ann NY Acad Sci. 1995; 761: 311–335.

42. Regidor PA, Schindler AE. Antiandrogenic and antimineralocorticoid health benefits of COC containing newer progestogens: dienogest and drospirenone. Oncotarget. 2017; 8 (47): 83334–83342.

43. Sitruk-Ware R. Pharmacology of different progestogens: the special case of drospirenone. Climacteric. 2005; 8 (Suppl 3): 4–12.

44. Bitzer J, Simon JA. Current issues and available options in combined hormonal contraception. Contraception. 2011; 84 (4): 342–356.

45. Archer DF, Ahrendt HJ, Drouin D. Drospirenone-only oral contraceptive: results from a multicenter noncomparative trial of efficacy, safety and tolerability. Contraception. 2015; 92 (5): 439–444.

46. Regidor PA, Colli E, Schindler AE. Drospirenone as estrogenfree pill and hemostasis: coagulatory study results comparing a novel 4mg formulation in a 24þ4 cycle with desogestrel 75 mug per day. Gynecol Endocrinol. 2016; 32 (9): 749–751.

47. Palacios S, Colli E, Regidor PA. Efficacy and cardiovascular safety of the new estrogen-free contraceptive pill containing 4mg drospirenone alone in a 24/4 regime. BMC Womens Health. 2020; 20 (1): 218.

48. Wiesinger H, Berse M, Klein S, et al. Pharmacokinetic interaction between the CYP3A4 inhibitor ketoconazole and thehormone drospirenone in combination with ethinylestradiol or estradiol. Br J Clin Pharmacol. 2015; 80 (6): 1399–1410.

49. Duijkers IJ, Klipping C, Zimmerman Y, et al. 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. 2015; 20 (6): 476–489.

50. Apter D, Zimmerman Y, Beekman L, et al. Bleeding pattern and cycle control with estetrol-containing combined oral contraceptives: results from a phase II, randomised, dose-finding study (FIESTA). Contraception. 2016; 94 (4): 366–373.

51. Apter D, Zimmerman Y, Beekman L, et al. 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. 2017; 22 (4): 260–267.

52. Kluft C, Zimmerman Y, Mawet M, et al. Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol. Contraception. 2017; 95 (2): 140–147.

53. Duijkers I, Klipping C, Kinet V, et al. Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function. Contraception. 2021; 103 (6): 386–393.

54. Huber LR, Hogue CJ, Stein AD, et al. Contraceptive use and discontinuation: findings from the contraceptive history, initiation, and choice study. Am J Obstet Gynecol. 2006; 194 (5): 1290–1295.

55. Hall KS, White KO, Rickert VI, et al. An exploratory analysis of associations between eating disordered symptoms, perceived weight changes, and oral contraceptive discontinuation among young minority women. J Adolesc Health. 2013; 52 (1): 58–63.

56. 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 and Russia. BJOG. 2022; 129 (1): 63–71.

57. Creinin MD, Westhoff CL, Bouchard C, et al. Estetrol-Drospirenone combination oral contraceptive: North American efficacy and safety results. Contraception. 2021; 104 (3): 222–228.

58. European Medicines Agency (EMA). Drovelis Assessment Report; [updated 25 March 2021. cited 2021 Nov 24]. Available from: https: //www.ema.europa.eu/en/documents/assessment-report/drovelis-epar-public-assessment-report_en.pdf.

59. Anttila L, Kunz M, Marr J. Bleeding pattern with drospirenone 3mgþethinyl estradiol 20 mcg 24/4 combined oral contraceptive compared with desogestrel 150 mcgþethinyl estradiol 20 mcg 21/7 combined oral contraceptive. Contraception. 2009; 80 (5): 445–451.

60. Mansour D, Westhoff C, Kher U, et al. Pooled analysis of two randomized, open-label studies comparing the effects of nomegestrol acetate/17beta-estradiol and drospirenone/ ethinyl estradiol on bleeding patterns in healthy women. Contraception. 2017; 95 (4): 390–397.

61. Nelson A, Parke S, Makalova D, et al. Efficacy and bleeding profile of a combined oral contraceptive containing oestradiol valerate/dienogest: a pooled analysis of three studies conducted in North America and Europe. Eur J Contracept Reprod Health Care. 2013; 18 (4): 264–273.

62. Marr J, Gerlinger C, Kunz M. A historical cycle control comparison of two drospirenone-containing combined oral contraceptives: ethinylestradiol 30 mug/drospirenone 3mg administered in a 21/7 regimen versus ethinylestradiol 20 mug/drospirenone 3mg administered in a 24/4 regimen. Eur J Obstet Gynecol Reprod Biol. 2012; 162 (1): 91–95.

