Profile of estetrol, a promising native estrogen for oral contraception and the relief of climacteric symptoms of menopause

Figures & data

Figure 1. Structure of the four natural estrogens, estrogen receptors (α and β) and ligand-binding domains. A: Structure of natural estrogens. E1 and E2: adult estrogens; E3 and E4: fetal estrogens. B: Estrogen receptors α and β (ERα and ERβ). Functional domains include the DNA-binding domain (DBD), ligand-binding domain (LBD), and two transcriptional activation functions, AF-1 and AF-2. The A/B domain, at the protein amino terminus (NH2), contains AF-1. The C domain binds to DNA motifs (consensus estrogen response elements [EREs]). The D domain (the hinge region) is involved in specific DNA binding and nuclear ER localization. The E domain is the LBD: it interacts with estrogens and selective estrogen receptor modulators (SERMs) and contains the AF-2 region. The carboxy terminus (COOH) is at the F domain. C&D: Ribbon diagrams. ERα-LBD structure complexed with estrogens (blue:E2; red:E3; green:E4). C: Ball-and-stick rendering of the ligand-binding site of the ligands and their interacting residues. Dotted lines: hydrogen bonds. D: LBDs depicted in C and the glucocorticoid receptor-interacting protein 1 (GRIP1) peptide fragment coactivator protein complexed with E3 or E4 only (darker red/green). Ligand: represented as space-filled model. Helix 12 position depicted by an arrow. Panel B adapted from Arnal JF, et al (2017) [3], and panels C and D from Abot A, et al (2014) [48].

Table 1. Clinical applications of E4

Combination/Dosage level	Indication	Study phase	ClinicalTrials.gov number
E4 15 mg/DRSP 3 mg	Contraceptive	III	NCT02817828/NCT02817841
E4 15–20 mg	Menopause	III	NCT04090957/ NCT04209543
E4 20–60 mg	Breast cancer	II	NCT02718144
E4 40 mg and androgen-deprivation therapy	Prostate cancer	II	NCT02718378
E4 15 mg (21 days)	SARS-CoV-2 infection	II	NCT04801836

E4: estetrol, CoV: corona virus, DRSP: drospirenone, SARS: severe acute respiratory syndrome

Figure 2. Comparison of E2- and E4-induced in vitro coregulator recruitment by ERα. Full-length estrogen receptor α (ERα) was stimulated with estradiol (E2) or estetrol (E4) and incubated with a set of 154 immobilized peptides representing coregulator-derived binding motifs; binding was detected using a fluorescently labeled ERα-antibody. The subset with ERα-interacting peptides is shown here. Each panel displays concentration-dependent (log(M), x-axis) modulation of ERα binding (arbitrary units’ fluorescence, y-axis) to a particular coregulator motif by E2 (red) or E4 (blue).

Figure 3. Effect of estetrol (E4) on hemostasis markers and sex hormone binding globulin (SHBG). A: Changes of hemostasis markers are significantly lower in the E4 15 mg/ drospirenone (DRSP) 3 mg group than in the ethinyl estradiol (EE)/DRSP group and always equivalent or lower than in the EE/levonorgestrel group. Columns represent median of percentage change from baseline to cycle 6. Parameters examined: PAI-1, plasminogen activator inhibitor type 1; SHBG, sex hormone-binding protein; t-PA, tissue plasminogen activator; TFPI, tissue factor pathway inhibitor; VWF, von Willebrand factor. B: nAPCsr is significantly lower in the E4/DRSP group than in the EE/LNG or EE/DRSP groups. C: Relative risk of venous thromboembolism (VTE RR) as a function of the change in normalized activated protein C sensitivity ratio (nAPCsr) during combined oral contraceptive (COC) use. * p < 0.05 vs baseline; # p < 0.05 vs E4/DRSP. Panel A and B: Published in Douxfils et al. 2020 [84]. Permission to use granted. Panel C: In silico-modeling based on the Cochrane network meta-analysis of de Bastos M. et al. Cochrane Database Syst Rev. 2014 published in Morimont, L., Dogné J-M., and Douxfils J. Permission to use granted [90].

Table 2. Phase 3 studies evaluating the E4 15 mg/DRSP 3 mg COC (24 active/4 inactive regimen)

Trial	Study design	Key inclusion criteria	Participants	Contraceptive efficacy^†			Scheduled bleeding		Safety		Reference
				PI (95% CI)	Method-failure PI^¶ (95% CI)	13-cycle pregnancy rate, % (95% CI)	Scheduled bleeding per cycle, %	Median duration, days	Adverse events, %	VTE
US/CAN NCT02817841	Multicenter, open-label, 13-cycle, phase 3 trial	Aged 16/18–50 years Sexually active Regular menstrual cycles BMI ≤35 kg/m^2	16–50 years: N = 1,864 16–35 years:N = 1,674 BMI≥30: 432 (23%)	2.65 (1.73–3.88)	1.43 (0.7–2.39)	2.1 (1.40–3.04)	82.9–87.0	4.5	Headache: 5.0 Metrorrhagia: 4.6	0	Gemzell Danielsson et al. [22]
EU/RUS NCT02817828			18-50 years: N = 1,553 18 to 35 years: N = 1,353 BMI≥30: 89 (5.7%)	0.47 (0.15–1.11)	0.29 (0.06–0.83)	0.45 (0.19–1.09)	91.9–94.4	4 to 5	Headache: 7.7 Metrorrhagia: 5.5	1	Creinin et al. [23]

^†In participants aged 16–35 years (US/CAN study) or 18–35 years (EU/RUS)

^¶Method failure PI excludes pregnancies due to user failure, i.e. due to not taking study treatment as per protocol during the cycle of conception, or use of co-medication interacting with COCs

BMI: body mass index, CAN: Canada, CI: confidence interval, EU: Europe, PI: pearl index, US: United States, VTE: venous thromboembolism

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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. 102(6): 396–402. 2020.

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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. Thromb Res. 2020;193(193):221–223. (Thrombosis Research 192 (2020) 40-51).

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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. Br J Obstet Gynaecol. 2022;129(1):63–71.

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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. .

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