Estetrol (E4): the new estrogenic component of combined oral contraceptives

Figures & data

Figure 1. Molecular structures of estrone (E1), estradiol (E2), estriol (E3) and estetrol (E4). The dashed line circles depict -OH groups.

Table 1. Experimental process of E4-containing oral contraceptives.

Phase	Outcomes	Comparator	E4 combinations tested	Sample size	Design	Reference
II	Dose-finding pilot study	Monophasic 20 µg EE/3 mg DRSP 24 + 4 regimen	5 or 10 mg E4/3 mg DRSP; 5, 10 or 20 mg E4/150 mg LNG 24 + 4	N = 109	Monocentre, observational	Dujskers et al. [10]
	Hemostatic effect	Monophasic 20 µg EE/3 mg DRSP 24 + 4 regimen	5 or 10 mg E4/3 mg DRSP	N = 47	Monocentre, observational	Kluft et al. [9]
	Liver function, lipid metabolism and bone and growth endocrine parameters	Monophasic 20 µg EE/3 mg DRSP 24 + 4 regimen	5 or 10 mg E4/3 mg DRSP; 5, 10 or 20 mg E4/150 mg LNG 24 + 4	N = 109	Monocentre, observational	Mawet M et al. [8]
	Cycle control	Quadriphasic E2 V/DNG	15 or 20 mg E4/3 mg DRSP; 15 or 20 mg E4/150 mg LNG	N = 396	Open-label, multi-center, randomized	Apter et al. [11]
	Acceptability and satisfaction	Quadriphasic E2 V/DNG	15 or 20 mg E4/3 mg DRSP; 15 or 20 mg E4/150 mg LNG	N = 396	Open-label, multi-center, randomized	Apter et al [12].
III	Efficacy and safety	Not applicable				Not yet published

Duijkers IJ, Klipping C, Zimmermann 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;20:476–489.

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

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Mawet M, Maillard C, Kipping 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;20:463–475.

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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.

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Apter D, Zimmerman Y, Beekman L, et al. Estretrol 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.

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