63. De Leo V, Musacchio MC, Cappelli V, et al. Hormonal contraceptives: pharmacology tailored to women’s health. Hum Reprod Update. 2016; 22 (5): 634–646.

64. Ahrendt HJ, Makalova D, Parke S, et al. Bleeding pattern and cycle control with an estradiol-based oral contraceptive: a seven-cycle, randomized comparative trial of estradiol valerate/dienogest and ethinyl estradiol/levonorgestrel. Contraception. 2009; 80 (5): 436–444.

65. Palacios S, Wildt L, Parke S, et al. Efficacy and safety of a novel oral contraceptive based on oestradiol (oestradiol valerate/dienogest): a Phase III trial. Eur J Obstet Gynecol Reprod Biol. 2010; 149 (1): 57–62.

66. Bachmann G, Sulak PJ, Sampson-Landers C, et al. Efficacy and safety of a low-dose 24-day combined oral contraceptive containing 20 micrograms ethinylestradiol and 3mg drospirenone. Contraception. 2004; 70 (3): 191–198.

67. European Medicines Agency (EMA). Assessment Report. Zoely. Procedure No. EMEA/H/C/001213 p44, Table 8; [cited 2022 May 19]. Available from: https: //www.ema.europa.eu/en/documents/assessment-report/zoely-epar-public-assessment-report_en.pdf.

68. Bitzer J. Pharmacological profile of estrogens in oral contraception. Minerva Ginecol. 2011; 63 (3): 299–304.

69. Hugon-Rodin J, Gompel A, Plu-Bureau G. Epidemiology of hormonal contraceptives-related venous thromboembolism. Eur J Endocrinol. 2014; 171 (6): R221–R230.

70. Paton DM. Estetrol and drospirenone: a novel oral contraceptive. Drugs Today. 2022; 58 (1): 1–8.

71. Guideline on Clinical Investigation of Steroid Contraceptives in Women. Available from: https: //www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-steroid-contraceptives-women_en.pdf.

72. Douxfils J, Morimont L, Bouvy C. Oral contraceptives and venous thromboembolism: focus on testing that may enable prediction and assessment of the risk. Semin Thromb Hemost. 2020; 46 (8): 872–886.

73. Klipping C, Duijkers I, Parke S, et al. Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. Drugs RD. 2011; 11 (2): 159–170.

74. Junge W, Mellinger U, Parke S, et al. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-Centre study. Clin Drug Investig. 2011; 31 (8): 573–584.

75. Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost. 2010; 8 (3): 445–453.

76. Morimont L, Haguet H, Dogne JM, et al. Combined oral contraceptives and venous thromboembolism: review and perspective to mitigate the risk. Front Endocrinol. 2021; 12: 769187.

77. Morimont L, Dogne JM, Douxfils J. Letter to the editors-in-Chief in response to the article of Abou-Ismail, et al. entitled “estrogen and thrombosis: a bench to bedside review” (thrombosis research 192 (2020) 40–51). Thrombosis Research. 2020; 193: 221–223.

78. De Bastos M, Stegeman BH, Rosendaal FR, et al. Combined oral contraceptives: venous thrombosis. Cochrane Database Syst Rev. 2014; 3 (3): CD010813.

79. Reed SK, DiBello J, Becker K, et al. Prospective controlled cohort study on the safety of a monophasic oral contraceptive containing nomegestrol acetate (2.5mg) and 17b-oestradiol (1.5mg) (PRO-E2 study): risk of venous and arterial thromboembolism. Eur J Contracept Reprod Health Care. 2021; 26 (6): 439–446.

80. Heinemann K, Franke C, Moehner S, et al. Cardiovascular safety in users of different combined oral contraceptives – Final results from the INAS-SCORE study abstract FC-03, book of abstracts: 15th congress of the European society of contraception and reproductive health. Eur J Contracept Reprod Health Care. 2018; 23 (Suppl 1): 40.

81. Fruzzetti F, Cagnacci A. Venous thrombosis and hormonal contraception: What’s new with estradiol-based hormonal contraceptives? Open Access J Contracept. 2018; 9: 75–79.

82. Shamseddin M, De Martino F, Constantin C, et al. Contraceptive progestins with androgenic properties stimulate breast epithelial cell proliferation. EMBO Mol Med. 2021; 13 (7): e14 314.

83. Burrows LJ, Basha M, Goldstein AT. The effects of hormonal contraceptives on female sexuality: a review. J Sex Med. 2012; 9 (9): 2213–2223.

84. Caruso S, Cianci S, Cariola M, et al. Improvement of low sexual desire due to antiandrogenic combined oral contraceptives after switching to an oral contraceptive containing 17betaestradiol. J Womens Health. 2017; 26 (7): 728–734.

85. Sanders SA, Graham CA, Bass JL, et al. A prospective study of the effects of oral contraceptives on sexuality and well-being and their relationship to discontinuation. Contraception. 2001; 64 (1): 51–58.

86. Graham CA, Ramos R, Bancroft J, et al. The effects of steroidal contraceptives on the well-being and sexuality of women: double-blind, placebo-controlled, two-Centre study of combined and progestogen-only methods. Contraception. 1995; 52 (6): 363–369.

87. Caruso S, Agnello C, Intelisano G, et al. Sexual behavior of women taking low-dose oral contraceptive containing 15 microg ethinylestradiol/60 microg gestodene. Contraception. 2004; 69 (3): 237–240.

88. Lee J-J, Low LL, Ang SB. Oral contraception and female sexual dysfunction in reproductive women. Sex Med Rev. 2017; 5 (1): 31–44.

89. Nappi RE, Serrani M, Jensen JT. Noncontraceptive benefits of the estradiol valerate/dienogest combined oral contraceptive: a review of the literature. Int J Womens Health. 2014; 6: 711–718.

90. Trussell J, Westoff CF. Contraceptive practice and trends in coital frequency. Fam Plann Perspect. 1980; 12 (5): 246–249.

91. Oddens BJ. Women’s satisfaction with birth control: a population survey of physical and psychological effects of oral contraceptives, intrauterine devices, condoms, natural family planning, and sterilization among 1466 women. Contraception. 1999; 59 (5): 277–286.

92. Caruso S, Iraci Sareri M, Agnello C, et al. Conventional vs. extended-cycle oral contraceptives on the quality of sexual life: comparison between two regimens containing 3mg drospirenone and 20 microg ethinyl estradiol. J Sex Med. 2011; 8 (5): 1478–1485.

93. Jensen JT, Bitzer J, Serrani M. Comparison of the pharmacologic and clinical profiles of new combined oral contraceptives containing estradiol. Open Access J Contracept. 2013; 4: 39–50.

94. Davis SR, Bitzer J, Giraldi A, et al. Change to either a nonandrogenic or androgenic progestin-containing oral contraceptive preparation is associated with improved sexual function in women with oral contraceptive-associated sexual dysfunction. J Sex Med. 2013; 10 (12): 3069–3079.

95. Robertson E, Thew C, Thomas N, et al. Pilot data on the feasibility and clinical outcomes of a nomegestrol acetate oral contraceptive pill in women with premenstrual dysphoric disorder. Front Endocrinol. 2021; 12: 704488.

96. Zethraeus N, Dreber A, Ranehill E, et al. Combined oral contraceptives and sexual function in women-a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2016; 101 (11): 4046–4053.

97. Pastor Z, Holla K, Chmel R. The influence of combined oral contraceptives on female sexual desire: a systematic review. Eur J Contracept Reprod Health Care. 2013; 18 (1): 27–43.

98. Garmshausen J, Kloas W, Hoffmann F. 17alpha-Ethinylestradiol can disrupt hemoglobin catabolism in amphibians. Comp Biochem Physiol C Toxicol Pharmacol. 2015; 171: 34–40.

99. Wedekind C. Fish populations surviving estrogen pollution. BMC Biol. 2014; 12: 10.

100. Kestemont P, Creinin MD, Nfon E, et al. P51. The potential environmental impact of estetrol, a native estrogen in development for oral contraception. Contraception. 2020; 102 (4): 293.

101. Bayer Limited. Yaz. Summary of Product Characteristics; [updated 19 November 2021. cited 2022 May 19]. Available from: https: //www.medicines.ie/medicines/yaz-0-02mg-3mgfilm-coated-tablets-34275/spc.

102. Bayer plc. Yasmin. Summary of Product Characteristics; [updated 23 November 2021cited 2022 May 19. Available from: www.medicines.org.uk/emc/product/1607/smpc#gref.

103. Bayer Limited. Yasminelle. Summary of Product Characteristics; [updated 19 November 2021. cited 2022 May 19. Available from: https: //www.medicines.ie/medicines/yasminelle-0-02- mg-3- mg- film-coated-tablets-34274/spc.